Gut-Brain Axis:
An Exploration
Tony Jelsma, Ph.D.
Professor of Biology
Dordt College
Initial Comments
I am not a practicing clinician
This field is large and rapidly expanding
Difficult to summarize concisely
Interdependence of multiple factors
People are different and so are their guts
I will describe some mechanisms and examples
I don’t know about its applicability to your practice
I believe there is promise but beware the hype
Overview
Anatomy of gut, brain, other relevant structures
Communication between gut and brain
Gut flora:
Types
Effects
Physiological changes involving gut flora
Psychological conditions affected by gut microbes
Feedback, review
Anatomy of the Digestive System
Organs of the Digestive System
Drainage of Blood from the Gut
Most blood drains into the
hepatic portal vein and is
processed by the liver
Rectal area drains into normal
venous circulation
Bypasses the liver
More direct access to brain
https://thoracickey.com/colon-and-rectum/
Four Layers of the Gut
Mucosa: digestion and absorption
Submucosa: blood & lymphatic
vessels, nerves
Muscularis externa: peristalsis
Serosa: thin covering
Mucosa varies with location/function:
Esophagus
Stomach
Small intestine
Large intestine
Cells of the Mucosa Vary with location:
Stomach (St)
Small intestine (SI)
Large intestine (LI)
Cell types:
Secretory cells (St)
Absorptive cells (SI, LI)
Mucous cells (St, SI, LI)
Enteroendocrine cells (St, SI, LI)
Stem cells (St, SI, LI)
Mucosa of Small Intestine
Function primarily in nutrient absorption
Organized in villi
Surface is mostly absorptive cells
Goblet cells produce mucus
Enteroendocrine cells at base secrete
hormones
Capillaries, lacteals underlay the epithelium
Many immune cells monitor intestinal
contents
Few bacteria
https://library.med.utah.edu/WebPath/GIHTML/GI162.html
Mucosa of Large Intestine
No villi, just crypts
Primarily absorptive cells and mucous cells
Recovery of water and electrolytes
Many bacteria (1012/g) in colon
How are we protected from its contents?
How do they benefit us?http://www.histology-world.com/factsheets/largeintestine.htm
Protection from Intestinal Contents
Mucus layer secreted by cells
Antimicrobial substances (in small intestine)
Antibodies secreted into intestine
Tight junctions prevent leaking between cells
Many immune cells in submucosa
M cells allow immune cells to monitor intestinal contents
Peyer’s Patches contain immune cells
Function in immune response
Found in small and large intestine
Cells proliferate to fight infections
Intestinal epithelia are tightly joined to
prevent leaking
How do immune cells monitor and attack
intestinal contents?
Microfold (M) Cells Monitor Gut Contents
Intestinal cells are linked by tight junctions
Prevents leaking between cells
M Cells are cup-shaped cells covering
Peyer’s patches
Intestinal samples are presented to immune
cells underneath
Dendritic cells pick up foreign antigens and
activate immune system
Summary of Gut Functions
Digestion and absorption of nutrients
Production of hormones to regulate digestion and
overall physiology, including neural physiology
Interactions with gut bacteria:
Monitor gut contents
Induce inflammation when necessary
Attack potential pathogens
Absorb nutrients produced by bacteria
Respond to metabolites produced by bacteria
Anatomy of the Nervous System
Brain Anatomy - Cerebrum
Carries out conscious brain functions:
Receives conscious sensory
information
Interprets sensory information
Decides on response
Sends out response signals
Brain Anatomy - Hypothalamus
Cerebrum, conscious brain functions
Hypothalamus, subconscious controls
Regulates autonomic nervous system
Mediates hormonal stress response
Regulates many hormone systems via pituitary
Regulates body temperature, hunger, thirst, …
Brain Anatomy – Limbic System
Cerebrum, conscious brain functions
Hypothalamus, subconscious controls
Limbic system, emotions
Motivated behaviors
Fear
Long term memory
Blood-brain barrier usually protects brain but is absent in some locations
Hypothalamus-Pituitary-
Adrenal (HPA) Axis
Mediates stress response
Regulated by negative
feedback
Glucocorticoid (cortisol)
mediate stress response:
Suppresses inflammation
Alters energy metabolism
http://goldfunctionalwellness.com/the-connection-between-oral-health-gut-health-and-overall-health/
Communication between Gut and
Brain
How does the Gut Communicate with the
Brain? Endocrine:
