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Copyright © 2012 John Wiley & Sons, Ltd.

Title: Probiotics as the potential biotherapeutics in the management of Type 2 Diabetes –

Prospects and Perspectives

Authors: Harsh Panwar*, Hogarehalli Mallappa Rashmi*, Virender Kumar Batish and Sunita

Grover

Molecular Biology Unit, Dairy Microbiology Division, National Dairy Research Institute,

Karnal - 132001, Haryana, INDIA

Correspondence:

Sunita Grover, Ph.D

Principal Scientist,

Molecular Biology Unit, Dairy Microbiology Division,

National Dairy Research Institute, Karnal -132001, Haryana, India.

E-mail: [email protected],

Tel No.:+91-184-2259100, Fax: +91-184-2250042

*First and second authors contributed equally

Abbreviations:T2D, Type 2 Diabetes; CVD, Cardio Vascular Diseases; GLP-1, Glucagon Like Peptide-1; HFD, High Fat Diet; NF-kB, Nuclear Factor kappa-B; LPS, Lipopolysaccharides; NGF, Nerve growth factor; TNF-α, Tumour Necrosis Factor-α; NIDDM , Non-insulin Dependent Diabetes Mellitus” NOD, Non-obese Diabetic; STZ, Streptozotocin, DCs, Dendritic cells; NK, Natural Killer.

Running Title: Probiotics for diabetes management

This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1002/dmrr.2376

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Abstract:

Diabetes Mellitus is a looming epidemic worldwide, affecting almost all the major sections of

the society causing burden on global health and economy. A large number of studies have

identified a series of multiple risk factors such as genetic predisposition, epigenetic changes,

unhealthy life style, altered gut microbiota that causes increased adiposity, β cell dysfunction,

hyperglycemia, hypercholesterolemia, adiposity, dyslipidaemia, metabolic endotoxemia,

systemic inflammation, intestina l permeability (leaky gut), defective incretins secretion,

oxidative stress associated with T2D as a multifactorial disorder. Recent studies have

proposed multi-factorial interventions including dietary manipulation in the management of

T2D and are also recommended by many national and international diabetes associations.

These studies are aimed at deciphering the Gut microbial influence on health and disease.

Interestingly, results from several genomic, metagenomic and metabolomic studies have

provided substantial information to target gut microbiota by dietary interventions for the

management of T2D. Probiotics particularly lactobacilli and bifidobacteria have recently

emerged as the prospective biotherapeutics with proven efficacy demonstrated in various in

vitro and in vivo animal models adequately supported with their established multifunctional

roles and mechanism of action for the prevention and disease treatment. The dietary

interventions in conjunction with probiotics - a novel multifactorial strategy to abrogate

progression and development of diabetes holds considerable promise through improving the

altered gut microbial composition and by targeting all the possible risk factors. This review

will highlight the new developments in probiotic interventions and future prospects for

exploring probiotic therapy in the prevention and control of life style diseases like T2D.

Key Words: Type 2 diabetes, Multifactorial approach, Gut Microbiota, Probiotics

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Introduction:

Over the past two decades, “Type 2 diabetes” (T2D) has become truly a larger

public health issue with significant socio-economic burden on global health. The prevalence

of type 2 diabetes continues to increase worldwide and by 2030, the number of people with

type 2 diabetes is expected to reach 552 million [1]. Numerous patho-physiological studies

identified several risk factors of type 2 diabetes, a multifactorial disorder caused by genetic,

epigenetic, environmental and life style related factors resulting in development of

pathophysiological manifestations such as β cell dysfunction, hyperglycemia,

hypercholesterolemia, adiposity, dyslipidaemia, metabolic endotoxemia, systemic

inflammation, intestinal permeability, defective incretin secretion, ectopic fat storage and

oxidative stress in the development of T2D [2,3] (Fig. 1). As a multifactorial disorder,

T2D calls for a multifactorial treatment approach targeting multiple risk factors. Yet, less

efforts have been made on integrated approaches targeting multiple risk factors.

