The Role Of Gut Microbiota In The Development Of Type 2 Diabetes Mellitus
Nesma Ali Ibrahim;
Abstract
The microorganisms that live on and inside humans are collectively called the human microbiota. Microbiota represents at least 10-fold more cells than exist in the human body. The main mass of microorganisms associated with humans resides in our intestinal tract. The human intestinal tract contains a large variety of micro-organisms, of which bacteria are the most dominant and diverse. In adults, Bacteroidetes and Firmicutes usually dominate the intestinal microbiota, whereas Actinobacteria, archaea, eukaryotes and viruses are in considerably minor proportion.
The fetal intestinal tract is sterile until birth and the microbial colonization of the gut begins in infants immediately after birth. The mode of delivery (vaginal versus Caesarian section) as well as the method of feeding (breast versus formula feeding) are influencing the gut microbiota. At about 3 years of age, the gut microbiota reaches a composition and diversity similar to adults and remains more or less stable over time in adulthood.
The composition and function of the gut microbiota are influenced by several factors; both host genotype and lifestyle factors such as diet, physical activity, antibiotics, age and probably several additional but yet unidentified factors may simultaneously influence the gut microbiota.
Traditionally, microbial communities have been characterized by culturing on specific plates, but this is only amenable to the culturable fraction of the members and has limited resolution. Culture-independent methods based on characterization of the 16S rRNA genes have been developed and also provide information for organisms that cannot be cultured. Shotgun sequencing of the whole genome provides information about the functional and metabolic potential of the community.
The gut microbiome has been directly implicated in the etiopathogenesis of a number of pathological states as diverse as obesity, circulatory disease, inflammatory bowel diseases (IBDs) and autism. The gut microbiota also influence drug metabolism and toxicity, dietary calorific bioavailability, immune system conditioning and response, and post-surgical recovery.
Several studies suggest that an altered composition and diversity of gut microbiota could play an important role in the development of metabolic disorders. T2DM is a metabolic disease characterized by a state of insulin resistance and low-grade inflammation. Microbial ecology can be an important regulator of energy homeostasis and glucose metabolism.
Microbes may influence host metabolism and hence T2DM through numerous mechanisms:
- Lipopolysaccharide. Lipopolysaccharide (LPS) originates from the outer membrane of Gram-negative bacteria and binds to Toll-like receptor 4 (TLR4), which activates pro-inflammatory signalling pathways resulting in low-grade inflammation and thus decreased insulin sensitivity.
- Short-chain fatty acids. Bacteria in the colon ferment dietary fibres to short-chain fatty acids (mainly butyrate, acetate and propionate). Acetate and propionate are used as substrates for gluconeogenesis and lipogenesis in the liver, whereas butyrate is an important energy substrate for colonic mucosa cells. Moreover, short-chain fatty acids bind to the G protein-coupled receptors GPR41 and GPR43 resulting in various effects depending on the cellular types affected. In immune cells, this signalling results in decreased inflammation and in the enteroendocrine L-cells it results in increased GLP1 and PYY levels together leading to improved insulin sensitivity.
- Bile acids. Primary bile acids are produced by the liver and recirculated to the liver from the gut. However, gut bacteria are capable of deconjugating primary bile acids hindering their recirculation. The primary deconjugated bile acids are further metabolised by gut bacteria to secondary bile acids. Secondary bile acids bind to the G protein-coupled receptor TGR5, which results in increased energy expenditure in muscles and GLP1 secretion in the enteroendocrine L-cells, both of which lead to improved insulin sensitivity.
- Besides, microbiota-dependent changes in gut tight-junction proteins, endocannabinoid system and intestinal alkaline phosphatase activity may be also involved in altered intestinal permeability and the pathogenesis of insulin resistance.
Gut microbiota helps harvesting energy from the diet and increases lipogenesis. By several mechanisms:
- It was found that gut microbiota conventionalisation results in a doubling of the density of capillaries in the small intestinal villus epithelium, thereby helping to promote intestinal monosaccharide absorption.
- Gut microbiota promote hepatic de novo lipogenesis through the expression of several key enzymes such as aceyl-CoA carboxylase (ACC) and fatty acid synthase (FAS).
- Gut microbiota promote fat storage through increasing the enzyme lipoprotein lipase (LPL) activity (as a consequence of suppressing the Fasting-Induced Adipose Factor (FIAF) in the gut).