Hormones are secreted by enteroendocrine cells,
travel through the blood to the brain
Neural:
Sensory neurons in the gut signal to the brain
Metabolic:
Gut microbes produce metabolites that cross the
intestinal wall and enter the bloodstream
Immune:
Gut inflammatory signals travel to the brain
Enteroendocrine Signaling to the Brain
Intestinal hormone production is altered in response to food
At least 18 hormones, including:
Cholecystokinin (CCK) induces satiety, increases anxiety
Ghrelin stimulates appetite
Peptide YY suppresses appetite
Glucagon-like peptide 1 promotes satiety
Hormones act on prefrontal cortex, amygdala, insula, and
hypothalamus to regulate appetite/satiety
These actions are affected by bacterial metabolites
Enteric Nervous System
500 million neurons, from esophagus to anus
Afferent and efferent
Many neurotransmitters, 90% of serotonin, 50%
of dopamine in the body is enteric
Receives sympathetic and parasympathetic
inputs
Parasympathetic (vagus nerve) stimulates
digestion
Motility
Secretion
Sympathetic inhibits digestion
https://www.nature.com/articles/nrgastro.2016.107.pdf
Enteric Nervous System
Many afferent (sensory) projections to CNS
80% of vagus nerve is afferent
Can operate independently of the CNS
Sensory neurons and interneurons reflexively
respond to stimuli in gut (food), inducing:
Secretion to stimulate digestion
Vasodilation for nutrient uptake
Peristalsis for movement
https://www.nature.com/articles/nrgastro.2016.107.pdf
Enterochromaffin Cells Activate Neurons
Subset (majority) of enteroendocrine cells
In small intestine (duodenum)
Sense contents of intestine by odorant receptors
Respond by secreting 5-HT (serotonin)
Serotonin stimulates gut motility
Affects weight gain and satiety
This activity is altered by spore-forming bacteria and
high fat diet (Besnard, 2012; Primeaux et al., 2013)
Enteroendocrine cells also directly
connect to brainstem
Enteroendocrine cells also
form synapses with vagal
afferent neurons
Faster communication
than via hormones
Kaelberer 2018
Is there a
Gut-Feet
Axis?
Summary of Neural/Hormonal Activity
Enteroendocrine cells respond to gut contents, secrete
hormones to regulate physiology
Enterochromaffin cells respond to gut contents, activate
enteric nervous system
Enteric nervous system also regulates gut activity
Gut MicrobiomeEffects on the body
Regulation of microbiome
Tools (Rodents and Humans)
Germ-free mice
Fecal microbiota transplantation
Antibiotic treatment
Probiotics (bacteria in food)
Prebiotics (food favorable to particular bacteria)
Cutting vagus nerve blocks afferent and efferent neural communication with brain
Genome sequencing to characterize bacteria
Other molecular analytical methods
Microbes in the Gut
Outnumber total human cells 2:1
Composition is reasonably stable but affected by diet
Bacteroidetes
Firmicutes, related to diabetes, obesity
Increased in high fat diet
Produce short-chain fatty acids to supply calories to
host
Increases gut permeability and inflammation
Other minor phyla
Some yeast
How do gut microbes affect our
physiology?
Proportions change with BMI
a: BMI < 18.5
b: BMI 18.5-24.9
c: BMI 25-29.9
d: BMI > 30
Bacteroidetes
decrease
Firmicutes increase
Correlation or
causation?
Effects of Bacterial Metabolites
Digestion of dietary fiber produces short chain fatty
acids (SCFAs) and other metabolites
These can enter the bloodstream and provide energy
SCFAs promote obesity by activating parasympathetic
activity via gut hormones
Gut microbes affect tryptophan metabolism
Gut Permeability, or “Leaky” Gut
Bacterial and viral pathogens compromise
tight junctions
Intestinal contents pass between cells
Associated with inflammatory diseases
Other factors also affect gut leakiness
By BallenaBlanca - Own work, CC BY-SA 4.0,
https://commons.wikimedia.org/w/index.php?curid=48122216
Psychological Effects of Gut Dysfunction
Stress
Depression
Cognition
Autism
Parkinson’s Disease
We will look at animal and human studies
Tryptophan metabolism
Tryptophan is an amino acid
Dietary uptake is for proteins and a variety of metabolites
1-2% is converted to serotonin and melatonin
Germ-free male mice have higher levels of serotonin in the
hippocampus, along with an increased stress response
(Clarke 2013)
The opposite effect was seen in the colon (Yano 2015)
Gut Microbiome and Stress
Gut Microbiome and Stress in Mice
Chronic treatment with a
Lactobacillus strain (Bravo et al.,
2011).