The normal commensal gut microflora by and large is stably maintained in individuals

and represent their distinct microbial fingerprints for optimal gut functionality. However, any

disturbance in the structure, composition and proportion of the normal gut microbiota is

indicative of some breach in the individual’s health status due to changes in the life style,

food habits, exposure to stress (hostile environmental conditions, indiscriminate use of

drugs), genetic predisposition and aberration in the immunity etc. resulting into onset of some

medical conditions. Under these situations, restoring the disturbed gut microflora back to

normal by applying innovative dietary strategies seems to be the viable proposition to reduce

the severity of these medical conditions. In this context, probiotic interventions in the form of

novel food formulations enriched with proven strains of probiotics could be very effective

dietary strategy to manage chronic intestinal diseases and life style metabolic inflammatory

disorders like T2D, obesity and “Cardio Vascular Diseases” (CVD) etc. Probiotics are the

“live micro-organisms which when administered in adequate amounts confer a specific health

benefit on the host” [4]. They are currently the major focus of attention across the world due

to their enormous health promoting functions which are highly strain specific. Lactobacilli

and Bifidobacteria - the two key members of this group used extensively in the development

of novel functional and health foods and other formulations, are now being explored as

biotherapeutics in the management of several diseases. The efficacy of probiotic strains and

their formulations against several gut related diseases such as diarrhoea, ulcerative colitis

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(UC), peptic ulcers, Inflammatory Bowel Diseases (IBD), Inflammatory Bowel Syndrome

(IBS), Crohn’s Disease (CD), Colon cancer, atopic dermatitis and topical allergies etc. has

been thoroughly investigated and well documented and proven through well designed in

vitro, in vivo and human clinical trials [5]. However, the prospects of probiotic therapy in the

management of life style diseases particularly T2D, obesity and CVD have not been explored

fully as yet. There are only a handful of studies initiated in this regard that too with mixed

responses. Nonetheless, some recent studies clearly point towards the antidiabetic prospects

of probiotic based interventions, thereby, leaving ample scope to pursue more indepth studies

to reach some consensus on the efficacy and effectiveness of probiotic therapy in T2D. This

review is specifically aimed to showcase the status of recent developments in probiotic

research and leads that emerged from the outcome of various studies on probiotic

interventions against life style diseases particularly with regard to T2D and future strategies

to be initiated on these lines.

Diabetes Mellitus: The silent killer

Diabetes Mellitus, the looming epidemic of the 21st century poses major threat to

global health and economic development. The recent study by International Diabetes

Federation has provided the global map on diabetes after analyzing 170 appropriate data

sources from 110 countries for 2011 and 2030 [1]. As per this study, the current figure of 366

million people with diabetes recorded in 2011 is expected to rise to 552 million by 2030. This

increasing trend in diabetic population is being witnessed in almost every country and more

than 70% of people with diabetes live in low and middle-income countries. Amongst the

middle income countries, the prevalence of diabetes is higher in upper middle-income

countries (10.1%) than in lower middle-income countries (8.6%) driven by an increase in the

adult population, urbanization and economic development. China and India have emerged as

the leading countries afflicted with diabetes. T2D is the most common form of diabetes and

accounts for almost 90% of all diabetes in high-income group and may account for an even

higher percentage in low and middle-income countries and put a huge burden on healthcare

agencies and governments [6,7]

Both type 1 and T2D are closely linked to CVD - the main cause of death in people

with diabetes. The mortality rate of diabetes varies sharply with the prosperity of the country.

In 2011, the disease caused more than 3.5 million deaths in middle-income countries, of

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which more than 1 million were in China and just less than a million were in India.

Approximately 1.2 adults die of a diabetes-associated illness per 1,000 cases in 2011 in low-

and middle-income countries.

Keeping in view the alarming increase in the incidence and prevalence of diabetics in

India, the World Health Organization has declared India as the Diabetic Capital of the World

[8]. Indians (40-59 yrs age groups) are particularly prone to diabetes due to several

environmental factors viz. psychological stress, socio-economic status, life style changes,

acquired obesity along with their genetic and phenotypic architecture and poor immunity. As

a result of alarming socio-economic impact of this disease and its other related health

implications on a vast majority of Indian population, diabetes has now become a major

challenge from the Indian perspective and requires immediate attention for taking appropriate

measures immediately for its eradication at National level on priority before it becomes a

catastrophe beyond control.

Type 2 diabetes: A Multifactorial catastrophe

As mentioned above, T2D is a polygenic disorder. Advances in genetic epidemiology

have increased our understanding of T2D. The recent developments in genome-wide

association studies (GWAS) in many thousands of samples from different populations and

meta-analyses across many studies have identified genes responsible for T2D susceptibility.

A recent large and comprehensive analysis of 50,000 genetic variants across 2,000 genes

linked to cardiovascular and metabolic function has identified the related genes and genetic

variants associated with T2D among multiple ethnic groups [9]. This decoding of genetic

background of T2D serves multiple goals ranging from expanding our knowledge on the

disease pathogenesis and identifying future targets for personalized drug development.

