CME INDIA Presentation by Dr. N. K. Singh, MD, FICP, FACP, FRSSDI, Director, Diabetes & Heart Research Centre, Dhanbad, Founder/Editor: CME INDIA.

Based on a presentation at RSSDI (Research Society for study of Diabetes in India) – Annual Conference at Mumbai on 16th November 2023.

Amazing it is

“Second human genome:” The gut microbiome

• The gut microbiome, particularly in the context of the second human genome, is now recognized as a distinct “organ” exhibiting unique metabolic and immune functions.
• The human gut harbors approximately 10 times more microbial cells than the entire human body, amounting to around 100 trillion microbes. This vast microbial community comprises as many as 5,000 different species and weighs approximately 2 kilograms. While other microbiome sites exist in the human body, such as the skin, oral cavity, and vaginal region, the gut stands out as the most populous and diverse neighbourhood in this intricate microbial ecosystem.
• The administration of antibiotic therapy has the potential to modify the composition of the gut microbiota. When administered early in life, particularly during infancy and childhood, antibiotics may influence the bacterial profile in a way that fosters conditions associated with obesity, metabolic irregularities, and/or autoimmune diseases.

Science is now corelating many disorders due to Dysbiosis

Know the Gut Microbiome

Imbalance of different microbiota is the key secret

• The intricate interactions among the functional elements within the gut govern diverse functions, with the gut microbiota playing a pivotal role.
• These microorganisms regulate the fermentation and absorption of dietary polysaccharides, yielding short-chain fatty acids—a critical mediator in the context of obesity and its related outcomes.
• Furthermore, gut bacteria are instrumental in shaping the host immune system, modulating inflammatory processes, extracting energy from the host diet, and influencing human gene expression. Studies indicate that dietary adjustments impacting the human colonic microbiota can bestow various health benefits upon the host.

Dysbiosis-2023 Perspective

• Dysbiosis, a shift in the bacterial composition of the gut microbiota, is associated with an increased predisposition to inflammation. Research indicates that this inflammatory response marks the initiation of disrupted gut homeostasis in individuals with diabetes.
• Microbiota community differences between participant cohorts Participant cohort Microbiota differences.

Normal physiological conditions

• 64% Firmicutes
• 23% Bacteroidetes
• 8% Proteobacteria
• 3% Actinobacteria

T2DM cohort usually have

Not alone responsible

• Increasing evidence suggests that the surge in obesity and type 2 diabetes cannot be solely attributed to alterations in the human genome, dietary habits, or a decline in daily physical activity.

Courtesy: Li, Bang-Yan & Xu, Xiao-Yu & Gan, Ren-You & Sun (Ref-2)

Know the molecular actors

Courtesy: Salgaço, M.K., Oliveira, L.G.S., Costa, G.N. et al (Ref-3)

1. A diet predominantly composed of carbohydrates and amino acids undergoes fermentation, resulting in the production of short-chain fatty acids (SCFAs). These SCFAs play a crucial role in maintaining gut integrity and influencing signalling pathways related to intestinal gluconeogenesis, gut wall integrity, GLP-1 (Glucagon-like peptide 1) secretion, beta cell function, and insulin secretion.
   • The primary mechanisms through which short-chain fatty acids (SCFAs) regulate metabolism and inflammation in Type 2 Diabetes (T2DM) involve their production through the conversion of dietary fibre by gut microbiota. These SCFAs then enter cells directly or interact with transmembrane receptors such as FFAR2, FFAR3, and GPR109A. These receptors play a role in enhancing pathways relevant to T2DM, including fatty acid oxidation, glucose metabolism, and the inflammatory response.
   • The gut microbiota produces short-chain fatty acids (SCFAs) such as propionate, acetate, and butyrate, which serve as vital nutrients for intestinal epithelial cells. These SCFAs play a role in modulating host energy and glucose metabolism by influencing appetite, energy expenditure, and insulin secretion.
   • SCFA concentrations are altered in type 2 diabetes. According to specific investigations, gut dysbiosis in people with type 2 diabetes affects the SCFA concentration significantly

2. Increased permeability of lipopolysaccharides (LPS) in the intestinal tract appears to be a key factor in chronic inflammation, leading to diminished insulin sensitivity.

3. The collaboration between the bile acid pool and the signalling of FXR (Farnesoid X receptor) and TGR5 (G-protein-coupled bile acid receptor), along with FGF19 (Fibroblast growth factor 1) signalling, stands out as significant molecular players in the gut microbiota.

