NAFLD (non-alcoholic fatty liver disease)

Leaky Gut & Fatty Liver Connection

Leaky Gut occurs when an increase in harmful bacteria and yeast (candida) within the intestine reaches a tipping point and the intestinal wall is

breached. These bacteria can literally burrow between the cells of the intestinal lining. Most of the time, we have a symbiotic relationship with intestinal bacteria from birth and they help reduce harmful effects of toxins, breakdown food and aid in immune function. As a matter of fact intestinal bacteria outnumber the cells in our body ten-to-one.

But harmful bacteria can do the opposite and often this is exactly what takes place after a (strong) round of antibiotics. It can also occur after a severe cold but more typically Americans get it from their diets over longer periods of time.

If you are eating a consistently poor diet with excessive sugar like most of the 300 Million people in America, you may well be on your way to having a Leaky Gut too.

Leaky Gut is commonly caused by:

Years of eating diets high in sugars, this can increase candida populations.Poor diet also increase bacteria colonies that are detrimental to good gut health.Use of antibiotics without immediate good bacteria reintroduction.Pesticides, GMOs and other harmful toxins that ravage the intestine walls and beneficial bacteria.When our intestinal wall is breached, this allows food particles to pass through and over time the immune system becomes overwhelmed with invaders. As if this is not bad enough, your immune system may also attack its own cells near the intestinal wall openings as a sort of collateral damage. This heightened immune state is often associated with chronic inflammation of other parts of the body like the back.

Over time, the increasing influx of food particles charging through is too

much and they must be processed some other way. The liver, which receives 70% of its blood flow from the intestine, is then charged with capturing and detoxifying the blood at this point.

If the necessary chemicals (i.e. Glutathione, NAC, Tocotrienols) are in short supply, the liver simply shuttles the toxins into fat cells to keep them from invading the rest of the body. These fat cells are stored in the liver and elsewhere throughout the body. This leads to obesity; cripples liver function and can be seen in higher than normal blood sugar levels, as the liver is critical in regulating insulin.

This is really the only option available to the liver at this point as it would be more dangerous to have these toxins floating in the blood disrupting other processes around the body.

The best way to counter this cycle is finding ways to alleviate stress, changing your diet and supplementing it with probiotics and strong liver anti-oxidants.

Supplements To Consider

Milk thistle is often used, but many people aren’t aware that the bioavailability is 10 times higher when taking the isolated active in milk thistle (slybin). People that have fatty liver should also be taking NAC, SAMe and Glutathione at the very least. Recently, there has also been a lot of research surrounding Red Palm Oil.

All these seem to act in a way that kick starts phase II detoxification in the liver, which changes fat-soluble toxins to water soluble to enable flushing them out of the body.

A good way to test for Leaky Gut is if you detect constant digestive problems such as gas, bloating, constipation and other food allergies. It’s this sensitivity to intake that is the sign of a problem.

Non-Alcoholic Fatty Liver Disease

IMPORTANCEThe liver is the second largest organ in your body.

The liver performs many jobs. It processes what you eat and drink into energy and nutrients your body can use. The liver also removes harmful substances from your blood.

WHAT IS NAFLD?Non-alcoholic fatty liver disease (NAFLD) is the build up of extra fat in liver cells that is not caused by alcohol. It is normal for the liver to contain some fat. However, if more than 5% - 10% percent of the liver’s weight is fat, then it is called a fatty liver (steatosis).

WHO IS LIKELY TO HAVE NAFLD?NAFLD tends to develop in people who are overweight or obese or have diabetes, high cholesterol or high triglycerides. Rapid weight loss and poor eating habits also may lead to NAFLD.However, some people develop NAFLD even if they do not have any risk factors. NAFLD affects up to 25% of people in the United States.

RISKSNAFLD may cause the liver to swell (steatohepatitis). A swollen liver may cause scarring (cirrhosis) over time and may even lead to liver cancer or liver failure.

SYMPTOMSNAFLD often has no symptoms.

When symptoms occur, they may include fatigue, weakness, weight loss, loss of appetite, nausea, abdominal pain, spider-like blood vessels, yellowing of the skin and eyes (jaundice), itching, fluid build up and swelling of the legs (edema) and abdomen (ascites), and mental confusion.

DIAGNOSISNAFLD is initially suspected if blood tests show high levels of liver enzymes. However, other liver diseases are first ruled out through additional tests. Often, an ultrasound is used to confirm the NAFLD diagnosis.

TREATMENTThere are no medical treatments yet for NAFLD. Eating a healthy diet and exercising regularly may help prevent liver damage from starting or reverse it in the early stages.

• See a doctor who specializes in the liver regularly• Talk to your doctor about ways to improve your liver health• Lose weight, if you are overweight or obese• Lower your cholesterol and triglycerides

• Control your diabetes• Avoid alcohol

PREVENTIONThere are ways to prevent NAFLD:

• Maintain a healthy weight• Eat a healthy diet• Exercise regularly• Limit alcohol intake• Only take medicines that you need and follow dosing recommendations.

NASHThe more severe form of NAFLD is called non-alcoholic steatohepatitis (NASH). NASH causes the liver to swell and become damaged. NASH tends to develop in people who are overweight or obese, or have diabetes, high cholesterol or high triglycerides. However, some people have NASH even if they do not have any risk factors.

Most people with NASH are between the ages of 40 and 60 years. It is more common in women than in men. NASH often has no symptoms and people can have NASH for years before symptoms occur.

NASH is one of the leading causes of cirrhosis in adults in the United States. Up to 25% of adults with NASH may have cirrhosis.

Leaky gut and the liver: A role for bacterial translocation in nonalcoholic steatohepatitis

AbstractGut flora and bacterial translocation (BT) play important roles in the pathogenesis of chronic liver disease, including cirrhosis and its complications. Intestinal bacterial overgrowth and increased bacterial translocation of gut flora from the intestinal lumen predispose patients to bacterial infections, major complications and also play a role in the pathogenesis of chronic liver disorders. Levels of bacterial lipopolysaccharide, a component of gram-negative bacteria, are increased in the portal and/or systemic circulation in several types of chronic liver disease. Impaired gut

epithelial integrity due to alterations in tight junction proteins may be the pathological mechanism underlying bacterial translocation. Preclinical and clinical studies over the last decade have suggested a role for BT in the pathogenesis of nonalcoholic steatohepatitis (NASH). Bacterial overgrowth, immune dysfunction, alteration of the luminal factors, and altered intestinal permeability are all involved in the pathogenesis of NASH and its complications. A better understanding of the cell-specific recognition and intracellular signaling events involved in sensing gut-derived microbes will help in the development of means to achieve an optimal balance in the gut-liver axis and ameliorate liver diseases. These may suggest new targets for potential therapeutic interventions for the treatment of NASH. Here, we review some of the mechanisms connecting BT and NASH and potential therapeutic developments.

INTRODUCTIONBacterial translocation (BT) and the derangement of gut flora are of substantial clinical relevance to patients with chronic liver disease and cirrhosis[1,2]. Intestinal bacterial overgrowth and increased bacterial translocation of gut flora from the intestinal lumen predispose patients to bacterial infections and major complications[3,4]. Furthermore, levels of bacterial lipopolysaccharide (LPS), a component of gram-negative bacteria, are increased in the portal and/or systemic circulation in several types of chronic liver disease. Bauer et al[5-7] have demonstrated this phenomenon in cirrhosis. Impaired gut epithelial integrity due to alterations in tight junction proteins may be the pathological mechanism underlying bacterial translocation. Over the last decade, increased gut permeability and increased LPS levels have been described in patients with alcoholic and nonalcoholic steatohepatitis (NASH)[8,9]. Increased serum LPS levels and activation of proinflammatory signaling cascades have been suggested to be important for disease progression in these settings[10]. Some potential mechanisms to explain the association

between BT and liver disease associated with lipid accumulation and the development of NASH are reviewed here. These mechanisms may suggest new targets for potential therapeutic interventions for the treatment of NASH.

Signs You Have A Leaky Gut (síndrome de intestino permeable) http://www.mindbodygreen.com/0-10908/9-signs-you-have-a-leaky-gut.html

The gut is the gateway to health. If your gut is healthy, chances are that you're in good health. However, there's a condition called leaky gut that can lead to a host of health problems.

What is a leaky gut? The gut is naturally permeable to very small molecules in order to absorb these vital nutrients. In fact, regulating intestinal

permeability is one of the basic functions of the cells that line the intestinal wall. In sensitive people, gluten can cause the gut cells to release zonulin, a protein that can break apart tight junctions in the intestinal lining. Other factors — such as infections, toxins, stress and age — can also cause these tight junctions to break apart.

Once these tight junctions get broken apart, you have a leaky gut. When your gut is leaky, things like toxins, microbes, undigested food particles, and more can escape

from your intestines and travel throughout your body via your bloodstream. Your immune system marks these "foreign invaders" as pathogens and attacks them. The immune response to these invaders can appear in the form of any of the nine signs you have a leaky gut, which are listed below.

Leaky gut can be a difficult diagnosis to establish for a number of reasons: It's associated with a wide range of seemingly unconnected symptoms; it has a lot of different causes; there's no specific test to confirm it; and evidence tying it to other conditions can be murky. As a result, there’s a fair amount of skepticism in the mainstream medical community about the legitimacy of leaky gut as a diagnosis. But as the evidence that this is indeed a real and recognizable condition grows, opinions are slowly changing. That's a good thing, because leaky gut is likely to emerge as one of the most significant medical concepts of our time.

How Leaky Gut Affects You

Our digestive lining serves an important barrier function. It's like a net with very small holes that allows only certain substances that are small enough to go through, while keeping out larger undesirable particles. With leaky gut, also known as increased intestinal permeability, the net becomes damaged, resulting in bigger holes that allow more things to pass through that ordinarily couldn’t.

The barrier function becomes compromised, so that bacteria, viruses, undigested food particles and toxic waste products can leak from the inside of your intestines through the damaged digestive lining into your bloodstream, where they're transported throughout your body and can trigger your immune system to react. The end result is inflammation in various parts of your body, leading to a wide variety of symptoms like bloating, cramps, fatigue, food sensitivities, flushing, achy joints, headache and rashes.

With leaky gut not only is the digestive lining more porous and less selective about what can get in, but normal absorption can also be affected. Nutritional deficiencies may develop as a result of damage to the villi - the finger-like projections in the small intestine that are responsible for absorbing nutrients.

Multiple food sensitivities are another hallmark of leaky gut, because partially digested particles of protein and fat may leak through the intestinal wall into the bloodstream and cause an allergic response. Increased intestinal permeability may potentially cause or worsen a number of other conditions, including Celiac disease, inflammatory bowel disease (IBD, which includes Crohn’s disease and ulcerative colitis), irritable bowel syndrome (IBS), arthritis, psoriasis, eczema and asthma.

What causes leaky gut? The main culprits are foods, strong antibiotic treatment, infections, and toxins. Gluten is the number one cause of leaky gut. Other inflammatory foods like dairy or toxic foods, such sugar and excessive alcohol, are suspected as well. The most common infectious causes are candida overgrowth, intestinal parasites, and small intestine bacterial overgrowth (SIBO). Toxins come in the form of medications, like Motrin, Advil, steroids, antibiotics, and acid-reducing drugs, and environmental toxins like mercury, pesticides and BPA from plastics. Stress and age also contribute to a leaky gut.

So what causes leaky gut or increased intestinal permeability? There's still much to be learned, but diet, chronic stress, certain medications and bacterial imbalance seem to play important roles. Eating a diet high in refined sugar can lead to overgrowth of yeast species, which has been associated with leaky gut. Preservatives and chemicals in processed foods can damage the lining, and so can consumption of

gluten – a protein found in wheat, rye and barley.