In addition to genetic predisposition, environmental and lifestyle factors also

contribute to the pathogenesis of T2D. Epigenetic changes may provide the link for

translating environmental exposures into pathological mechanisms. Studies from the last five

years explored the epigenetic mechanisms in the development of T2D. The recent

comprehensive DNA methylation profiling of pancreatic islets from T2D uncovered 276

CpG loci affiliated to promoters of 254 genes displaying significant differential DNA

methylation in diabetic islets [10].

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Like genetic and epigenetic changes, gut microbiota is also considered as one of the

most important environmental factor in the development and management of T2D by

impacting host physiology and metabolism.

Gut microbiota and Diabetes

The gut microbiota is now virtually recognised as a complex whole organ consisting

of incredible amount of at least 1014 bacteria of thousands of species. The collective genome

of the entire gut micorbiota designated as ‘microbiome’ exceeds the human nuclear genome

by at least 100 times [11]. Over the last five years, an intense research effort has been made

to understand the crucial role of gut microbiota in health and disease by various metagenomic

and metabolomic studies using with high-throughput sequencing technologies, mass and

nuclear magnetic resonance (NMR) spectroscopy that enabled in-depth analysis of gut

microbial compositional changes, structural elements and metabolites in host physiology and

metabolism under different conditions [12,13,14]. Gut microbiota has also been reported to

play a pivotal role in pathogenesis of T2D, obesity and related inflammatory metabolic

disorders. Accumulating evidence supports the new hypothesis that metabolic diseases like

obesity and T2D develop due to low grade, systemic and chronic inflammation by disruption

of the normal gut microflora induced by dietary intake of high fat and fructose diet. In this

context, nutrition can play a significant role in directly modulating our microbiomes and

health phenotypes. Poorly balanced diets can shift the gut microbiome from healthy

microflora towards unhealthy ones with the predominance of pathogenic microflora in

chronic disease [15]. Hence, the microbiome data of human gut under different conditions

could serve as the important resource material for exploring customized novel dietary based

strategies in the management of specific gut related diseases.

The gut microbiota of human adults with T2D studied by high-throughput, tag-

encoded amplicon pyrosequencing of the V4 region of the 16S rRNA gene showed

decreased proportions of phylum Firmicutes and Clostridia, increased proportions of

Betaproteobacteria and increased ratios of Bacteroidetes to Firmicutes and Bacteroides-

Prevotellagroup to C. coccoides - E. rectale group in correlation with plasma glucose

concentration [16] (Fig. 2.) In addition, numerous metagenomic studies also investigated the

gut microbial changes in obesity - the main precursor in the development of T2D in various

animal and human studies [17]. In these human studies, the gut microbiota showed variable

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profiles where bacteroidetes-related taxa have been reported to increase, remain neutral or

decrease after weight loss [18,19,20].

Interestingly, the recent studies have revealed the compositional changes in the group

of bifidobacteria and lactobacilli during the onset of insulin resistance in “High Fat Diet”

(HFD) mice. The gut microbial profile of these studies recorded reductions in

Bifidobacterium spp. and Lactobacillus spp. with increased plasma “Lipopolysaccharides”

(LPS) that caused metabolic endotoxemia via NF-κB “Nuclear Factor kappa B” activation on

the molecular onset of Insulin resistance [21,22]. In addition, relationship among gut

microbial changes, gut permeability and metabolic endotoxemia was also studied in HFD

mice which revealed reduced proportions of lactobacilli in gut microbial profile, reduced

transepithelial resistance and increased metabolic edotoxemia in HFD mice [23].

Currently, lot of attention is duly being paid to elucidate the role of gut microbiota in

energy homeostasis through microbe-gut-brain axis. Changes in gut microbiota that sends

altered enteroendocrine signals through the secretion of gut hormones to the Central Neroous

System (CNS) have been reported by several investigators. The gut hormones such as GIP

(Glucose Dependent Insulinotropic Peptide), GLP-1 “Glucagon Like Peptide -1”, GLP-2

(Glucagon Like Peptide -2), PYY that regulates energy homeostasis through insulinotropic,

satietogenic properties that affect β-cell mass and function, energy intake, nutrients

absorption and energy storage, insulin secretion have been investigated in relation to food

intake. In this context, recent studies proposed prebiotics as a safe and cost-effective dietary

strategies for modulating the gut microbiota to promote improved host:bacterial interactions

in obesity and insulin resistance [24,25,26].