Implication of this Knowledge

The role of diet and prebiotics/probiotic supplementation modulating the gut microbiota

The Mediterranean diet

• The Mediterranean diet, characterized by a high intake of plant-based foods, low levels of animal protein and saturated fat, and rich in fibre and omega-3 fatty acids, has been associated with elevated concentrations of short-chain fatty acids (SCFA), as well as higher levels of Prevotella and Firmicutes. These bacterial groups are recognized for their role in breaking down dietary fibre.
• Clinical trials revealed that a decreased abundance of Bifidobacteria in mice on a high-fat diet resulted in increased endotoxemia. However, supplementation with prebiotics reversed this effect. In the group consuming plant-derived foods, there was an observed increase in the synthesis of amylase, glutamate, and riboflavin. Conversely, the consumption of animal-based foods prompted an adaptation of gut microbial function toward enhanced catabolic processes, such as the degradation of glycans and amino acids.

Gut Microbiota-Obesity-T2 DM Triangle

• Individuals with diabetes and those who are obese often share similar microbiota compositions characterized by lower microbial gene richness, reduced microbial diversity, and a decreased Firmicutes-Bacteroidetes ratio. In obese individuals, an increase in bacteria producing butyrate was observed, while decreased glycine levels were associated with an elevated risk of developing type 2 diabetes.
• Both diabetic and obese individuals exhibited increased intestinal absorption of short-chain fatty acids (SCFAs) through gene regulation, promoting heightened fat storage compared to non-obese individuals. Obesity also led to increased permeability for bacterial toxins to cross the intestinal barrier, contributing to intestinal dysbiosis, low-grade inflammation, and insulin resistance.
• After bariatric surgery, individuals who lost at least 10 kg showed reduced production of branched-chain amino acids in the gut, potentially contributing to improved glucose control. In patients undergoing Roux-en-Y gastric bypass, an increase in oral bacteria such as Fusobacteria, Veillonella, and Granulicatella was noted, leading to pH changes that directly influenced gut microbiota diversity.

FMT: This is a new era of “organ” transplant!

• Faecal microbiota transplant (FMT) is a therapeutic approach with historical roots dating back over 1000 years to Chinese practitioners. It was first published as a modern intervention in 1958. The procedure involves transplanting a faecal sample from a “healthy” individual into the gastrointestinal tract of a diseased patient using methods such as enema, nasogastric tube, or colonoscopy.
• A very innovative way of targeting to change the composition of the intestinal microbiota: FMTs.
• Treatments focused on transforming a “dysbiotic” microbiota into a symbiotic state or increasing beneficial bacteria in the gut microbiome have demonstrated promising results. Faecal microbiota transplantations (FMTs), particularly when conducted for a limited duration, have shown moderate effects on metabolic disorders.
• The observed tolerance of oral formulations and faecal microbiota transplant therapy in individuals, along with the noted changes in the intestinal microbiome, appears highly promising and revolutionary.
• Faecal microbiota transplant from lean and healthy donors has been observed to successfully enhance insulin sensitivity in men with metabolic syndrome.
• Faecal microbiota transplantation improves metabolic syndrome parameters: systematic review with meta-analysis based on randomized clinical trials.

Courtesy: Proença IM, Allegretti JR, Bernardo WM, et al. Nutr Res. 2020, 83:1-14. 10.1016/j.nutres.2020.06.018

The Miracle of Exercise

Courtesy: Karen Marlenne Herrera-Rocha, Mar Larrosa et al(Ref-13)

Complications of Diabetes: Microbiota matters

Understanding effects of antidiabetic drugs on the relative abundance of gut microbes

Metformin:

• Metformin stands out with robust data regarding its impact on the gut microbiota among all anti-diabetic medications. Its use has been demonstrated to foster the growth of various healthy bacteria producing short-chain fatty acids (SCFAs).
• Additionally, metformin usage is linked to an increase in the mucin-degrading microbiota, specifically Akkermansia muciniphila. This particular bacterium influences glucose metabolism by regulating gut permeability, reducing lipopolysaccharide (LPS), and enhancing postprandial insulin secretion through interaction with GLP-1.
• Considering the substantial body of evidence, it can be confidently asserted that metformin consistently exhibits a beneficial effect on improving both gut health and cardiovascular health.