Chronic stress can lead to a weakened immune system, affecting your ability to fight off invading bacteria and viruses and worsening the symptoms of leaky gut. Medications like aspirin and non-steroidal anti inflammatories (NSAIDs) that can damage the lining of your gut, as well as antibiotics that kill off your essential good bacteria are also associated with increased intestinal permeability. In fact, an imbalance between beneficial and harmful species in your gut called dysbiosis is one of the leading theories about what causes increased intestinal permeability. Excessive alcohol consumption, infection with parasites, radiation and chemotherapy can damage the lining of the intestine and are also risk factors.

In addition to bloating and digestive distress, a lot of the patients I see with leaky gut have a combination of other symptoms like food allergies, chronic sinus infections, achy joints, fatigue, brain fog or unexplained rashes. Typically they’ve been to multiple doctors trying to make sense of their symptoms, and conventional tests and imaging studies have been unrevealing. There can be a feeling of hopelessness and despair, because the symptoms seem so unrelated.

When you think of leaky gut not so much as a disease, but as a mechanism by which a number of different conditions can develop, it starts to make sense. A leaky gut is the pathway for how toxins enter the body through the GI tract and create all kinds of mayhem once they're in, sort of like party crashers who slip through security and proceed to make a mess of the venue.

What Tests Are Available for Leaky Gut?

Leaky gut is a clinical diagnosis, and while there's no specific test that can tell you with 100% certainty that you have it, a positive Intestinal Permeability Test is strongly associated with the condition. This test measures the ability of two non-metabolized sugar molecules – mannitol and lactulose – to get through the digestive lining.

Mannitol is a small molecule that normally passes through easily and serves as a marker of how well nutrients are being absorbed. Lactulose is a larger molecule that doesn't normally pass through very well and serves as a marker for whether there are large holes in the lining. To perform the test, the patient mixes pre-measured amounts of lactulose and mannitol and drinks it. The test measures the amount of lactulose and mannitol recovered in a 6-hour urine sample.

Low levels of both mannitol and lactulose indicate malabsorption. Elevated levels of both lactulose and mannitol suggest general increased intestinal permeability, consistent with leaky gut. Permeability to lactulose may be increased, suggesting leaky gut, while permeability to mannitol may be decreased, suggesting malabsorption of small molecules. The lactulose/mannitol ratio is a useful value; an elevated ratio indicates that the effective pore size of the gut lining has increased, allowing larger, possibly harmful molecules to gain access to the body.

Are There Any Solutions?

There’s no miracle cure for treating leaky gut, but there are things you can do if you’re suffering from it that can help heal inflammation and restore the integrity of your gut lining.

An anti-inflammatory diet that eliminates refined sugars, dairy, gluten, alcohol and artificial sweeteners – some of the biggest offenders when it comes to inflammation – can be very helpful. Consuming lots of anti-inflammatory essential fatty acids in fish and nuts, and filling up on green leafy vegetables, high-fiber and fermented foods that help to promote the growth of good bacteria is also crucial.

A robust probiotic that contains large amounts of good bacteria can help heal a damaged intestinal lining by restoring balance in the gut flora.

Supplements like glutamine have been shown in some studies to

help with intestinal injury after chemotherapy and radiation and may be beneficial in leaky gut.

Most people will notice improvement within 6 weeks, although it may take several months and even years to heal a damaged intestinal lining in extreme cases of leaky gut. Because we’re still learning about leaky gut, many of the treatment guidelines are drawn more from anecdotal observation than from rigorous scientific studies. But they’re sensible recommendations that can lead to improvements in your overall health, whether or not you have increased intestinal permeability.

Leaky gut is one of those diagnoses that bridges the gap between conventional and alternative medicine, between what we can see and touch and what we can feel in our bodies. I refuse to believe that the hundreds of patients I see in my office with unusual and seemingly unrelated complaints are crazy, or just stressed out.

I believe them when they say they feel like they're being poisoned, or that they think there's a connection between all their symptoms, even though they don't know what it is. My hunch is that as our knowledge grows, the theories behind leaky gut will become the foundation for lots of diseases that are widely prevalent in our society, and millions of people will be in a better position to find relief from their suffering.

What Is It?The normal gut has a mucous lining that serves as a barrier between the food we eat and the blood stream. Nutrients from digested food normally and properly cross this border to enter the blood stream. When this lining is irritated, by foods you are allergic to, or asprin and similar non-steroidal anti-inflammatories, then undigested food particles and other large molecules escape from the gut into the blood stream. The immune system reacts, sending white blood cells to attack them. This overactivity of the immune system can contribute to ailments like joint pain, head-aches, fibromyalgia, Autism, Chron’s disease and ulcerative colitis. More Information on Leaky Gut.

What Else Can Be Done?Testing in order to know if you have gluten sensitive genes. So that you get a definitive answer so you can make a definitive decision as to not to ingest any gluten (no grain foods) for the rest of your life, so that you can completely repair and heal your gut lining so that no impurities end up contaminating your precious blood stream. Measure intestinal damage and intestinal inflammation. A simple urine test can measure the permeability of your intestinal lining. In addition, chew your food at least 25-50 times per bite.

This makes it easier for the digestive enzymes to do their job. Take digestive enzymes 1-2 hours after meals. Get tested for food allergies or do an allergy elimination diet, and take these food allergies seriously. Avoid anti-inflammatory medicines like Motrin. Use instead, natural ones like MSM, curcumin, boswellia and bromelain. For arthritis try glucosamine, chondroitin, and niacinamide. Take friendly bacteria and treat any infections in the gut, like candida or bacterial overgrowth. Try L-glutamine, an amino acid that is fuel for the intestinal cells. L-glutamine may help repair these cells and relieve leaky gut. But if you are sensitive to MSG, then avoid this, as glutamine converts to MSG.

if you suffer from any of the following conditions, it’s likely that you have a leaky gut:

9 Signs You Have a Leaky Gut

1. Digestive issues such as gas, bloating, diarrhea or irritable bowel syndrome (IBS).

2. Seasonal allergies or asthma.

3. Hormonal imbalances such as PMS or PCOS.

4. Diagnosis of an autoimmune disease such as rheumatoid arthritis, Hashimoto’s thyroiditis, lupus, psoriasis, or celiac disease.

5. Diagnosis of chronic fatigue or fibromyalgia.

6. Mood and mind issues such as depression, anxiety, ADD or ADHD.

7. Skin issues such as acne, rosacea, or eczema.

8. Diagnosis of candida overgrowth. Clean the Colon to Check Candida

By Andrew Gutauskas and Monica O'KaneThe diet of the average North American consists of food that is over processed, low in fiber, and high in refined sugar. We also consume large amounts of red meat, dairy products, and wheat. According to a 1977 Journal of American Medical Association article, this kind of diet results in fewer "friendly" bacteria in the intestinal tract. Furthermore, many of us eat too much, too often, and we mix too many different kinds of food at the same meal.These and other factors can cause a thick coat of mucus and impacted food residue, which combines to form on the walls of the large intestine. Not only does this encrusted matter contribute to further dysfunction of the colon, but, according to Bernard Jansen, D.C., in his boldly illustrated book, Tissue Cleansing through Bowel Management, disease actually begins here because toxins are absorbed to cause malnutrition of our body cells while absorption of nutrients is prevented.Candida albicans, a normal inhabitant of a healthy colon, prefers to live in this toxic filth where it is warm, putrid, and lacking in oxygen. Consequently, this family of yeast does well in most colons. In many cases, as noted by Trowbridge and Walker in The Yeast Syndrome, they become so prolific that they escape the confines of the intestinal tract and cause havoc throughout the rest of the body.According to a research pioneer, C. Orian Truss, MD, in a paper published in a 1978 issue of The Journal of Orthomolecular Psychiatry, Candida albicans proliferates in the intestines because of several factors, including stress, lowered immune system, antibiotic overuse, oral contraceptives, and use of cortisone or prednisone. It can change from the harmless non-invasive, sugar fermenting yeast like organism to the mycelial, or fungal, form with long, root like structures that can penetrate the membrane lining of the digestive tract.

If an individual can restore proper colon hygiene, the Candida will, instead, retreat to their former subdued state. Dr. David Soil, a University of Iowa biologist reported in a 1985 Science magazine article that Candida albicans is capable of changing from benign to virulent and change back to benign. In many cases, when the Candida returns to the benign form, the immune system will clear Candida from the rest of the body. Without paying close attention to the restoration of proper colon cleanliness, the immune system will be forced to continually battle Candida and its toxins.So a clean colon is essential in the battle against Candida, and the accumulation of filth here can be decreased, if not eliminated, with proper dietary modifications. First, adapt these nutritional steps:• Eliminate refined sugar and refined, bleached, chemically treated flour;

• Eliminate meats treated with synthetic hormones or chemicals;

• Eliminate hydrogenated fats (such as that which exists in peanut butter, baked goods, margarine, etc.);

• Reduce fats (use those rich in Omega-3 --fish and olive oils);

• Eat fresh and raw vegetables**** For more complete diet recommendations, see the WholeApproach® Diet Pages

Eat nothing unless it will spoil or rot, but eat it before it does so. At the grocery store, shop at the outer fringes of the building, avoiding canned, packaged products. Exercise regularly.

Next, eliminate colon toxicity. This can be accomplished by using two natural agents, Psyllium and Bentonite. Neither one is absorbed into the system, but rather, each absorbs and then expels toxic materials in the feces.

Psyllium (pronounced "silly-um") is a seed, grown commercially in India. Its husk is used as a bulk forming laxative in numerous products, and Constance Kies, PhD, in a 1982 issue of Prevention wrote, "As it absorbs water in the digestive tract, the Psyllium expands, stimulating and speeding up elimination." Psyllium also looks as though it is a cholesterol fighter, as Kies found in an experiment with healthy volunteers whose cholesterol levels dropped, on average, from 193 to 168 when they added Psyllium to their customary diets.

Gastroenterologist Jack D. Welsh, MD at the University of Oklahoma Health Sciences Center, noted in the June, 1982 edition of the American Journal of Clinical Nutrition that Psyllium entirely prevented the expected gas pain and nausea. If Psyllium seed powder is added to the husk powder in the proper ratio, the preparation becomes an intestinal cleanser. The Psyllium seed fragments are very hard; they tend to scrape away at the toxic plaguing on the walls and clean it away over a period of months.

Bentonite, a volcanic ash, acts toward toxic material as fly paper does with flies when processed into a very fine liquid suspension. The unique properties of Bentonite were reported in the Medical Annals of the District of Columbia in June of 1961 by Frederick Damrau, MD, who established that Bentonite adsorbs toxins, bacteria, and viruses both in laboratory dishes and in humans. Because Bentonite, itself, is not absorbed, whatever it adsorbs is removed in the feces. This includes miscellaneous intestinal poisons and toxins generated by Candida albicans.

The restoration of proper colon hygiene using this method takes anywhere from three to 24 months, depending on the age and condition of the individual. Caprylic acid can be added to help reduce the Candida albicans. Its anti fungal properties were the subject of a 1961 Japanese study at the Niigata University School of Medicine and were reported in the Japanese Journal of Microbiology: "....the fungicidal effect of Caprylic acid on C. albicans was exceedingly powerful." It was also noted in journal, "Caprylic acid exhibits the most remarkable fungiastatic and fungicidal

properties of all the normal saturated fatty acids with even numbered carbon atoms studied. The fungicidal activity of Caprylic acid depends upon the concentration of the acid, the period of contact, and the pH of the media."

Traditional Caprylic acid preparations exist as capsules or tablets, but the one we prefer is liquid Caproyl. This was designed to take advantage of other health benefits of oleic acid from Safflower oil and to interact with the Psyllium to amplify its fungicidal effects far beyond what Caprylic acid has traditionally offered. We recommend that liquid Caprylic acid be mixed with the Psyllium powder, Bentonite, and water to be taken orally once or twice daily.