Furthermore, the role of gut microbial metabolites in glucose homeostasis is of

considerable research interest in the field of metabolomics. In this context, the role of gut

microbial metabolites such as Short Chain Fatty Acides (SCFA) in the down regulation of

inflammatory markers and upregulation of gut hormone secretion via FFAR2 (Free Fatty

Acid Receptor 2) activation were studied in relation to glucose homeostasis [27,28]. Other

gut flora associated metabolites such as hippuric acid, methylxanthine, methyluria acid and 3-

hydroxyhippuric acid were reduced considerably in individuals with impaired glucose

tolerance. In this study, UPLC-qTOF-MS approach was established and validated by

metabonomic analysis of clinical samples like serum and urine [29,30]. These metabonomic

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studies further supported the role of gut microflora in pathogenesis of diabetic and pre-

diabetic states. Gut microbiota associated metabolite biomarkers were decreased in urine

samples of individuals with impaired glucose tolerance indicating important role of gut

microbiota in energy metabolism and immune function of host [31].

In another study that included 40 diabetic and 60 control individuals, diabetic

individuals could be differentiated from healthy individuals on the basis of presence of

secondary metabolites of bile acids - the products of gut microflora in diabetic individuals.

Cholate was more frequently detected in control or healthy individuals while its secondary

product, deoxycholate was found to be more prominent in diabetic group. The outcome of the

study clearly indicated alterations in bile acid pool and their biosynthetic pathway in diabetic

patients and ascribed the same to the role of altered gut microflora as a result of higher rate of

conversion of primary bile acids to secondary bile acids [32].

Hence, the data that emerged from various studies by different investigators have

provided sufficient evidence that modulating the gut microbiota through dietary interventions

may contribute in the prevention and control of inflammatory metabolic disorders including

T2D and obesity etc.

Probiotics as multifactorial biotherapeutics

Probiotics are currently the subject of intensive investigation as the prospective

natural biotherapeutics due to their enormous health promoting potentials and inbuilt ability

to fight specific diseases including metabolic syndrome such as T2D. Since, many of the

novel multifactorial physiological functions of putative probiotics are highly strain specific,

judicious pre selection of appropriate probiotic strains based on the expression of functional

biomarkers associated for a particular medical condition is extremely crucial to demonstrate

their functional efficacy. The interest and scope for taking new R&D initiatives on probiotics

to fully explore their biotherapeutic potentials in the management of T2D and other life style

diseases have dramatically increased across the world over the recent years. The antidiabetic

efficacy of probiotics and probiotic preparations has been investigated in different

independent studies in established in vitro cell lines and animal models and validated by

double blind placebo controlled randomized clinical trials in target human population with

mixed responses. The major significant findings of these studies on exploring the efficacy of

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probiotics in the management of T2D both under in vitro and in vivo conditions are briefly

reviewed below.

Probiotic efficacy in in-vitro cell line models

The multigenic approach of using probiotics as biotherapeutics in the management of

type T2D has been evaluated in various cell line models for their hypoglycemic, anti-

inflammatory, antioxidative, insulinotropic and satietogenic effects (Fig. 3.). In one of the

studies carried out by Ma et al., 2004, the human colonic adenocarcinoma T84 and HT29

were challenged with live and killed Lactobacillus reuteri cells and the expression of “Nerve

growth factor” (NGF) and anti-inflammatory molecules were analysed. The live probiotic

bacterial cells were able to upregulate the expression of NGF, inhibited the cellular

accumulation and secretion of IL-8 induced by “Tumour Necrosis Factor-α” (TNF-α).

However, expression of IL-10 remained unaffected in both T84 and HT29 cells [33]. In

another study, HeLa cell line was explored as a model to investigate the activation of NF-kB

signalling in the pregression of inflammation [34]. In this study, preincubation of the HeLa

cells with live Lactobacillus reuteri cells for 1-2 hrs prevented translocation of NF-kB to the

nucleus, inhibited degradation of IkB, prevented expression of various pro-inflammatory

cytokines under NF-kB regulation. In a previous study, Neish et al., 2000 [35], reported that

heat inactivated and conditioned culture media lacked this NF-kB attenuating activity,

indicating that bacterial-epithelial cell contact was required to bring about the positive effect.

Since, gut hormones play an important role in glucose and energy homeostasis

through their insulinotropic and satietogenic mechanisms, the insulinotropic effect of

genetically engineered Escherichia coli Nissle 1917 for GLP-1 and transcriptional activator

PDX-1 secretion was examined in Caco-2 cell line. The cell free culture supernatant of

engineered strain stimulated the epithelial cells and caused the secretion of insulin

corresponding to blood insulin concentration of 164 pmol/ml to 164 nmol/ml respectively for

106 to 109 cfu/ml survivability of engineered strain under unoptimized conditions. They

reported that optimized conditions may further improve the ability of engineered strain to

increase insulin secretion to the magnitude as would be required for normal metabolism [36].