Reduced corticosterone and
anxiety- and depression-related
behavior
i.e. involved the HPA axis
Altered GABA receptor levels
consistent with antidepressant
effects
Effects required the vagus nerve
Effects were strain-dependent
Gut Microbiome and Stress
Corticotropin-releasing factor (CRH) from hypothalamus
activates ACTH release from pituitary in response to stress
But – CRH also increases intestinal permeability and
activates inflammation (Overman et al., 2012, pig study)
Gut Microbiome and Stress in Humans
Acute stress (public speaking) increased CRH and
intestinal permeability (Vanuytsel et al., 2014)
Cold pain stress increases intestinal permeability (in
women only, Alonso et al., 2012)
Maternal prenatal stress altered the gut microbiome of
infants and resulted in more GI symptoms (Zijlmans et al.,
2015)
Gut Microbiome and
Depression
Effects of Gut Microbiome on
Depression - Mouse
Diet-induced obesity in mice induces stress and anxiety
This is associated with decreased insulin signaling and
increased inflammation in brain
Effects are dependent on gut microbiota, can be
transferred to germ-free mice (Soto 2018)
This suggests that the gut microbiome can contribute to
obesity
Effects of Gut Microbiome on
Depression - Human
Increased co-morbidity of psychiatric disorders and
irritable bowel syndrome (Singh et al., 2012)
Marital distress and depression work in tandem to
increase gut permeability and inflammation (Kiecolt-
Glaser, 2018)
Gut Microbiome and Cognition
Cognition – Mice
Long-term administration of a Lactobacillus strain
reduced cognitive decline in a senescence-
accelerated mouse model (Corpuz, 2018)
Behavioral effects
Gene expression changes in hippocampus and
cortex
Cognition - Human
Western diet impairs hippocampal-dependent learning
and memory (Noble 2017)
Altered gut permeability
Altered blood-brain barrier integrity
Autism and the Gut
Autism and the Gut
Autism is frequently associated with GI disturbances
Some genetic variants are associated with both ASD
and gut development/function
Could a leaky gut cause or exacerbate ASD features?
Mouse model of inducible autism
Inject a viral mimetic around E12, induces inflammation
Autism features: vocalizations, sociability,
repetitive/stereotyped behavior
Susceptibility regulated by gut microbiota of the mother
Caused by segmental filamentous bacteria
Reside in ileum, not colon
Mediated by inflammatory signal IL-17a
Could be neutralized
Thus, prenatal inflammation may be associated with the
development of autism (Hsiao 2013)
Ivanov et al., 2009 Cell 139:485
Mouse model of inducible autism
Probiotic treatment
(Bacteroides fragilis) reverses
the process
Hsiao et al., 2013, Cell 155:1451
Autism and the Gut – Human
Autism and prenatal conditions:
Premature birth is associated with higher rates of autism
In utero inflammation is a contributing factor
Gut-blood-brain barrier is compromised
Brain inflammation contributes to autism (Angelidou
2012)
Autism and the Gut - Human
Excessive production of bacterial metabolites (SCFAs)
may be linked to autism (MacFabe 2012)
Injection of SCFAs into rat ventricles induces autism-like
behaviors and neurochemical changes
Some humans are partial metabolizers of SCFAs, resulting
in accumulation
Parkinson’s Disease and the Gut
Parkinson’s Disease
Mulak and Bonaz, 2015
GI dysfunction in 80% of PD patients, including
constipation, nausea, defecatory dysfunction
Alpha-synucleinopathy affects all levels of the brain-gut
axis
Triggers inflammation in the colon, increases gut
permeability
Bacterial overgrowth in small intestine is common (>50%)
Now for something different…
Ketogenic diet (KD, low carbs)
Used for rapid weight loss
Extra fat breakdown leads to ketone body accumulation
Also used to control refractory epilepsy
Gut microbiota are necessary and sufficient for these
effects in a mouse model (Olson et al., 2018)
Ketogenic diet increases proportion of certain bacteria
These bacteria mediate the effects of KD
Summary of Effects of Gut Microbes
“Good” and “bad” microbes in colon, affected by diet
Good microbes provide beneficial metabolites
Inflammation allows harmful substances to enter the
blood, crosses blood-brain barrier
Enteric nervous system effects
Vagus nerve
Too many microbes in small intestine can be harmful
Summary
There is an Interplay of Multiple Factors
Diet, probiotics
Gut microbiome composition
Gut permeability
Inflammation
Stress, HPA axis, cortisol
Vagus nerve
Caveats to all of this
Research is in its early stages
Much research has been done in rodents, not humans
Human studies are much more complex, effects may be
more subtle
Need to tease out generalized benefits vs. effects on
specific deficits
How important is a “normal” diet?
Many different types of bacteria, hard to generalize
Understanding mechanisms is difficult
Be careful of publication bias
Two Recent Studies Urge Caution
Microbiome regeneration after antibiotic use is delayed
by probiotics in humans (Suez 2018)
Autologous fecal transplants may be more effective
Gut microbiomes are individualized, one-size-fits-all
probiotics may not be effective
Microbes in stool samples may not accurately reflect
those acting on the gut (Zmora 2018)
Mucus layer has a distinct microbiome
Probiotics do not colonize this mucus layer very well
Are Probiotics Ready for Treatments?
Not yet
We are individuals and have individual gut microbiomes
We don’t know the right microbes to use for a particular
situation
We don’t understand how the various microbes work
What dosages and frequencies are effective and not
harmful?
More work needs to be done
Thank you for your attentionAny questions?