As the Psyllium gel presses up against the intestinal walls, some unique and beneficial things occur:• the liquid Caprylic acid is released into the intestinal wall at a rate determined by the gel, not by

the intestinal pH conditions, which vary widely among individuals. Consequently, results are predictable; consistent, and favorable. Caprylic acid is slowly released through the entire length of the intestinal tract.

• As the gel rubs itself against the intestinal wall, it acts as a paint brush in delivering the liquid Caprylic acid to the intestinal wall. Not a square millimeter of wall is missed through the entire length of the intestines.

• Because the Candida albicans micro-organisms are buried deep into the toxic accumulations on the intestinal walls, access to them is difficult. But the bulking action of the gel forcibly rubs liquid Caprylic acid into the filth and onto the Candida.

Liquid Caprylic acid, dispersed in a Psyllium gel, will rid most people of major yeast symptoms in three to eight weeks. If these people really want to improve their health, however, or merely stay well, they will need to continue to eradicate the originating site and cause of the problem. They will need to clean up their intestinal environment.

While other colon cleansers may be touted, we know that over a period of many months, using the Psyllium/Bentonite mixture once or twice daily and adding the liquid Caprylic acid every fourth week for five consecutive days will clean out a colon and keep the Candida in check.

9. Food allergies or food intolerances.

How do you heal a leaky gut?

Eliminate Grain, Pasta and Cereals for these are the main source of gluten. 2nd, if it comes with a label, eliminate it. Preparing real food.

In my practice, I have all of my patients follow The Myers Way comprehensive elimination diet, which removes the toxic and inflammatory foods for a certain period of time. In addition, I have them follow a 4R program to heal their gut. The 4R program is as follows.

1. Remove.

Remove the bad. The goal is to get rid of things that negatively affect the environment of the GI tract, such as inflammatory and toxic foods, and intestinal infections.

2. Replace.

Replace the good. Add back the essential ingredients for proper digestion and absorption, such as digestive enzymes, hydrochloric acid and bile acids.

3. Reinoculate.

It’s critical to restore beneficial bacteria to reestablish a healthy balance of good bacteria.

4. Repair.

It’s essential to provide the nutrients necessary to help the

gut repair itself. One of my favorite supplements is L-glutamine, an amino acid that helps to rejuvenate the lining of the gut wall.

If you still have symptoms after following the above recommendations, I would recommend finding a Functional Medicine physician in your area to work with you and to order a comprehensive stool test

Leaky Gut - The syndrome linked to autoimmune diseases

"Leaky gut" syndrome

Hyperpermeability or "leaky gut" syndrome is the name given to a very common disorder in which the cells lining the intestines become "leaky" due to inflammation. The abnormally large spaces present between the cells of the gut wall allow the entry of toxic material into the bloodstream that would normally be eliminated.

The gut becomes leaky in the sense that bacteria, fungi, parasites, undigested protein, fat and toxic waste normally not absorbed into the bloodstream in the healthy state, pass through a damaged, hyperpermeable gut membrane. This can be verified by special gut permeability urine tests or microscopic examination of the lining of the intestinal wall.

Common causes of leaky gut• Infections - fungal overgrowth, parasitic infections• Drugs like NSAIDS, chemotherapeutic agents• Crohn's disease or Ulcerative Colitis• Celiac disease• Chronic alcoholism• Strenuous exercise• Food allergies

Leaky gut and the connection to autoimmune disease

Leaky gut syndrome is almost always associated with autoimmune disease. In fact, reversing symptoms of autoimmune disease depends on healing the lining of the gastrointestinal tract. Any other treatment is just symptom suppression. An autoimmune disease is defined as one in which the immune system makes antibodies against its own tissues. Diseases in this category include lupus, alopecia areata, rheumatoid arthritis, polymyalgia rheumatica, multiple sclerosis, fibromyalgia, chronic fatigue syndrome, Sjogren's syndrome (dry eyes & dry mouth), vitiligo, thyroiditis, vasculitis, Crohn's disease, ulcerative colitis, urticaria (hives), type 1 diabetes and Raynaud's syndrome. Fortunately doctors are beginning to realize the essential role that the gut plays in these disease. Understanding the leaky gut phenomenon helps us see why allergies and autoimmune diseases develop and how to design therapies to restore intestinal integrity and reverse leaky gut.

Inflammation is a key trigger for leaky gut

Inflammation causes the spaces between the cells of the gut wall to become larger than usual. Then protein molecules are absorbed before they have a chance to be completely broken down. The immune system starts making antibodies against these larger molecules because it recognizes them as foreign, invading substances. Antibodies are made against these proteins derived from previously harmless foods. The immune system becomes hyperstimulated and over-reactive to substances that are not necessarily supposed to be dangerous.

Human tissues have proteins & antigens very similar to those on foods, bacteria, parasites, candida or fungi. The antibodies created by the leaky gut phenomenon against these

antigens can get into various tissues and trigger an inflammatory reaction in that tissue when the corresponding food is consumed or the microbe is encountered. Autoantibodies are thus created and inflammation becomes chronic. If this inflammation occurs in a joint, autoimmune arthritis (rheumatoid arthritis) develops. If it occurs in the brain, myalgic encephalomyelitis (chronic fatigue syndrome) may be the result. If it occurs in the blood vessels, vasculitis (inflammation of the blood vessels) is the resulting autoimmune problem... and so on.

If the antibodies end up attacking the lining of the gut itself, the result may be colitis or Crohn's disease. If it occurs in the lungs, asthma is triggered on a delayed basis every time the individual consumes the food which triggered the production of the antibodies in the first place. It is easy to see that practically any organ or body tissue can become affected by food allergies created by the leaky gut. Because the foods can trigger delayed reactions, it can often be very hard to pinpoint the triggering entity.

Leaky gut may cause increase risk of infection and sensitivity to environmental chemicals

This ongoing inflammation also damages the protective coating of antibodies normally present in a healthy gut called IgA. Since IgA helps us ward off infections we become less resistant to viruses, bacteria, parasites and candida. These microbes are then able to invade the bloodstream and colonize almost any body tissue or organ. In the clinic we often find patients with leaky gut or autoimmune disease also have microbial infections ongoing in the gut.

Not only can leaky gut create food allergies as the proteins we consume are activating antibodies, but the microbes in the gut can cross over into the blood stream creating a toxic burden that overwhelms the liver's ability to detoxify. Often in severe cases

of leaky gut, patients will develop sensitivities to perfume, cigarette smoke or other environmental chemicals. Common complaints are also "brain fog", confusion, poor focus/concentration, or memory loss.

Leaky gut also causes malabsorption and nutritional deficiencies

Finally, leaky gut may contribute to a long list of mineral deficiencies because of the ongoing inflammation and damage to carrier proteins. The most common are iron deficiency, vitamin B12 deficiency, magnesium deficiency which can lead to fatigue, neuropathies or muscle pain. Zinc deficiency due to malabsorption can result in hair loss or baldness as occurs in alopecia areata. Copper deficiency can occur in an identical way leading to high blood cholesterol levels and osteoarthritis. Further, bone problems develop as a result of the malabsorption of calcium, boron, silicon and manganese.

Common Disorders of the Intestinal Tract: Intestinal Permeability/Leaky Gut

In this section we will take a hard look at the most common disorders of the intestinal tract, with a focus on the physiologic mechanisms that lead to these disorders and how they can be corrected with natural compounds and dietary changes.  We will start this section by examining the literature on a topic that is gaining a lot of attention in gastroenterology research as well as the field of immunology: intestinal permeability or “leaky gut”.  Let’s start by explaining exactly what this condition

refers to.

What is Leaky Gut?

The lining of the gastrointestinal (GI) tract is composed of small epithelial

cells that lie side-by-side each other forming tight junctions. These tight junctions act as a barrier between the interior of the body (blood/circulatory system) and the exterior of the body (the lumen of the GI tract).   There are two primary functions of the epithelial lining of the GI tract: the first is to absorb small micromolecules, such as digested food particles, which are used as fuel sources and other processes for the body. These micronutrients are absorbed directly into the epithelial cells or between the cells and enter the bloodstream after passing through the gut-associated lymphoid tissue (GALT), the underlying intestinal immune system. The GALT serves as a containment system, preventing potentially harmful antigens from reaching systemic circulation.

“A more attentive analysis of the anatomic and functional arrangement of the gastrointestinal tract,

however, suggests that another extremely important function of this organ is its ability to regulate the trafficking of macromolecules between the environment and the host through a barrier mechanism.”[275]

The second function of the epithelial lining of the GI tract, is to act as a barrier and prevent the absorption of larger macromolecules which should not normally penetrate through the intestinal barrier. When the tight junctions (TJs) of the intestinal mucosa are compromised, they become widened and permeable to large undigested food compounds, toxins and bacteria.  This is known as intestinal permeability or “leaky gut”. The larger compounds of absorbed yet undigested proteins are reacted against by the immune system of the gut,

called the GALT (gut-associated lymphoid tissue). This reaction then promotes exaggerated immune responsiveness and intestinal inflammation.

Think of the cells of your intestinal lining, where

absorption of micromolecules takes place, as bricks which sit side by side along the basement membrane. These “bricks” are held together by proteins that form the tight junctions (TJs), which act as the “mortar” between the bricks. Micronutrients are absorbed into the epithelial cells and transported through the cells and basement membrane where they enter the bloodstream. If the “mortar” starts to break down, you get penetration of foreign molecules through the intestinal barrier which can then enter the bloodstream (hence the term “leaky gut”). Sometimes the epithelial cells, or “bricks” themselves, start to break down allowing passage of toxins through the cells (transcellular passage) into the blood.  These foreign molecules may include undigested food molecules, toxins or bacteria.

Intestinal Permeability Leads to Systemic Inflammation

(san jose functional medicine)

If anything penetrates through this gastrointestinal barrier that is foreign, the immune system is activated to eliminate or destroy these unwelcome molecules. This activation of the immune system leads to an inflammatory response. If you look at the anatomy of the intestinal lining, it is mostly immune cells with a thin layer of epithelial cells protecting it. If that epithelial layer gets breached, there is no

question there will be an inflammatory immune response. So it is no surprise to see systemic inflammation and risk of autoimmunity when there is breach of this thin epithelial lining.  Increases in inflammatory responses increase risk of all chronic disease, including depression and neurodegenerative diseases, cardiovascular disease, bone loss, autoimmune disease, inflammatory bowel disease and chronic pain.  A person’s intestinal barrier integrity will influence their inflammatory load and their potential for deteriorating mechanisms throughout the body.

Health Conditions Associated with Leaky Gut Syndrome

The following conditions have been associated with leaky gut syndrome:

•Autoimmune disorders•Multiple food sensitivities•Multiple chemical sensitivities•Chronic fatigue syndrome•Heart failure•Depression•Chronic inflammatory conditions•Chronic pain

•Inflammatory bowel•Chronic yeast overgrowth syndromes•Brain fog

Intestinal Permeability and Autoimmune Disease

There is a growing amount of evidence establishing the connection between intestinal permeability and the development of autoimmune disease.  This review paper was published in 2009 in the prestigious Annals of New York Academy of Science.  This journal is one of the top-rated most powerful scientific journals available:

“There is growing evidence that increased intestinal permeability plays a pathogenic role in various autoimmune diseases. Therefore, we hypothesize that loss of intestinal barrier function is necessary to develop autoimmunity.”[276]

Basically, what this paper is saying, is that the research is pointing to intestinal permeability, or leaky gut, as a precondition for the development of all autoimmune disease, such as type I diabetes, rheumatoid arthritis (RA), lupus (SLE), multiple sclerosis (MS), Lou Gehrig’s disease (ALS), Hashimoto’s

hypothyroidism, Grave’s disease, Crohn’s disease, ulcerative colitis, Celiac disease, and hundreds of other diseases.