Furthermore, in a recent study conducted by Paszti-Gere et al. [37], it was reported

that oxidative stress that imposed damage to insulin-secreting ß-cells was prevented by

metabolites of Lactobacillus plantarum 2142. In this study, the spent culture supernatant

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(SCS) of Lactobacillus plantarum 2142 lowered the oxidative stress-induced overexpression

of proinflammatory cytokines IL-8 and TNF-α in IPEC-J2 cell line.

Probiotic efficacy in animal models

Different animal models have been extensively explored to study the multiple

mechanisms of probiotics in the management of diabetes. Initially, antidiabetic effects of oral

administration or diet supplementation of heat killed Lactobacillus casei were studied in three

different mice models such as : 1) “non-insulin-dependent diabetes mellitus” (NIDDM ) mice

model using KK-Ay mice 2) insulin-dependent diabetes mellitus model i.e NOD “Non-obese

diabetic mice” 3) Alloxan-induced diabetes in mice. In all these studies, the oral

administration (0.05%) or diet supplementation (0.1%) of heat killed cell of Lactobacillus

casei reduced the plasma glucose level and occurrence of diabetes [38,39,40].

In another study, using neonatal STZ “streptozotocin”-induced diabetic (n-STZ) rats,

feeding of diet containing Lactobacillus rhamnosus GG for a period of 9 weeks (from the age

of 9 weeks to 18 weeks) lowered the blood hemoglobin level and improved glucose

tolerance in comparison to control group fed with common diet. In the Lactobacillus

rhamnosus GG treatment group, the serum insulin level at 30 min after glucose loading was

significantly higher than in the control group (p<0.05) [41]. Working on similar lines,

Calcinaro et al. [42] reported that the feeding of VSL#3 decreased β-cell destruction and

inflammation in NOD mice. This prevention was associated with increased IL-10 secretion in

pancreas, Peyer’s patches and spleen that improved inflammation and prevented β cell

destruction in the treated group.

In a different study, the feeding of probiotic dahi containing 108 cfu/g of

Lactobacillus acidophilus NCDC14 and Lactobacillus casei NCDC19 significantly decreased

the blood glucose and glycosylated hemoglobin, free fatty acids and trigycerides in fructose-

induced diabetic rats [43]. The feeding of the same probiotic dahi to the STZ-induced rats

significantly suppressed STZ-induced oxidative damage in pancreatic tissues by inhibiting

the lipid peroxidation, formation of nitric oxide and improved the antioxidant potential

glutathione, superoxide dismutase, catalase and glutathione peroxidase. These results suggest

that the oral administration of probiotic dahi improved the risk factors such as hyperglycemia,

dyslipidemia and oxidative stress in diabetic rats [44]. Similarly, in a parallel study, it was

revealed that probiotic pre-treatment with a mixture of Lactobacillus acidophilus,

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Bifidobacterium lactis and Lactobacillus rhamnosus reduced the blood glucose and improved

the bioavailability of gliclazide, a second generation sulphonylurea used to treat non-insulin

dependent diabetes mellitus in alloxan induced diabetic rats [45].

Probiotics have also been reported to exert their antidiabetic effects against insulin

resistance by increasing liver ”Natural Killer” T (NKT ) cells. Liver is the principal target

organ responsible for inflammation mediated insulin resistance, where inflammation is

regulated through NKT cells by balancing the production of pro-inflammatory and anti-

inflammatory cytokines. Depletion of NKT cells in liver led to over production of pro-

inflammatory cytokines and HFD is known to induce depletion of hepatic NKT cells

resulting into development of insulin resistance. However, HFD induced depletion of NKT

cells in male wild type C57BBL-6 mice was found to be significantly improved on oral

administration of VSL#3 probiotic preparation for 4 weeks after mice had been on HFD for 8

weeks. This probiotic treatment also reduced the weight, improved insulin resistance and

inflammation by modulating TNF- α expression and reducing NF-kB binding activity [46].