GLP-1RA

• While the available data on the impact of GLP-1 receptor agonists (GLP-1 RAs) on gut microbiota is currently limited, it suggests that the clinical benefits of GLP-1 RAs may be mediated by the modulation of gut microbiota.
• According to existing data, the expression of GLP-1 could potentially be stimulated by the binding of short-chain fatty acids (SCFAs), produced through the breakdown of carbohydrates by gut bacteria, to the free fatty acid receptor 2.
• Studies indicate that GLP-1 RAs are associated with a reduction in dysbiosis, particularly an increase in the Bacteroidetes to Firmicutes ratio. There is also evidence of a decrease in microbiota phenotypes related to obesity and an increase in those associated with leanness. Additionally, GLP-1 RAs have been linked to an increase in the abundance of Akkermansia, a bacterium associated with various health benefits.

DPP4 Inhibitor

• Dipeptidyl peptidase-4 (DPP-4) inhibitors have been found to alter the pattern of metabolites associated with carbohydrate, amino acid, and nucleic acid metabolism. A notable trend indicates an increase in short-chain fatty acids (SCFAs) and other organic acids such as succinate. These metabolites are already recognized for their potential to enhance glucose tolerance and insulin sensitivity.

SGLT2 Inhibitor

• Empagliflozin (EMPA) has been observed to improve Type 2 Diabetes Mellitus (T2DM)-related Diabetic Nephropathy (DN) by influencing the gut microbiota. Notably, EMPA leads to a reduction in bacteria that produce lipopolysaccharides (LPS) and an increase in bacteria that produce short-chain fatty acids (SCFAs).

Acarbose/Voglibose

• The administration of acarbose treatment resulted in an enrichment of five genera, notably Lactobacillus and Dialister. Conversely, there was a corresponding decline in six genera, including Butyricicoccus, Phascolarctobacterium, and Ruminococcus.
• Acarbose also plays a role in utilizing lactate, which is a potentially harmful end product of carbohydrate metabolism. It facilitates the conversion of lactate into beneficial short-chain fatty acids (SCFAs), including propionate, acetate, and butyrate.

SU

• The data so far, suggest a lack of positive effect on the gut microbiota by the use of sulfonylurea.

Quick Refresh

Prebiotics

• Promote the growth or action of beneficial microbes and include fructooligosaccharides or galactooligosaccharides, lactulose, and nondigestible carbohydrates (eg, inulin, cellulose, and pectin). Both inulin and the inulin-like fructan OFS have shown promise for ameliorating T2D phenotypes.

Probiotics

• These are live microorganisms, predominantly commensal gut bacteria such as Lactobacillus and Bifidobacterium, which maintain gut homeostasis and regulate the metabolic activities of other gut microbes.

Postbiotics

• These are the byproducts of the metabolic processes of probiotic bacteria, including exopolysaccharides, GABA) and extracellular vesicles (EV). Exopolysaccharide has been found to inhibit adipogenesis and pancreatic a-amylase by activating the AMPK signaling pathway. It has been reported that GABA improves glucoseintolerance, b-cell mass, and inflammatory response.

Obesity and weight management: microbes as friends or foe?

CME INDIA Learning Points

• The ongoing research on the gut microbiome in the diabetes field has evolved progressively, transitioning from initial correlation studies that established a strong association to the exploration of causality and potential underlying mechanisms.
• It is foreseeable that the gut microbiota will serve not only as a biomarker for diabetes but also as a target for potential therapeutic interventions.
• The gut microbiota exhibits a notably strong and consistent association with diabetic individuals, characterized by consistent patterns of alterations in short-chain fatty acids (SCFA), modified bile acid metabolism, changes in lipopolysaccharides, shifts in bacterial compositions, and modifications in energy production.
• The disruption of the normal colonic flora serves as the foundational issue that initiates a cascade in the gut microbiome, ultimately leading to dysbiosis. A comparison of the efficacy between plant-based and animal-based diets revealed differences in bacterial compositions and disproportionate ratios of bacterial phyla. This observation indicated an enhanced design of beneficial bacteria and a reduction in the activation of inflammatory cytokines, ultimately resulting in improved insulin sensitivity.
• The use of drugs such as metformin and post-bariatric surgery has the potential to aid in the restoration of intestinal dysbiosis observed in diabetic individuals.
• Fecal microbial transplantation has demonstrated favorable effects on gut mechanics. Ongoing extensive research in the field of gut microbiota holds promise for future therapeutic prospects, potentially leading to the emergence of new forms of therapy.
• An innovative approach to managing metabolic diversity could revolutionize therapeutic options in the near future, opening up new avenues for treatment.
• We need to learn more before advocating for microbial-based disease interventions.
• Our comprehension of the microbiome and its impact on human health is still in its early stages. Currently, caution must be exercised in applying interventions like probiotics that claim to influence diseases and outcomes.
• Ultimately, it is crucial to acknowledge the holistic nature of the human system and recognize that manipulations of any factor in one direction can have implications in another.