Here’s another paper supporting this discovery:

“Together with the gut-associated lymphoid tissue and the neuroendocrine network, the intestinal epithelial barrier, with its intercellular tight junctions, controls the equilibrium between tolerance and immunity to non-self antigens. When the finely-tuned trafficking of macromolecules is dysregulated in individuals, both intestinal and extraintestinal autoimmune disorders can occur.”[275]

One of the hallmarks of a healthy immune system is immune tolerance to self-tissue. This prevents our immune system from attacking one’s own tissue of the body.  We are born

with an immune system that is able to differentiate self-tissue from foreign pathogens and does not attack self-tissue under normal circumstances.  One of the things the research is showing is once these tight junction proteins get compromised, there is such immune zealousness and activation, this whole immune self-tolerance is lost and the immune system is prone to attacking self-tissue. When this occurs, any tissue is up for grabs for autoimmune destruction. The type of tissue that is targeted for destruction determines the type of autoimmune disease that develops.

Symptoms of Intestinal Permeability

Symptoms of intestinal permeability vary significantly and have a varied presentation. There is a spectrum of severity of intestinal permeability from mild to severe forms.  Here is a list of the most common symptoms associated with intestinal permeability:

•Bloating•Poor Digestion•Inflammation•Food Sensitivities•Chronic Pain•Brain Fog/Poor Memory•Depression•Fatigue

People with intestinal permeability will often react to certain types of foods, especially common food allergens such as wheat and dairy. Gluten sensitivity is very common with these patients. Digestive abnormalities such as gas, bloating and food sensitivities are common symptoms of leaky gut.  On the other side of the scale are people who never have intestinal symptoms but have other symptoms of chronic inflammation such as chronic pain, depression, brain fog or fatigue. They are too tired or in too much pain to go to the gym and exercise on a regular basis.  When we see patients that present with these symptoms, we have to consider intestinal permeability issues.

Common Imbalances Associated with Leaky Gut

There are a number of common imbalances that often occur together with leaky gut. These include:

•Malabsorption/malnutrition•Bacterial/yeast overgrowth/dysbiosis (imbalance of

beneficial and pathogenic bacteria)•Intestinal lining degeneration/impaired intestinal

immune integrity•Immune activation/immune

dysregulation/autoimmunity•Food sensitivities

Mechanisms Leading to Leaky Gut

There are many different environmental and dietary factors that may damage the epithelial lining of the GI tract, including a diet high in refined sugar, intake of food allergens, such as wheat and dairy, alcohol use, use of medications such as antibiotics or NSAIDs, such as ibuprofen and aspirin, stress, chronic infections, nutrient deficiencies, hormonal deficiencies (thyroid, estrogen or testosterone) and metabolic disturbances, such as diabetes or pre-diabetes.[277-286]  All of these factors have been shown to contribute to intestinal permeability.  Alterations in intestinal physiology may affect the integrity of the intestinal epithelium tight junction protein structures.  These mechanisms basically include physiological shifts that induce greater ongoing catabolism (breakdown) versus anabolism (buildup) of the epithelial mucosa.  Additionally, systemic inflammation, which occurs in autoimmune conditions, promotes leaky gut.  So this becomes a

vicious cycle of leaky gut, leading to systemic inflammation, leading to further leaky gut.

What are the Causes of Leaky Gut?

• Diet (refined sugar, wheat, dairy, etc.)

•Medication (antibiotics, NSAIDs, etc.)•Infection (bacterial, viral, parasitic)•Stress•Hormonal Imbalances (thyroid, estrogen,

testosterone, etc.)•Neurologic Issues (stroke, brain injury, etc.)•Metabolic Issues (diabetes, pre-diabetes, etc.)•Autoimmunity

Conventional Management of Intestinal Permeability

There is currently no drug available to treat intestinal permeability and most doctors have not

even heard of it.  However, this may change in the near future because drug companies are now working on drugs that modulate gut permeability.  There is currently a tight junction regulator being developed, intended for the treatment of patients with celiac disease which has just recently passed Phase IIb human drug trial development and will start Phase III clinical trials for the assessment of the oral drug’s efficacy and safety.[287]  Once this drug is approved, doctors, or at least gastroenterologists, will become more familiar with intestinal permeability.  However, at present, these drugs appear to be limited to approval for the treatment of this one particular intestinal autoimmune disorder (celiac disease).  So patients with intestinal permeability with diagnoses of other autoimmune conditions (or any other condition) will not be able to get drug treatments for the foreseeable future.

How to Find Out For Sure If You Have Leaky GutThere are several tests that have been developed, and more on the way, that can tell you if you have some degree of leaky gut.

1. There is a urine test that involves first swallowing a carbohydrate that will only make it across your intestinal lining and into your blood and urine if your gut is leaky.

2. It is also possible to identify leaky gut by checking for IgG and IgA antibodies to food in a blood test – and this test is often preferable because it gives us two pieces of information:• Whether or not there is leaky gut; and• Which foods you can avoid to help heal the leaky gut (if it’s there).

You can order a food sensitivity test here and complete it at home.

3. A blood test that measures zonulin as well as a substance called actomyosin which is released when intestinal cells are damaged.

4. A breath test which, like the lactulose-mannitol test, involves first swallowing sugar mixed in water, and then breathing into tubes which will identify a gas (carbon dioxide) that is only produced if your gut is healthy.I can help you with determining which test is best for you: please make an appointment!Note: Leaky gut cannot be found with an endoscopy or colonoscopy, and does not show on standard bloodwork, so it is missed by most practitioners.

Clinical Management of Intestinal Permeability in Functional Medicine

Fortunately, intestinal permeability usually responds very well to dietary and supplement intervention and can often be well-managed through these interventions alone.  The treatment of leaky gut should include an aggressive program designed to break the vicious cycle of leaky gut.

This involves a restricted dietary regimen and nutritional supplements that have been shown to help

reduce intestinal inflammation and help repair the intestinal lining. The dietary program may need to be conducted for an extended period of time for more progressed cases, depending on the factors involved in promoting leaky gut.  One of the things that will create variables for how long this will take are the mechanisms involved that are causing the leaky gut. If the person is still consuming alcohol or consuming inflammatory foods or has hormonal deficiencies or has blood sugar issues, this will take longer to correct. There will be some people that will have chronic leaky gut for the rest of their life, such as severe autoimmune conditions and people with systemic inflammatory conditions.

Nutritional Compounds Shown to Repair the Intestinal Lining

There are various plant compounds, vitamins and minerals that have been shown in the literature to have a restorative effect on a damaged intestinal barrier.  These include the following: L-glutamine [288-292], deglycyrrhinized licorice [293-303], N-acetyl glucosamine [304-307], aloe leaf extract [308-312], spanish moss [313-317], marshmallow extract [318-321], methylsulfonylmethane (MSM) [322-325], gamma oryzanol [326-330], slippery elm bark [331-334], german chamomile [335-337], marigold flower extract [338-341], glutathione [342-347], zinc

carnosine [348], vitamin D [349-351].

“Regarding intestinal permeability, zinc carnosine caused an approximate threefold increase in gut integrity and repair”[348]

“VDR (vitamin D receptor) plays a critical role in mucosal barrier

homeostasis by preserving the integrity of junction complexes and the healing capacity of the colonic epithelium.  Therefore, vitamin D deficiency may compromise the mucosal barrier, leading to increased susceptibility to mucosal damage and increased risk of IBD (inflammatory bowel disease).”[349]

“There is growing appreciation of the importance of the pleiotropic hormone vitamin D in the development of tolerance, immune system defenses, and epithelial barrier integrity” [350]

“1,25(OH)2D3 (vitamin D) may play a protective role in mucosal barrier homeostasis by maintaining the integrity of junction complexes and in healing capacity of the colon epithelium. 1,25(OH)2D3 may represent an attractive and novel therapeutic agent for the adjuvant therapy of IBD (inflammatory bowel disease).”[351]

NSAID-Induced Enteropathy

NSAID-induced enteropathy refers to intestinal damage that occurs from the use of non-steroidal anti-inflammatory drugs (NSAIDs).  Examples of NSAIDs are ibuprofen (Advil®, Motrin®), naproxen (Aleve®, Naprosyn), Celebrex® and aspirin.  The use of NSAIDs, including aspirin, is common in the treatment of pain, inflammation, and fever. Additionally, low-dose aspirin is used routinely in the prevention of heart attack and stroke. These drugs, both through prescription and over-the-counter (OTC) use, are the most widely used class of medications in the United States.[352] Not surprisingly, NSAID use increases among the elderly. In a survey of people 65 years of age and older, 70% used NSAIDs at least once weekly, and 34% used them at least daily! The prevalence of at least weekly aspirin usage was 60%![353] More than 111 million NSAID prescriptions were written in 2004.[354]

Much of this usage comes from pain conditions, such as arthritis and related musculoskeletal complaints. In 1990, the estimated prevalence of self-reported arthritis in the U.S. was 37.9 million cases, or 15% of the

population! By 2020, it is projected that 59.4 million will be affected—a 57% increase from 1990![355] As the incidence of arthritis complaints increases, the use of prescription and OTC NSAIDs is also expected to increase.[356]  However, the use of NSAIDs does not come without risks.  The most common risk of NSAID use is damage to the stomach (gastropathy) and intestinal lining (enteropathy).  Iron-deficient anemia is a common first sign of NSAID-enteropathy (due to internal bleeding), and serious complications can include massive bleeding, perforation and strictures, sometimes leading to death.[357]

“The prevalence and clinical significance of NSAID-enteropathy continues to be greatly under-recognized. NSAID-induced enteropathy and bleeding occur more frequently than NSAID induced gastropathy. Significant small intestinal damage and bleeding can be observed in about 70% of chronic NSAID users, and in the majority of patients the injury is sub-clinical.”[357]

Wow!  Significant damage to the small damage occurs in 70% of chronic NSAID users! This information should be more widely publicized!  These medications should be clearly labeled and doctors should be warning their patients about the risks associated with these drugs with every prescription. On top of that, in most cases the injury is subclinical (meaning it does not cause any

symptoms or signs)! 

If the injury is subclinical, it can’t be very serious, right?  Unfortunately, that’s not the case.

“…even minor and subclinical injury to the intestinal mucosa can result in significant, though delayed, metabolic consequences, which may seriously affect the health of an individual.” [358]

“With improvements in the detection of NSAID-induced damage in the small intestine, it is now clear that this injury and the associated bleeding occurs more frequently than that occurring in the stomach and duodenum, and can also be regarded as more dangerous.”[357]

It is common practice in primary care and pain management to prescribe acid-suppressing medications (PPIs such as omeprazole) together with

NSAIDs in order to protect the intestinal tract and

reduce risk of GI adverse effects.  However, recent research indicates that this can worsen the damage to the GI tract.

“Moreover, recent studies suggest that commonly used drugs for protecting the upper gastrointestinal tract (i.e., proton pump inhibitors) can significantly worsen NSAID-induced damage in the small intestine.”[357]

“The frequent use of PPIs can exacerbate NSAID-induced small intestinal injury by altering intestinal microbiota. Thus, the use of PPI is considered to be an independent risk factor associated with NSAID-associated enteropathy.”[358]

Mechanism of Injury of NSAIDs

to Gut Lining

How do NSAIDs cause damage to the gut?  Let’s take a more in-

depth look at how NSAIDs injure the gut lining.  This may be a bit technical for some readers but others will find this informative.  NSAIDs cause topical injury to the mucosal lining of the GI tract and systemic effects (throughout the body) by inhibiting the COX enzymes resulting in prostaglandin depletion.  COX (cyclooxygenase) is an enzyme that

is responsible for the production of prostaglandins and thromboxane.  Prostaglandins are lipid compounds that have a wide range of hormone-like effects in the body.  Tissue prostaglandins are produced via two distinct enzyme-dependent pathways: a COX-1 and a COX-2 pathway.