In two subsequent studies carried out at the same time, the probiotic treatment with L.

plantarum DSM 15313 and Lactobacillus reuteri GMNL-263 was found to lower the blood

glucose and glycosylated hemoglobin respectively in HFD C57BL/6J mice and STZ-induced

diabetic rats [47,48]

Differential stimulation of dendritic cells by probiotics has been the subject of

intensive discussion to understand the exact mechanism involved in conferring the

therapeutic effect of probiotics against T2D. In this context, “dendritic cells” (DCs) from

NOD were stimulated with three different strains of lactobacilli including Lactobacillus

casei, Lactobacillus reuterii and Lactobacillus plantarum for 24hrs. Out of the three strains

tested, Lactobacillus casei was found to induce DCs to produce highest level of IL-10 and

lowest level of IL-12 expression. When the Lactobacillus casei stimulated dendritic cells

were transferred again to NOD mice, they demonstrated a significant delay in diabetes

incidence [49]. In a related study, Bifidobacterium longum CGMCC

NO.2107 supplementation in HFD was reported to reduce the metabolic endotoxin (LPS)

concentrations of plasma, improved intestinal inflammation and increased expression of

intestinal Reg I as a regulatory growth factor in a HFD rats [50]

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Interestingly, a recent study by Amar et al. [51] investigated the effect of probiotic

treatment on mucosal dysbiosis, bacterial translocation and glucose metabolism using various

mouse models. The results showed that, increased bacterial translocation was prevented in

mice lacking the microbial pattern recognition receptors Nod1 or CD14. However, it was

increased in Myd88 knockout and ob/ob mouse under the same conditions. The probiotic

treatment with Bifidobacterium animalis subsp. lactis 420 reduced bacterial translocation to

mesenteric adipose tissue, decreased the expression of major pro-inflammatory cytokines

TNF-α, IL-1β, PAI-1 and IL-6 in mesenteric adipose tissue, liver and muscle, improved the

insulin sensitivity and fasting hyperinsulinemia in treated HFD mice when compared with

untreated HFD control mice [51]. The major outcome of these studies have been recorded in

Table 1.

Probiotic efficacy in human clinical trials

Although, the efficacy of probiotics as such or other formulations in food formats against

diabetes has been extensively studied and demonstrated in appropriate human epithelial cell

lines and animal models, the purported antidiabetic effects of probiotics have not been

adequately validated in the target human population. This is precisely because very few

attempts have been made in this regard to explore efficacy of probiotic therapy in diabetes on

the affected human subjects. There are only a handful of published reports available in this

context. Nonetheless, the leads that emerged from in vitro cell culture and in vivo animal

studies described in the previous sections clearly demonstrate that probiotics do have the

potential to control diabetes and hence their antidiabetic effects can be exploited in the

treatment of T2D effectively. Hence, in the backdrop of the present scenario whatever

information is available in this particular context is reviewed here.

As oxidative stress, hypercholesterolemia and altered lipid profile play a major role in

the pathogenesis and progression of diabetes, randomized, double-blind, placebo controlled

clinical trials were conducted in separate studies by the same investigators to assess the

effects of probiotic on blood glucose, antioxidant status and lipid profile in T2D. In these

studies, patients with T2D mellitus were assigned into two groups. The patients in the

probiotic intervention group consumed 300 g/d of probiotic yogurt containing 106 cfu/ml

Lactobacillus acidophilus La5 and 106 cfu/ml Bifidobacterium lactis Bb12 and those in the

control group consumed 300 g/d of conventional yogurt for 6 wk. The probiotic intervention

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groups in these studies showed significant decrease in fasting blood glucose and hemoglobin

A1c (P < 0.05), increased the erythrocyte superoxide dismutase and glutathione peroxidase

activities and total antioxidant status (P < 0.05) compared to control group. The probiotic

yoghurt consumption also decreased the total cholesterol by 4.54%, LDL-C by 7.45% in

intervention group. The total cholesterol:HDL-C ratio and LDL-C:HDL-C ratio as

atherogenic indices were significantly decreased in the probiotic group compared with the

control group [52,53]. From the above two studies, it is quite evident that consumption of

probiotic yoghurt significantly improved the antioxidant status and lipid profile in the

intervention group and presented multigenic approach for the management of T2D.

Recently, a randomized, double-blind, placebo-controlled study conducted on twenty

volunteers (ten for placebo group and ten for symbiotic group), aged 50 to 60 years, over a

total test period of 30 days to study the effect of a symbiotic drink (a preparation with a

combination of both probiotics and prebiotics) on glycemia and cholesterol levels in elderly

people with T2D mellitus. The results of the symbiotic group that consumed 108 cfu/ml of

Lactobacillus acidophilus,108 cfu/mL Bifidobacterium bifidum and 2 g oligofructose showed

a significant increase (P < 0.05) in HDL (High Density Lipoprotein) cholesterol, non-

significant reduction (P > 0.05) in total cholesterol and triglycerides and a significant

reduction (P < 0.05) in fasting glycemia. However, no significant changes were recorded in

the placebo group [54].