CME INDIA Tail Piece

• Many commercial tests available costing approximately 10K, to test your Microbiome health, they have contact numbers, stool sample is collected from home and result is shared. It looks logical but no definite recommendations from reputed societies.

Read experiences of Indian physicians in 2nd part:

References:

1. The relationships between gut microbiota and diabetes mellitus, and treatments for diabetes mellitus. Craciun CI, Neag MA, Catinean A, et al. https://doi.org/10.3390/biomedicines10020308 Biomedicines. 2022;10
2. Li, Bang-Yan & Xu, Xiao-Yu & Gan, Ren-You & Sun, Quancai & Meng, Jin-Ming & Shang, Ao & Mao, Qian-Qian & Li, Hua-Bin. (2019). Targeting Gut Microbiota for the Prevention and Management of Diabetes Mellitus by Dietary Natural Products. Foods. 8. 440. 10.3390/foods8100440.
3. Salgaço, M.K., Oliveira, L.G.S., Costa, G.N. et al. Relationship between gut microbiota, probiotics, and type 2 diabetes mellitus. Appl Microbiol Biotechnol 103, 9229–9238 (2019). https://doi.org/10.1007/s00253-019-10156-y
4. Lee CB, Chae SU, Jo SJ, Jerng UM, Bae SK: The relationship between the gut microbiome and metformin as a key for treating type 2 diabetes mellitus. Int J Mol Sci. 2021, 22: 10.3390/ijms22073566
5. Ojo, O.; Feng, Q.-Q.; Ojo, O.O.; Wang, X.-H. The Role of Dietary Fibre in Modulating Gut Microbiota Dysbiosis in Patients with Type 2 Diabetes: A Systematic Review and Meta-Analysis of Randomised Controlled Trials. Nutrients 2020, 12, 3239. https://doi.org/10.3390/nu12113239
6. Beam A, Clinger E, Hao L: Effect of diet and dietary components on the composition of the gut microbiota . Nutrients. 2021, 13:10.3390/nu13082795
7. Proença IM, Allegretti JR, Bernardo WM, et al.: Fecal microbiota transplantation improves metabolic syndrome parameters: systematic review with meta-analysis based on randomized clinical trials. Nutr Res. 2020, 83:1-14. 10.1016/j.nutres.2020.06.018
8. Iatcu, C.O.; Steen, A.; Covasa, M. Gut Microbiota and Complications of Type-2 Diabetes. Nutrients 2022, 14, 166. https:// doi.org/10.3390/nu14010166
9. Whang A, Nagpal R, Yadav H. Bi-directional drug-microbiome interactions of anti-diabetics. EBioMedicine. 2019 Jan;39:591-602. doi: 10.1016/j.ebiom.2018.11.046. Epub 2018 Dec 13. PMID: 30553752; PMCID: PMC6354569.
10. Deng L, Yang Y, Xu G. Empagliflozin ameliorates type 2 diabetes mellitus-related diabetic nephropathy via altering the gut microbiota. Biochim Biophys Acta Mol Cell Biol Lipids. 2022 Dec;1867(12):159234. doi: 10.1016/j.bbalip.2022.159234. Epub 2022 Sep 19. PMID: 36185030.
11. Wu J, Yang K, Fan H, Wei M and Xiong Q (2023) Targeting the gut microbiota and its metabolites for type 2 diabetes mellitus. Front. Endocrinol. 14:1114424. doi: 10.3389/fendo.2023.1114424
12. Van Hul, Matthias and Patrice D Cani. “The gut microbiota in obesity and weight management: microbes as friends or foe?” Nature Reviews Endocrinology (2023): 1-14.
13. Karen Marlenne Herrera-Rocha, Mar Larrosa et al. Effect of high-resistance training at intestinal level,morphological and systemic changes, consumption of natural sources as a therapeutic alternative. TIP Rev.Esp.Cienc.Quím.Biol.https://doi.org/10.22201/fesz.23958723e.2021.344

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