The COX-1 pathway is the predominant constitutive (replenishing) pathway; prostaglandins derived from this enzyme mediate many

effects, most notably aiding in gastroduodenal protection, renal perfusion, and platelet activity. The COX-2 pathway, in contrast, is inducible by inflammatory stimuli and primarily mediates effects through prostaglandins which result in inflammation, pain, and fever.  NSAIDs work by blocking these two important enzymes throughout the body.  Inhibition of the COX-1 pathway blocks production of prostaglandins that play an important protective role in the stomach by increasing mucosal blood flow, stimulating the synthesis and secretion of mucus critical for the mucosal lining, and promoting proliferation of the epithelial lining.  Secretion of mucus and epithelial proliferation are critical aspects to gut health in order to prevent intestinal permeability or leaky gut!

The inhibition of these prostaglandins by NSAIDs impairs these protective factors, resulting in a gastric lining that is more susceptible to acid, pepsin, and bile salts and more permeable to toxic intestinal compounds (affect intestinal permeability).  A major consequence of prostaglandin depletion is to create an environment that is conducive to peptic ulcer formation, bleeding and serious GI complications. Since prostaglandins are essential to both the maintenance of intact GI defenses and normal platelet function, NSAIDs, including aspirin, promote ulcer formation as well as bleeding.[356]  This is why NSAIDs are also considered a major risk factor for intestinal permeability.

Selective COX-2 Inhibitors

What about the newer class of NSAIDs, known as the selective COX-2 inhibitors or “coxibs”, such as Celebrex®?  Aren’t they safer for the gut than the other NSAIDS?  In the 1990’s, a tremendous amount of research was focused on understanding the physiology and pharmacology of these two distinct COX enzymes, largely fueled by the interest of several large pharmaceutical companies in the notion that selective inhibitors of COX-2 would provide all of the anti-inflammatory activities of NSAIDs without the major adverse effects on the GI lining.[357]

“However, as the science of COX-2 caught up with the marketing of COX-2, it became evident that the delineation of functions of the two COX enzymes was not so clear-cut as had been proposed and heavily promoted. COX-1 contributes significantly to inflammation while COX-2 contributes significantly to many physiological functions, including mucosal defense.”[357]

So we now know that these selective COX-2 inhibitor

medications, which were touted as safe for the stomach and GI tract by the pharmaceutical companies, are not safe for the gut either.

Conventional Management of NSAID-Induced

Enteropathy

There is no known drug treatment for NSAID-induced enteropathy, other than the withdrawal of use of NSAIDs.  Some doctors may still recommend the use of PPIs in these cases, however, as we have seen, recent literature has shown that the use of PPIs increases intestinal damage, rather than alleviates it.

“Moreover, recent studies suggest that commonly used drugs for protecting the upper gastrointestinal tract (i.e., proton pump inhibitors) can significantly worsen NSAID-induced damage in the small intestine.”[357]

Clinical Management of NSAID-Induced Enteropathy in Functional Medicine

As we have seen from the previous section on natural

compounds used in the treatment of intestinal permeability, various plant compounds, vitamins and minerals have been shown in the literature to have a restorative effect on a damaged intestinal lining.[288-351]  Many of the compounds that are used to treat intestinal permeability or gastric and duodenal ulcers are also used to in the treatment for NSAID-induced enteropathy.  The reason for this is because these compounds have a restorative effect on the mucosal epithelial lining of the GI tract.  In other words, they help the GI tract regenerate healthy epithelial cells which make up the GI lining. 

As you may have noticed, in addition to NSAID-induced enteropathy, NSAIDs are a risk factor for both gastric and duodenal ulcers and intestinal permeability.  This is because NSAIDs cause damage to the epithelial lining that lead to all of these conditions which are closely related.  They are all mediated by damage to this epithelial lining.  In fact, one of the methods used to study the effects of drug or plant compounds on a damaged gastric or

intestinal mucosal lining is to give rats high-dose NSAIDs to induce this mucosal damage.[293-295,299]   In addition to these plant compounds used for the treatment of damage to the gastric and intestinal lining, the omega-3 polyunsaturated fatty acids (n-3 PUFAs) found in

fish oils (EPA and DHA) have been found to have a significant protective effect on the GI lining against NSAID-

induced GI damage.[359]  In fact, a large gastroenterology medical journal just recently published an article claiming that, due to the protective effects of these fatty acids, the next generation of NSAIDs will include these omega-3 fatty acids in the drug.

“Because n-3 PUFAs have been proven to attenuate cytotoxicity, inhibit lipid-raft-associated harmful signaling, and relieve oxidative stress relevant to NSAIDs, n-3 PUFA based NSAIDs will be next-generation GI-safe NSAIDs.”[359]

Irritable Bowel Syndrome (IBS)

Irritable bowel syndrome (IBS) affects as many as 5%-20% of individuals worldwide and has a significant impact on quality of life.  IBS symptoms range from diarrhea to constipation, or a combination of the two, with abdominal pain or discomfort and gas or bloating, referred to as “abdominal distension”.  The degree of symptoms varies in different patients from tolerable to severe, and the time pattern and discomfort varies immensely from patient to patient. Some patients complain of daily symptoms, while others report intermittent symptoms at intervals of weeks or months.

[360,361] There are no biomarkers used in the diagnosis of IBS so diagnosis is based on assessment of symptoms.[362,363]  IBS is divided into subtypes,

depending on symptoms such as diarrhea-predominant IBS (IBS-D), constipation-predominant IBS (IBS-C) and mixed diarrhea and constipation-predominant IBS (IBS-M).[364,365]  IBS is not known to be associated with the development of serious disease or with excess mortality. However, IBS causes a reduced quality of life with the same degree of impairment as major chronic diseases.[366,367]  The annual costs in the United States, both direct and indirect, for the management of

patients with IBS are estimated at $15-30 billion.[368,369]

What Causes IBS?

The pathogenesis of IBS seems to be multifactorial, with the following factors most likely playing a central role in the pathogenesis of IBS: heritability and genetics, diet, gut flora, low-grade inflammation, and disturbances in the neuroendocrine system (NES) of the gut, which includes the enteric nervous system (ENS).[360,361]  One hypothesis published recently in a worldwide gastroenterology journal

proposes that the cause of IBS is an altered NES of the gut, which accounts for abnormal GI motility, secretions and sensations.[360] All of these abnormalities are characteristic of IBS. The researchers propose that alterations in the NES could be the result of one or more of the following causative factors of IBS: genetic factors, diet, intestinal flora, or low-grade inflammation.[360]  Let’s take a look at each of factors that are believed to contribute to the development of IBS.

IBS: Heritability and Genetics

Genetics appear to play a role in IBS. Up to 33% of patients with IBS had a family history of IBS compared to 2% of the controls in one study.[370] In another study of a family cluster, a significant association was reported between having a first degree family member with bowel symptoms and presenting with IBS. In contrast, those who reported having a spouse with bowel symptoms were no more likely to have IBS symptoms than the general population.[371] It was also shown that the prevalence of IBS was 17% in the relatives of patients compared to 7% in the relatives of spouses.[372] Another study showed that patients with IBS were more likely to present a family history of IBS

than controls (33.9% and 12.6%, respectively).[373]

IBS: Diet

Most patients with IBS believe that their diet has a significant influence on their symptoms and they are interested in finding out which foods they should avoid.[374-377] There is some evidence supporting dietary influence on IBS symptoms.  In one study, about 60% of IBS patients reported a worsening of symptoms following specific food ingestion: 28% within 15 min after eating and 93% within 3 hrs.[377]  Many IBS patients report specific foods as triggers, most commonly implicating dairy and wheat products, but other foods as well such as onion, peas and beans, hot spices, cabbage, certain meats, smoked products, fried food and caffeine.[378]

The reaction of IBS patients to certain food items has been attributed to a number of short-chain carbohydrates called FODMAPs that are poorly digested and absorbed so that a significant portion of the ingested carbohydrates do not get digested

properly and enter the small intestine and colon. Once there, these unabsorbed carbohydrates provide a substrate for bacterial fermentation with the production of gas and distension of the intestinal tract and an increase in intra-abdominal pressure (IAP). This leads to abdominal discomfort or pain. [360] Sound familiar?  This is the same mechanism described earlier that lead to GERD and as we will see, also occurs in small intestinal bacterial overgrowth (SIBO).

IBS: FODMAPs

FODMAPs include fructose, lactose, fructans, galactans and sugar alcohols, such as sorbitol, maltitol, mannitol, xylitol and ismalt. Fructose and lactose are present in apples, pears, watermelon, honey, fruit juices, dried fruits, milk and dairy products. Polyols are used in low calorie food products. Galactans and fructans are present in common dietary food, such as wheat, rye, garlic, onions, legumes, cabbage, artichokes, leeks, asparagus, lentils, inulin, soy, brussel sprouts and broccoli.[379]

IBS: Fiber

A deficiency in dietary fiber was once widely believed to be the primary cause of IBS.[380] Although increasing the amount of dietary fiber continues to be a standard recommendation for patients with IBS, clinical practice has shown that increased fiber intake in these patients increases abdominal pain, bloating and distension.[380]  In one study, IBS patients assigned to fiber treatment showed persistent symptoms or no improvement in symptoms after treatment compared to patients taking the placebo or a low-fiber diet but these patients were using common bran types of fiber.[380]  It is noteworthy that the role of FODMAPs and fiber on IBS symptoms is associated with the intestinal flora. The presence of gut bacteria that break down FODMAPs and fiber and produce gas, such as Clostridia spp., can cause distension of the small and large intestine with abdominal discomfort or pain and lead to small intestinal bacterial overgrowth (SIBO).[381,382]

IBS: Intestinal Flora

Most bacteria in the GI tract exist in the colon. The colon of each individual contains between 300 and 500 different species of bacteria, and each person has his own unique intestinal flora.[360] The intestinal flora is affected by several factors, such as diet, climate changes, stress, illness, aging and medications, such as acid-suppressing medication and antibiotic treatment.[383] The intestinal flora in IBS patients has been found to differ considerably from that of healthy controls, as IBS patients have fewer Lactobacillus and Bifidobacterium spp. than healthy subjects.[384] These bacteria bind to epithelial cells and inhibit pathogen binding as well as enhancing barrier functioning.[385] Furthermore, these bacterial species do not produce gas upon fermenting carbohydrates, which is an effect that would be amplified as they also inhibit the Clostridia spp.[385]  Probiotics have been shown to decrease colonic fermentation and stabilize the colonic microbiota, and several studies on probiotics have shown improvements in flatulence and abdominal distension, with a reduction in the composite IBS symptom score.[385-387]

A recent systematic review with meta-analysis published in a worldwide gastroenterology journal examined the efficacy of probiotics in the treatment of IBS.  A total of 1,793 patients were included in the meta-analysis.  Distension, bloating, and flatulence were evaluated using an IBS severity scoring system in three trials (two studies) to compare the effect of probiotic therapy in IBS patients with placebo.  The review concluded the following:

“Probiotics reduce pain and symptom severity scores. The results demonstrate the beneficial effects of probiotics in IBS patients in comparison with placebo.”[388]

IBS: Low-Grade Inflammation

Low-grade systemic inflammation appears to play a role in the development of IBS.  In a subset of IBS patients, GI symptoms appear following gastroenteritis, with about 25% of patients showing diarrhea-predominant IBS (IBS-D) symptoms 6 months post- infection and approximately 10% developing persistent symptoms.[389-392] Post- infectious (PI)-IBS has been reported after viral, bacterial, protozoa and nematode infections[383], with the incidence of PI-IBS varying between 7% and 31%.[389-392] One study showed that 6% to 17% of sporadic IBS patients believed that their symptoms began with an infection.[383] Following infection, the initial inflammatory response shows an increase in certain types of lymphocytes (white blood cells) and macrophages.[389] These changes rapidly decrease in most subjects but a small number of patients with persistent symptoms continue to have signs of infection.[393]

There are several pieces of evidence showing that inflammation and immune cells affect the neuroendocrine system (NES) of the gut, which controls and regulates GI motility and sensitivity. [394] There is also evidence of IBS patients having increased intestinal permeability and gut barrier issues than in the non-IBS population.[395-396]

For a more in-depth perspective on the neuroendocrine system (NES) of the gut and the brain-gut axis and how abnormalities of the NES and the brain-gut axis may contribute to IBS, click on: The Neuroendocrine System of the Gut and the Brain-Gut Axis

IBS: Is SIBO the Culprit?