In another recent study conducted on similar lines to assess by Shao et al. [55], the

effect of microbiological and immunological enteral nutrition in patients with gastrointestinal

cancer complicated with diabetes mellitus was investigated. In this study, 67 patients with

gastrointestinal cancer complicated with diabetes mellitus were randomized into the treatment

group (n=33, enteral nutrition with probiotics, glutamine, and fish oil) and the routine group

(n=34, regular enteral nutrition). Fasting blood glucose (FBG), insulin (FINS), number of

lymphocytes including CD3(+)T cell, CD4(+)T cell, CD8(+)T cell, CD4(+)/CD8(+) and NK

cells of treated and routine groups were measured on the day before surgery and

postoperative day 3 and 7. Insulin resistance index (InHOMA-IR) was also calculated by

using the homeostasis model assessment (HOMA) for both groups and the supplementary

data on incidence of nosocomial infections , intestinal function recovery time and length of

hospital stay were also collected during the study. The enteral intervention with probiotics,

glutathione and fish oil lowered fasting insulin and Insulin resistance index, increased the

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number of CD4 and NK cells compared to routine group. There were however no significant

differences in nosocomial infection and intestinal function recovery between the two groups.

Moreover, the length of hospital stay [(17 ± 3.8) d vs (21 ± 4.2) d] was significantly reduced

from 21 to 17 shorter in the treatment group.

In a different but related study carried out by Luoto et al. [56], the impact of maternal

probiotic-supplemented dietary counseling during pregnancy on colostrum adiponectin

concentration in neonatal metabolism, nutrition, and immune function was recorded in a

randomized, placebo-controlled study. In this study, 256 pregnant women were randomized

into three study groups: dietary intervention with probiotics (diet/probiotics), with placebo

(diet/placebo) and a control group (control/placebo). The combination of Lactobacillus

rhamnosus GG and Bifidobacterium lactis were used in probiotic intervention group. Dietary

intake was evaluated by food records at every trimester of pregnancy. Breast milk samples

were collected after birth (colostrum) for adiponectin concentration analysis. As a result, the

dietary intervention with probiotics significantly increased the colostrum adiponectin

concentration when compared with control (12.7 ng/ml vs. 10.2 ng/ml, P=0.024). This

improved adiponectin concentration is a measure of neonatal metabolic homeostasis and is

also indicator of reduced chances of gestational diabetes.

Notwithstanding the positive efficacy of probiotics on diabetic patients as obtained

form the aforesaid studies, conflicting results were also recorded in one clinical trial while

assessing the effects of probiotic on attenuating systemic inflammation and improving

insulin sensitivity. In this randomized, double-blinded, clinical trial, the commercial probiotic

Lactobacillus acidophilus NCFM was used as intervention together with placebo in a group

of forty-five males for a period of 4 weeks. In this case, even after 4 weeks of intervention,

no changes in the expression of baseline inflammatory markers and the systemic

inflammatory response were observed, thereby, indicating ineffectiveness of the probiotic

therapy in diabetic patients [57]. However, this inconsistency in results could be attributed to

heterogenicity with regard to probiotic strain and population demographics. As we mentioned

earlier, biotherapeutic effects of probiotics are both strain and host specific and thus should

be designed for a specific group with a specific strain which is the hallmark of probiotic

functionality.

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Conclusion and Future Perspectives

Hence, based on the outcome of these limited studies, it would not be proper at the

moment to draw a clear cut demarcation on probiotic functionality to claim efficacy of

probiotic therapy in diabetes in the target human population with conviction due to lack of

sufficient scientific evidence in support of the health claims to prove this hypothesis.

Nevertheless, there is a good reason to believe from the interesting leads that emerged from

extensive in vitro cell line and animal studies that probiotics do have the potential to prevent

and reduce the severity of T2D diabetes and other metabolic syndromes possibly through

modulating gut microbiota, immune response and other mechanisms. However, since T2D

has a multigenic aetiology associated with multiple risk factors, the exact mechanism of

specific target based action of the antidiabetic effects of probiotics at molecular level have

still to be worked out and thus better understanding of probiotic action is important to exploit

their biotherapeutic potential maximally in the management of this chronic disease. Thus,

future research should be directed to move beyond profiling human gut microbial species and

focus on functional properties of probiotics to ensure optimal health benefits for the host.

Furthermore, rapid advancements made during the last few years in genomics,

transcriptomics, proteomics, metabolomics, metabonomics and nutrigenomics in the

backdrop of conclusion of human whole genome project, progression of ongoing human

microbiome projects and the availability of whole genome sequences of several proven

commercial probiotic strains as public domain are likely to generate very useful information

that could further widen the scope and future prospects of probiotics as natural food

supplements and biotehrapeutics specifically targeted against diabetes mellitus. In this

context, concept of designer probiotics suitably manipulated by applying advanced genetic

engineering and PCR techniques specifically for diabetic population is already on the cards

and it would soon emerge as the future therapy for the management of diabetes. The

evaluation of probiotic efficacy in free living target human population is however far more

complex than under controlled experimental conditions since many of the confounding

factors such as use of antibiotics, diet, endotoxin content of ingested food and frequency of

meals along with physical activity may also affect gut microbiota, energy balance, glucose

metabolism, insulin secretion and other gut hormones like incretins. Hence, understanding

these factors may enable the researchers to design future trials and better understand the

relative effect of probiotics on diabetes. It is, therefore, imperative to carry out more

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extensive well designed metabolic clinical studies involving a wide range of target human

population with clearly defined proven probiotic strains or their formulations to reach some

meaningful conclusion as far as their efficacy against T2D is concerned. Thus, the prospects

of exploring probiotics and their formulations as antidiabetic therapy are quite bright and

could prove to be an asset in the near future by providing adequate relief to the mass diabetic

population across the world.

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Table 1 : Antidiabetic efficacy of probiotic interventions in animal models

Probiotic Strain Animal model Result Reference

L. casei NOD mice Improved blood glucose and host immune response

38

L. casei NIDDM -KK-Ay mice Lowered plasma glucose level and modified the host immune responses.

39

L. casei Alloxan treated BALB/c mice

Inhibited the disappearance of insulin-secreting beta-cells

40

L. rhamnosus GG Neonatal streptozotocin induced diabetic rats

Lowered blood HbA1, suppressed oxidative stress, improved glucose tolerance and enhanced insulin secretion

41

VSL#3 NOD mice Decreased rate of β -cell

destruction with increased

production of IL-10

42

Lactobacillus

acidophilus

NCDC14 and

Lactobacillus

casei NCDC19

Fructose-induced diabetic

rats

Significantly lowered the blood glucose and HbA1c levels and free fatty acids and triglycerides

43

Lactobacillus

acidophilus

NCDC14 and

Lactobacillus

casei NCDC19

STZ-induced diabetic rats Improved diabetic

dyslipidemia, inhibited lipid

peroxidation and nitrite

formation

44

Probiotic mixture

Lactobacillus

acidophilus,

Alloxan induced diabetic

rats

Reduced blood glucose by

improving gliclazide

bioavailability in diabetic rats

45

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Bifidobacterium

lactis and

Lactobacillus

rhamnosus

VSL#3 HFD C57BBL-6 mice Increased NKT cells, improved insulin resistance, reduced inflammation

46

L. plantarum

DSM 15313

HFD C57BL/6J mice Lowered

plasma glucose levels

47

Lactobacillus

reuteri GMNL-

263

STZ-induced diabetic rats Reduced glycated hemoglobin

and blood glucose

48

L. casei, L. reuterii, L. plantarum

Dendritic cells from NOD mice stimulated with probiotic lactobacilli for 24hrs

L. casei induced DC to produce high level of IL-10, delay in diabetes incidence

49

Bifidobacterium

longum (BIF

CGMCC NO.

2107 )

HFD rats Reduced metabolic endotoxin

(LPS) concentrations and

intestinal inflammation and

increased the expression of

intestinal Reg I as a regulator

of growth factor

50

Bifidobacterium

animalis subsp.

lactis 420

C57bl6, ob/ob, CD14-/-,

ob/obxCD14-/-, Myd88-/-,

Nod1-/-, Nod2-/- with

normal chaw diet and

HFD

Reversed bacterial

translocation process,

improved animals

inflammatory and metabolic

status

51

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Figure 1. Type 2 Diabetes - Multifactorial Catastrophe

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Figure 2. Role of Gut Microbiota in the Development and Control of Type 2 Diabetes

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Figure 3. Probable Mechanisms of Probiotics Action in the Management of Type 2 Diabetes

probiotics as the potential biotherapeutics in the ... as the... · chronic disease [15]. hence,...

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