Some researchers now believe that irritable bowel syndrome (IBS) may be caused by bacterial overgrowth in the small intestine (SIBO).[487] An article was published in JAMA in 2004 proposing

that small intestinal bacterial overgrowth (SIBO) might explain the symptoms of altered gut motility, visceral hypersensitivity, abnormal brain-gut interaction and immune activation seen in IBS.[487] This is supported by multiple lines of evidence.  First, SIBO is found in up to 78%-84% of IBS patients undergoing lactulose breath testing indicating bacterial overgrowth.[488,489]  Second, the distribution of inflammatory mediators and/or inflammatory cells have been shown to be disturbed in a percentage of patients with IBS.[490]

It is thought that SIBO may contribute to many of the clinical manifestations of IBS through bacterial fermentation and stimulation of a gut immune response, characterized by release of inflammatory mediators (such as interleukins and tumour necrosis factor-α) which may affect motility, secretion and sensation.[487,491]  Additionally, postinfectious IBS, which occurs in 4%-31% of patients after an episode of acute gastroenteritis[492], also supports a causative role of bacteria in IBS.[493]

Conventional Treatment of IBS

“A wide range of medications (prokinetics, antispasmodics, sedatives, tranquilizers, laxatives, fecal bulking agents, probiotics and antibiotics) along with lifestyle and diet modifications have been proposed for this highly prevalent condition; however to date there is no definite effective cure for this state.”[494]

Conventional treatment options for IBS include pharmacological drugs aimed at symptomatic relief of the primary symptoms involved in IBS, namely pain, diarrhea and constipation.[494]  In addition, antibiotic drugs such as rifaximin are recently being used to treat IBS due to evidence of bacterial overgrowth in this condition.[495]  Treatment for abdominal pain include antispasmodics, which encompass several different drug classes (smooth-muscle relaxants, antimuscarinics, anticholinergics) and other agents (pinaverium, trimebutine). 

The anticholinergic properties of these agents restrict their usefulness in clinical practice.[494] Other drugs used for abdominal pain include opioid receptor agonists (exogenous opioids), GLP-1 (glucagon-like peptide 1) and membrane stabilizers (ketotifen).  Membrane stabilizers act by blocking mast cell degranulation.[496] The number of mucosal mast cells has been studied and found positively correlated to abdominal pain.[497]

Treatment for diarrhea-predominant IBS (IBS-D) include anti-diarrheals (loperamide), 5-HT3 antagonists or serotonin-blockers (alosetron, cilansetron, ramosetron), anti-inflammatory drugs (mesalamine) and antibiotic drugs (rifaximin).  The potential use of antibiotics in IBS treatment has been supported by a growing body of evidence showing the important role that intestinal bacterial overgrowth plays in the development of IBS. Various lines of evidence suggest that small intestinal bacterial overgrowth (SIBO) may lead to many of the symptoms seen in IBS, such as altered gut motility, visceral hypersensitivity, abnormal brain-gut interaction and immune activation seen in IBS.[494,498]  The American Task Force systematic review of IBS treatments concludes that rifaximin has shown improvement of global IBS symptoms and bloating in trials included in their analysis.[499]

Treatment for constipation-predominant IBS (IBS-C) include laxative-based treatments (osmotic agents, and stool softeners), prokinetics (drugs to stimulate movement of bowels), prosecretory agents (drugs that augment intestinal secretion, thus acting as a stool lubricant and facilitating its evacuation, such as lubiprostone and linaclotide), serotonin-boosting drugs (serotonin receptor modulators and 5-HT4 agonists such as tegaserod) and bile acid modulators (CDC and elobixibat). Bile acid modulators have been used to treat constipation disorders based on the observation of increased incidence of diarrhea in patients taking bile acids for gallstones or cholestatic liver diseases.[500]

However, these drugs have limited effects in their

use due to their symptomatic approach and risk of various side effects.

“Pharmacologic treatments for IBS-C have largely been unsatisfactory, mainly due to the multifaceted and poorly understood pathophysiology of this disorder.”[501]

“The multifactorial pathogenesis of the disease and the ill-defined drug targets make the goal of manufacturing a “universal drug” for IBS-C a hard one to attain.”[500]

Evidence of the long-term benefit of pharmacological treatment has been sparse, and new drugs that have proven to be effective have raised issues concerning safety.[502,503]  These agents have limited usefulness as most of them are directed toward the symptoms of IBS, rather than

the underlying causes of this condition, with the possible exception of antibiotic therapy.  Alternative therapies, such as cognitive behavioral therapy and gut-directed hypnotherapy, have been used with good results.[504]  A more efficient approach would be to address the underlying factors that appear to be related to the development of IBS, such as excess carbohydrate consumption, food sensitivities, insufficient HCl and pancreatic enzyme production, balanced intestinal flora, low-grade intestinal inflammation and the brain-gut axis.  This is exactly how we approach IBS in the functional medicine model.

Clinical Management of IBS in Functional Medicine

Clinical management of IBS in the functional medicine model starts with a thorough evaluation of the gut.  This may include a comprehensive stool analysis in addition to a stool microbiology assay, assessing for dysbiosis and ruling out pathogenic

bacterial, fungal or parasitic infection.  A comprehensive stool analysis can provide a great deal of information about gut function including markers of protein and fat digestion, pancreatic function, and production of short-chain fatty acids such as butyric acid which are important for colon health. 

A stool analysis can also assess for inflammatory gut conditions such as inflammatory bowel disease (ie: ulcerative colitis and Crohn’s disease) without undergoing intestinal biopsy and rule out GI bleeding.  Assessment of related gut conditions, such as intestinal permeability and small intestinal bacterial overgrowth should be considered in conditions involving gas and bloating.  Routine blood chemistry is usually done to assess inflammatory markers and assess other organ function that impact the gut such as thyroid function.  Food sensitivity testing and nutritional analysis to assess for nutrient deficiencies should be considered as well.

Management of IBS can vary greatly from person to person depending on the findings of the stool analysis as well as other conditions that may impact stomach and GI health such as intestinal permeability and food sensitivity.  Treatment goals in the functional medicine model are to eliminate

pathogenic infection, restore balance to the gut flora, and restore normal function of the stomach and GI tract (normal secretion of HCl and pancreatic enzymes, normal digestion of food and normal motility/movement of the intestines).  This can normally be attained through the use of herbal anti-microbial compounds, probiotics and digestive enzyme therapy.  Assessment of related organ function (particularly the thyroid, immune system, liver and brain) should be conducted to assess for imbalances in these organ systems as well (see Gut Connections with Other Organs).

Most IBS patients suffer from some degree of dysbiosis, so the use of probiotics and prebiotics are often employed to restore gut flora balance.  Several specific bacterial probiotic strains have been shown to improve symptom severity and abdominal pain in IBS patients in numerous studies.[462,466-479]  There are some species that in clinical trials appear to be more effective than others, such as Bifidobacterium species (B. infantis 3564 and B.

bifidum MIMBb75) [470,474,476] and Lactobacillus species (Lactobacillus acidophilus-SDC 2012, 2013, L. paracasei B2106, L. plantarum 299V, and L. rhamnosus GG).[469,473,475]  These probiotics appear to be effective in reducing abdominal pain and discomfort in adults and in children. Several studies have also suggested that combinations of different probiotic strains, such as VSL3# or mixtures of Bifidobacterium and Lactobacillus species, are able to decrease abdominal pain and discomfort in patients with IBS.[466,478,479]

Addressing low-grade inflammation and intestinal permeability through gut-restorative and anti-inflammatory botanicals as well as dietary intervention is also important in IBS.  There are a wide variety of compounds shown to repair the damaged intestinal lining, improve gut barrier integrity and decrease low-grade inflammation in the GI tract as described in the Intestinal Permeability section above.[288-351]

Dietary compounds can induce immune responses in the GI tract and contribute to low-grade inflammation, particularly in gut permeability issues, therefore food sensitivity testing can be of value in IBS patients. This involves assessing for levels of IgA and IgG antibodies to various foods in the blood through a lab that offers specialized food sensitivity testing.  Elimination of these foods from the diet is important when trying to repair a leaky gut or improve IBS symptoms.  Lastly, assessing for small intestinal bacterial overgrowth (SIBO) and implementing a specific-carbohydrate diet (SCD) and/or low FODMAP diet in these cases is also important to reduce bacterial fermentation causing gas, bloating, abdominal discomfort and improve bowel regularity.   We will learn more about the assessment of SIBO and how this condition is managed in the next section.

Small Intestinal Bacterial Overgrowth

Small intestinal bacterial overgrowth (SIBO) is defined as the presence of excessive bacteria in the small intestine. SIBO is frequently found to be the cause of chronic diarrhea and malabsorption. Patients with SIBO may also suffer from unintentional weight loss, nutritional deficiencies, and osteoporosis.[505] A common misconception is that SIBO affects only a limited number of patients, such as those with an anatomic abnormality of the gastrointestinal (GI) tract or those with a motility disorder. However, the recent literature shows that SIBO may be more prevalent than previously thought. This apparent increase in prevalence may have occurred partly due to readily available diagnostic tests which have improved our ability to diagnose SIBO.[505]

Prevalence of SIBO

Only limited data are available regarding the prevalence of SIBO in healthy populations but age appears to be an important risk factor. In a study of 294 non-hospitalized older adults in which 34 younger adults (mean age 33.6 years) served as healthy controls, the prevalence of SIBO, as determined by glucose breath test, was 5.9% in the control group versus 15.6% in the older group.[505] Healthy elderly volunteers from the United Kingdom had a 14.5% prevalence rate for SIBO based on a positive glucose breath test.[505]

“Small bowel bacterial overgrowth is an important and under-recognized clinical syndrome in the elderly. It is the most common cause of malabsorption among older adults”[506]

Irritable bowel syndrome (IBS) is another known risk factor for SIBO. Studies have shown that up to 78% to 84% of patients who met the Rome I criteria for IBS had an abnormal lactulose breath test suggestive of SIBO compared to 20% of healthy volunteers.[507,508]  In summary, although data are limited, the prevalence rates of SIBO appear to be consistently higher in patients with IBS. However, it is also common in children with chronic gastrointestinal symptoms and abdominal pain.

“Similar to adults with irritable bowel syndrome, there is a significantly higher prevalence of SIBO in children with chronic abdominal pain”[509]

“…SIBO may be more common in children with gastrointestinal symptoms and apparent carbohydrate malabsorption than previously recognized”[510]

Prevalence of SIBO in Various Conditions

•3% of patients with celiac disease•66% of patients with celiac disease with persistent

GI symptoms•15% of elderly population•53% of patients with antacid medication use•78% of patients with IBS•33% of patients with chronic diarrhea•34% of patients with chronic pancreatitis•90% of alcoholics [505]

Causes of SIBO

“SIBO can result from failure of the gastric acid barrier, failure of small intestinal motility, anatomic alterations or impairment of systemic and local immunity”[511]

“In the intact intestine, small intestinal bacterial overgrowth is prevented by the actions of gastric acid, pancreatic enzyme activity, small intestinal motility, and the ileocecal valve”[512]

Intestinal bacterial overgrowth develops when the normal homeostatic mechanisms that control gut bacterial populations are disrupted. The two most common conditions that predispose to bacterial overgrowth are diminished gastric acid secretion (hypochlorhydria) and decreased small intestinal motility (sluggish bowels). Let’s take a brief look at how these conditions lead to SIBO.

SIBO: Low Gastric Acid Production

As discussed in Common Stomach Disorders: Hypochlorhydria, gastric acid suppresses the growth of ingested bacteria, thereby limiting bacterial counts in the stomach and upper small intestine. Diminished acid production (hypochlorhydria) is a risk factor for bacterial overgrowth simply because there is less acid available to prevent bacteria from growing. As discussed in the hypochlorhydria section, there are a number of factors that can lead to this condition, including colonization with H. pylori, stress and as a consequence of aging.[505]  SIBO can also result from PPI use in the treatment of GERD. 

A prospective study of 47 outpatients treated with either omeprazole (20 mg/day) or cimetidine (800 mg/day) found that bacterial overgrowth was present in 53% of patients who received omeprazole (PPI), compared to only 17% who received cimetidine (a weaker acid-suppressing medication).[513] In another study, 20 patients treated with 4 weeks of omeprazole had a significant increase in duodenal bacterial counts (compared to baseline) as measured by endoscopic aspiration.[514] These studies clearly show the importance of stomach acid

production in preventing bacterial overgrowth.

SIBO: Motility Disorders

Normal GI motility involves a complex, tightly coordinated series of events designed to move material through the GI tract. During periods of fasting, a migrating motor complex (MMC) develops approximately every 90-120 minutes to sweep residual debris through the GI tract. Several studies have demonstrated that abnormalities in the MMC may predispose to the development of SIBO.[515-517]  There are a number of conditions that can lead to decreased motility including hypothyroidism, age-related enteric nervous system degeneration, brain injury leading to poor vagal tone, neurodegenerative disease, chronic pancreatitis and chronic diabetes.

Small bowel motility disorders predispose to the development of SIBO simply because bacteria (and any undigested food which the bacteria need to flourish) may not be effectively swept from the small intestine into the colon for elimination. Gastroparesis, a chronic disorder of delayed gastric emptying, can also lead to SIBO due to stasis of food and bacteria in the upper GI tract. Patients with chronic renal failure have neuropathic-like motor abnormalities in the small intestine and are more likely to develop bacterial overgrowth as well.[518] In addition, neuropathic processes, such as chronic intestinal pseudo-obstruction (CIP), and myopathic processes, such as scleroderma and polymyositis, are likely to be associated with SIBO.[519]

SIBO: Underlying Conditions

There are various underlying conditions that can lead to alterations in the amount of gastric acid available to neutralize bacteria or lead to motility disorders via an altered migrating motor complex (MMC) which predispose to bacterial overgrowth. SIBO can also result from anatomical defects leading to bacteria pooling and scarring of intestinal wall from chronic inflammation. Below is a list of some of these conditions that appear to be risk factors for SIBO.

Underlying Conditions that Predispose to SIBO

•Hypochlorhydria: lack of acidity to neutralize bacteria and pH homeostasis of small intestine

•Proton pump inhibitor use for gastric reflux: lack of acidity to neutralize bacteria and pH homeostasis of small intestine

•Hypothyroidism: lack of thyroid hormone activation of vagal motor nuclei and migrating motor complex

•Age-related enteric nervous system degeneration: lack of brainstem vagal motor nuclei to stimulate enteric nervous system

•Brain injury leading to poor vagal tone: lack of brainstem vagal motor nuclei to stimulate enteric nervous system

•Neurodegenerative disease: alpha synuclein or Lewy body infiltration of intestinal migrating motor complex

•Chronic pancreatitis: neuropathic destruction of migrating motor complex from oxidative stress

•Chronic diabetes: neuropathic destruction of migrating motor complex from oxidative stress

•Abdominal anatomical disturbances: anatomical location for bacteria pooling

•Fistula: anatomical location for bacteria pooling•Diverticula: anatomical location for bacteria

pooling•Postsurgical alteration: damage of ileocecal valve

or promotion of anatomical location for bacteria pooling

•Scleroderma: scarring of intestinal wall from chronic inflammation

•Celiac disease: scarring of intestinal wall from chronic inflammation

•Significant immunodeficiency: immunodeficiency to regulate to regulate enteric bacterial populations of small intestine

•Radiation-induced enteropathy: oxidative damage to migrating motor complex of intestines [520]

Hypothyroidism and SIBO

Hypothyroidism is a major risk factor for the development of bacterial overgrowth in the small bowel. Thyroid hormone is critical for normal activity of the enteric motor complex and vagal motor complex that regulate intestinal motility and ileocecal valve control. Low levels of thyroid hormone in the gut leads to decreased thyroid hormone activation of enteric and vagal motor complex and decreased intestinal motility. It also leads to decreased vagal activation of gastric acid production which prevents bacterial overgrowth. In summary, hypothyroidism leads to the following:

•Decreased ileocecal valve control of trafficking bacteria from large intestine to small intestine

•Decreased gut motility leading to bacteriostasis in

small intestine•Decreased vagal activation of HCl release leading

to inability to suppress bacterial growthAll of these dysfunctions lead to SIBO as well as the following conditions:

•Bacterial disruption in the small intestinal lumen•Interference with thyroid medication absorption•Decreased thyroid response on receptor sites

SIBO and Irritable Bowel Syndrome

There is a significant amount of interest in the connection between SIBO and IBS and in particular,

the role of SIBO in the development of IBS. First, many IBS symptoms are nonspecific (bloating, distention, cramping, abdominal discomfort) and can mimic symptoms of SIBO.[521] Delayed transit, disordered motility, or abnormalities in the MMC, all of which can occur in IBS patients, could potentially predispose these patients to SIBO.[522]  

Additionally, studies show a high prevalence of SIBO in IBS patients. In an uncontrolled study, Pimentel and colleagues found that 157 of 202 patients (78%) who met the Rome I criteria for IBS had an abnormal lactulose breath test suggestive of SIBO.[507] A blinded, randomized study found that 84% of patients who met Rome I criteria for IBS had an abnormal lactulose breath test consistent with SIBO, compared to 20% of healthy volunteers,[508] while another group reported a SIBO prevalence rate of 65% in 98 consecutive IBS patients.[523]

Another line of evidence in support of SIBO contributing to IBS is evidence of IBS symptoms improving when treated for bacterial overgrowth. In the above study which showed 78% of IBS patients having SIBO, these patients were then treated with

antibiotics. Of the 47 patients that had follow-up testing after antibiotic treatment, 25 of the 47 subjects (53%) had eradication of their bacterial overgrowth. Those that had the SIBO condition eradicated revealed a statistically significant improvement in IBS symptoms of diarrhea and abdominal pain compared to those that failed to eradicate SIBO. 48% of the patients who eradicated SIBO no longer met criteria for IBS.[507]  The researchers concluded the following:

“Small intestinal bacterial overgrowth is associated with irritable bowel syndrome. Eradication of the overgrowth eliminates irritable bowel syndrome by study criteria in 48% of subjects.”[507]

SIBO, IBS and GERD: Common Pathophysiology?

The overlap of shared symptoms between SIBO and IBS, the high incidence of SIBO in IBS and the high percentage of elimination of IBS in the eradication of SIBO is compelling evidence that SIBO is a contributing factor in a large percentage of IBS patients.[507,487-489] Additionally, research has shown a high incidence of IBS in patients with GERD. A study performed at the GI Motility Center at Cedars-Sinai Medical Center in 2002 found that 71% of GERD patients tested positive for IBS – double the percentage seen in non-GERD patients examined. The researchers concluded:

“There is a higher prevalence of IBS in

subjects with GERD compared with subjects without GERD.”[524]

Based on these findings that most IBS patients have SIBO and most GERD patients have IBS, we would expect to see a high prevalence of SIBO in GERD patients. This is consistent with some of the most recent literature that is starting to examine this connection. In the largest retrospective cohort study done to date, risk factors for SIBO were assessed and correlated with diagnosis of small intestinal bacterial overgrowth (SIBO). Diagnostic testing for SIBO was performed using the D-xylose breath test (XBT). The XBT was performed on 932 patients with symptoms of bloating, abdominal pain, abdominal distension, weight loss, diarrhea, and/or constipation based on a clinical suspicion for SIBO. In the 932 subjects studied, 513 had a positive XBT. Medical records of the 932 patients who completed the XBT were reviewed. The researchers found a significant correlation between a documented history of GERD (P = 0.04) or peptic ulcer disease (PUD) (P ≤ 0.01) and a positive XBT indicating

SIBO.[525] Recall from the previous sections on GERD and peptic ulcer disease (PUD), both of these conditions have been associated with low stomach acid production (hypochlorhydria) which explains the high incidence of SIBO, as this is a known cause of SIBO. The researchers made the following remarks that might explain the results of the study:

“Many of these (SIBO and PUD) patients are placed on lifelong acid suppression therapy, often using high-potency pharmacotherapies (ie: PPIs). A less acidic gastric milieu could create an environment more conducive to SIBO.”[525]

Based on the above studies, it is evident that hypochlorhydria induces SIBO and there appears to be a significant correlation between GERD, IBS and SIBO. Taken together, these data support the theory presented earlier in the Hypochlorhydria section above that hypochlorhydria induces GERD and may

be involved in the pathophysiology of IBS as well.  Which begs the question: Why are acid-suppressing medications, such as PPIs, being used in the treatment of GERD?

SIBO, GERD and the Use of Proton Pump Inhibitors

If hypochlorhydria induces both GERD and SIBO, we would expect to see a higher prevalence of SIBO in GERD patients with increased suppression of stomach acid production by PPI therapy. This is consistent with the current literature on PPI use in GERD patients and risk of SIBO. In one study, two groups of patients with GERD were studied. One group was given omeprazole (PPI) and the other group acted as a control group and were not given omeprazole. 37% of the PPI-treated group of GERD

patients developed SIBO within 3 months compared to 10% of the GERD patients not treated with the PPI.[526] The researchers concluded the following:

“Proton pump inhibitor therapy in patients with GERD results in a high prevalence of gastric bacterial overgrowth. These findings may have implications in the pathophysiology of gastroesophageal mucosal injury.”[526]

Another more recent larger study confirmed the earlier results that the use of PPIs was associated with increased risk of SIBO. In this study, glucose

hydrogen breath tests (GHBTs) were used to assess for SIBO. These GHBTs were given to 450 consecutive patients (200 with gastroesophageal reflux disease (GERD) who received PPIs for an average of 36 months; 200 with irritable bowel syndrome (IBS) with no PPI treatment for at least 3 years; and 50 healthy control subjects that had not received PPIs for at least 10 years).

SIBO was detected in 50% of patients using PPIs, 24.5% of patients with IBS, and 6% of healthy control subjects. There was a statistically significant difference between GERD patients using PPIs and those with IBS or healthy control subjects (P < .001). The prevalence of SIBO increased after 1 year of treatment with PPIs.[527] The researchers concluded the following:

“SIBO, assessed by GHBT, occurs

significantly more frequently among long term PPI users than patients with IBS or control subjects.”[527]

A large meta-analysis conducted in 2013, which reviewed all the studies available showing a correlation between the use of PPIs and risk of SIBO, concluded the following:

“Use of proton pump inhibitors (PPIs) could predispose individuals to small intestinal bacterial overgrowth (SIBO) by altering the intraluminal environment and bacterial flora”[528]

Disruptions to Normal

Physiology Caused by SIBO

Small intestinal bacterial overgrowth causes various disruptions to normal physiology which lead to a wide range of symptoms and signs, such as increased gas formation leading to abdominal distension and bowel irregularity, constipation and diarrhea (as a result of fermentation of undigested food in GI tract); protein deficiency and ammonia production (as a result of excess intestinal bacteria leading to bacterial competition with host for protein); nutrient malabsorption (as a result of enterotoxin production from excess gram-negative intestinal bacteria and damage to brush border mucosa); fat malabsorption (as a result of excess intestinal bacteria metabolizing bile salts to unconjugated or insoluble compounds, leading to impairment of bile salt micelle complex and fat malabsorption);

production of lithocholic acid and enteric nervous system degeneration (as a result of excess bacteria in small intestine metabolizing bile salts to

unconjugated or insoluble compounds); and destruction of intestinal tight junctions, systemic inflammation and destruction of intestinal migrating motor complex (as a result of excess bacteria in small intestine leading to enterotoxin production from gram-negative bacteria and destruction of intestinal tight junctions). Destruction of intestinal tight junctions leads to lipopolysaccharide (LPS) translocation and activation of hepatic macrophages leading to release of hepatotoxic factors and increased systemic and local intestinal inflammation.[520]

Summary of Disruptions to Normal Physiology Caused by SIBO

•Increased gas formation leading to abdominal distension and bowel irregularity, such as constipation and diarrhea (as a result of fermentation of undigested food in GI tract)

•Protein deficiency and ammonia production (as a result of excess intestinal bacteria leading to bacterial competition with host for protein)

•Nutrient malabsorption (as a result of excess enterotoxin production from gram-negative intestinal bacteria and leading to damage to brush border mucosa)

•Fat malabsorption (as a result of excess intestinal bacteria metabolizing bile salts to unconjugated or insoluble compounds, leading to impairment of bile salt micelle complex formation and fat malabsorption)

•Production of lithocholic acid and enteric nervous system degeneration (as a result of excess intestinal bacteria metabolizing bile salts to unconjugated or insoluble compounds)

•Destruction of intestinal tight junctions, systemic inflammation and destruction of intestinal migrating motor complex (as a result of enterotoxin production from excess gram-negative intestinal bacteria and destruction of intestinal tight junctions)

•Destruction of intestinal tight junctions leads to lipopolysaccharide (LPS) translocation and activation of hepatic macrophages leading to release of hepatotoxic factors and increased systemic and local intestinal inflammation

Assessment of SIBO

“The diagnosis of SIBO is controversial. There is substantial disagreement in the literature regarding which test is the most appropriate in either the

clinical or research setting. Two tests are commonly employed: bacterial culture and breath tests.”[505]

Two tests are commonly used to assess for SIBO: bacterial culture and breath tests. The most direct method of assessing the bacterial population of the gut is to perform bacterial colony counts of small bowel contents on aspiration; however, the cost of endoscopy and the invasive nature of this procedure with its low but measurable risk, makes this approach less than ideal. There are also several technical hurdles which make this test impractical in many cases.  First, many bacterial species do not grow in routine culture media, and quantitative culture may underestimate the bacterial population. Additionally, there are multiple problems inherent in performing this procedure including contamination of the endoscope and catheter as the instrument is passed through the GI tract, difficulty aspirating a sufficient sample, and other issues such as proper specimen handing which affects accurate sampling.[505]

For these reasons, hydrogen breath tests are the most common diagnostic tool for SIBO since they are noninvasive, cheap, simple and safe. These tests are based on the measurement of hydrogen and methane in breath samples. These gases are produced by bacteria as a consequence of carbohydrate fermentation after oral ingestion of

glucose and lactulose, and pass through the blood circulation where they are expelled in the lungs. The diagnosis of SIBO is established on the increase of hydrogen and methane gases with respect to the baseline sample. Unfortunately, breath tests have not yet been standardized, in terms of substrate concentration, duration of tests, time intervals of breath sampling and cut-off values.[529] As a result, hydrogen breath tests are still not well-accepted as a specific test for SIBO in the field of gastroenterology.[505] However, hydrogen breath tests remain the most common diagnostic tool for SIBO.

“Although not without shortcomings, hydrogen breath testing provides the simplest non-invasive and widely available diagnostic modality for suspected SIBO.  Diagnostic accuracy of hydrogen breath testing in SIBO can be maximized by careful patient selection for testing, proper test preparation, and standardization of test performance as well as test interpretation.”[530]

Conventional Treatment of SIBO

Conventional treatment aimed at correcting the underlying cause of SIBO primarily includes surgical and drug therapies. Surgical revision of altered small bowel anatomy may be beneficial in patients with SIBO secondary to small bowel diverticulosis, fistulas, or strictures. Medications should be reviewed to determine if they are playing a role in the development of symptoms. Prokinetic drugs (to increase intestinal peristalsis) are used in cases of dysmotility or gastroparesis. The mainstay of conventional treatment for SIBO remains antibiotic therapy. A variety of antibiotics have been used in the treatment of SIBO, most with little supporting evidence. Ideally, antibiotic therapy would be based on bacterial culture and sensitivity data. However, this approach is impractical in the clinical setting and treatment is thus directed at likely organisms based on reports of culture data from SIBO patients.[505] Early antibiotics used in the treatment of SIBO

included tetracycline and its derivatives and other broad-spectrum antibiotics such as amoxicillin/clavulanate, ciprofloxacin, and doxycycline.  However, these recommendations were based on uncontrolled data.[505] More recently, antimicrobials such as Rifaximin and metronidazole have shown efficacy in improving hydrogen breath test results and symptoms of SIBO. [531-533]

The optimal duration of antibiotic therapy is not known, and most trials employed a 7- to 10-day course. However, one of the drawbacks to the use of antibiotics in the treatment of SIBO is recurrence of SIBO and the need for additional courses of antibiotics. In fact, one trial demonstrated an average duration of symptom improvement of only 22 days, which translates into a need for at least 12 courses (presuming 7 days) of antibiotics per year to provide persistent symptom relief.[534]

“Glucose breath test positivity recurrence rate was high after antibiotic treatment”[534]

“Patients with evidence of GBT positivity recurrence showed gastrointestinal symptoms relapse thus suggesting SIBO recurrence.”[535]

“Inadequate or incomplete response to antibiotic therapy is common…”[536]

Clinical Management of SIBO in Functional Medicine

In the functional medicine model, we address the underlying causes that lead to this condition as well as the pathophysiology involved in bacterial overgrowth using botanical and other natural compounds. As we learned earlier, SIBO is prevented by the following physiologic functions:

1. Actions of gastric acid2. Pancreatic enzyme activity3. Small intestinal motility4. Normal activity of the ileocecal valve

Therefore, it is important to assess these bodily functions in the individual and support them when deficient. As discussed earlier, the most common causes of this condition are hypochlorhydria (low stomach acid) and decreased intestinal motility (sluggish bowels).

Hypochlorhydria and pancreatic enzyme deficiency can usually be addressed by supplementing with hydrochloric acid (HCl) and pancreatic enzymes. Discontinuation of PPI therapy in the treatment of GERD is also important in the treatment of SIBO and this can be accomplished by supporting gastric acid levels and pancreatic enzyme levels which as we have seen are at the root cause of both GERD and SIBO. There are a number of factors that can contribute to decreased intestinal motility as

discussed above, such as hypothyroidism and decreased vagal activation, so assessing for these underlying conditions and addressing these causes when present is important. Thyroid hormone levels must be normalized prior to addressing the bacterial overgrowth. Decreased vagal activation can be supported by providing the patient exercises to increase vagal output, such as gargling with water throughout the day and promoting the gag reflex. Coffee enemas can also be used to induce activation of enteric motility and activate the brain-gut axis.[520]

As discussed above, there are a number of physiologic imbalances that take place in SIBO, including increased gas formation leading to abdominal distension and bowel irregularity, constipation and diarrhea, protein deficiency and ammonia production, nutrient malabsorption, fat malabsorption, production of lithocholic acid and enteric nervous system degeneration, destruction of intestinal tight junctions, systemic inflammation and destruction of intestinal migrating motor complex, lipopolysaccharide (LPS) translocation and

activation of hepatic macrophages. All of these conditions should be assessed and supported when indicated. This can be done with herbal/botanical and nutritional compounds shown in the literature to support these physiologic imbalances in most cases. In some cases of severe or chronic SIBO, anti-microbial therapy is indicated.  Nutritional support, particularly in those patients with weight loss or vitamin and mineral deficiencies, is an important component of SIBO treatment. Supplementation and maintenance of vitamin B12 and fat-soluble vitamins, with correction of calcium and magnesium deficiencies, are key components of treatment.

Probiotics and SIBO

Recent studies have shown that patients with bacterial overgrowth conditions can benefit from the use of probiotics although further studies are needed to define the role of probiotic therapy in SIBO. A randomized, double-blind, placebo-controlled study on 22 patients with proven bacterial overgrowth and chronic diarrhea showed

improvement in frequency of symptoms after 15 days and 21 days and the effect was sustained at 7 days and 15 days after withdrawal.[537] The strains used were Lactobacillus casei and L. acidophillus strains (LC). A significant decrease in hydrogen gas concentration was noted in hydrogen breath testing at 7 days (p < 0.005) at 15 days, and 21 days (p < 0.0001) with these probiotics and at 7 days after withdrawal. The researchers concluded the following:

“In summary, this study provides evidence that LC are effective for treatment of bacterial overgrowth–related chronic diarrhea, and suggest that probiotics must be used with continuity.”[537]

In another randomized study of 50 patients with chronic abdominal distension and diagnosis of SIBO made by a lactulose hydrogen breath test, the effects of probiotics were compared to metronidazole, a common antimicrobial medication used to treat SIBO. The probiotic administered to the treatment group contained Lactobacillus casei, Lactobacillus plantarum, Streptococcus faecalis, and Bifidobacterium brevis (Bioflora) for 5 days. The population was divided into two treatment groups of 25 patients in each group. Both groups went on the same diet, which consisted in reduced consumption of alcohol, legumes, dairy products and leafy green vegetables. 13 subjects (52%) receiving metronidazol and 20 (82%) receiving the probiotic showed improvement in symptoms after the treatment. The probiotic group showed a statistically significant difference in symptoms (P = 0.036).[538] The researchers concluded:

“Based on this pilot study results, we can suggest that the probiotic herein used has a higher efficacy than metronidazole in the early clinical response of patients with chronic abdominal distension and SIBO.”[538]

Other studies have shown the following:

“In uncomplicated cases, symptom-free condition could be reached with probiotics, whereas in long lasting,

chronic small intestinal bacterial overgrowth, antibiotic treatment should be considered”[539]

“Decontamination of the small intestine is more successful when probiotics are prescribed (both after antibiotics and independently), which suppress the opportunistic flora, protect the mucous coat, improve digestion and arrest diarrhea”[540]

Dietary Intervention and SIBO

Diet is critical in the bacterial overgrowth patient since many of the overgrowth problems result directly from incomplete carbohydrate digestion and absorption. Some types of carbohydrates such as sugars (fructose, lactose, galactose, etc.), grains (including gluten and gluten-free grains, rice and corn products), dairy (lactose and casein), legumes (galactans) and certain fruits (high-fructose) and vegetables (high-fructan, high starch vegetables) induce bacterial overgrowth. Therefore, eliminating

these foods from the diet is an important part of recovering from bacterial overgrowth. For a more detailed list of the specific-carbohydrate diet (SCD) we recommend, please read the upcoming article on SIBO in part 8 of the Successful Aging series.

More Disorders of the Intestinal Tract coming summer 2015…

Related Articles:

Functions of Gastrointestinal Tract

Gut Connections with Other Organs

The Neuroendocrine System of the Gut and the Brain-Gut Axis