- The microbiota also impacts muscle metabolism and consequently influences the regulation of insulin resistance. In response to a high-fat diet, the gut microbiota inhibit AMP-activated kinase dependent fatty acid oxidation.
The metabolic impact of the complex interaction between gut microbiota and the host has driven interest in manipulating microbiota in order to develop new therapeutic targets for T2DM.
The composition and functional capabilities of the human gut microbiota rapidly adapt to changes in macronutrient content of the diet. Also, evidence for the existence of a modulating effect of physical activity on the gut microbiota is accumulating.
Antibiotic treatment is another method of gut microbiota modulation. And, bariatric surgery promotes evident changes in intestinal bacterial composition. These changes could reinforce the beneficial effects of the surgical intervention on host’s appetite and insulin sensitivity.
Changing gut microbiota by the mean of prebiotics protects against high-fat diet induced metabolic endotoxemia and the development of metabolic disorders. Prebiotic treatment increases Bifidobacterium-spp., decreases plasma LPS levels and improved insulin sensitivity, steatosis, and normalized low-grade inflammation. Also, the modulation of gut microbiota by prebiotics treatment modulates the endogenous production of gut peptides associated with energy homeostasis.
Probiotics may be involved in the maintenance of a healthier gut microbiota, and have also been identified as effective adjuvants in insulin resistance therapies. Probiotic consumption increases the number of bifidobacteria, and increased expression of adhesion proteins reduces intestinal permeability, impairing the activation of TLR4 by LPS. Probiotics influence the enteric immune system through the production of IgA or the induction of anti-inflammatory molecules such as Il10. Also, probiotics have been shown to improve the absorption of antioxidants and reduce post-prandial lipid concentrations, actions directly related to oxidative stress.
Fecal microbiota transplantation raised interest in the therapeutic effect of fecal transplantation in metabolic syndrome and T2DM. The main principle of fecal transplant is the possibility of this procedure to replace pathogenic microbes by beneficial communities, thus restoring the gut microbiota balance and enabling the cure of the disease.
The fetal intestinal tract is sterile until birth and the microbial colonization of the gut begins in infants immediately after birth. The mode of delivery (vaginal versus Caesarian section) as well as the method of feeding (breast versus formula feeding) are influencing the gut microbiota. At about 3 years of age, the gut microbiota reaches a composition and diversity similar to adults and remains more or less stable over time in adulthood.
The composition and function of the gut microbiota are influenced by several factors; both host genotype and lifestyle factors such as diet, physical activity, antibiotics, age and probably several additional but yet unidentified factors may simultaneously influence the gut microbiota.
Traditionally, microbial communities have been characterized by culturing on specific plates, but this is only amenable to the culturable fraction of the members and has limited resolution. Culture-independent methods based on characterization of the 16S rRNA genes have been developed and also provide information for organisms that cannot be cultured. Shotgun sequencing of the whole genome provides information about the functional and metabolic potential of the community.
The gut microbiome has been directly implicated in the etiopathogenesis of a number of pathological states as diverse as obesity, circulatory disease, inflammatory bowel diseases (IBDs) and autism. The gut microbiota also influence drug metabolism and toxicity, dietary calorific bioavailability, immune system conditioning and response, and post-surgical recovery.
Several studies suggest that an altered composition and diversity of gut microbiota could play an important role in the development of metabolic disorders. T2DM is a metabolic disease characterized by a state of insulin resistance and low-grade inflammation. Microbial ecology can be an important regulator of energy homeostasis and glucose metabolism.
Microbes may influence host metabolism and hence T2DM through numerous mechanisms:
- Lipopolysaccharide. Lipopolysaccharide (LPS) originates from the outer membrane of Gram-negative bacteria and binds to Toll-like receptor 4 (TLR4), which activates pro-inflammatory signalling pathways resulting in low-grade inflammation and thus decreased insulin sensitivity.
- Short-chain fatty acids. Bacteria in the colon ferment dietary fibres to short-chain fatty acids (mainly butyrate, acetate and propionate). Acetate and propionate are used as substrates for gluconeogenesis and lipogenesis in the liver, whereas butyrate is an important energy substrate for colonic mucosa cells. Moreover, short-chain fatty acids bind to the G protein-coupled receptors GPR41 and GPR43 resulting in various effects depending on the cellular types affected. In immune cells, this signalling results in decreased inflammation and in the enteroendocrine L-cells it results in increased GLP1 and PYY levels together leading to improved insulin sensitivity.
- Bile acids. Primary bile acids are produced by the liver and recirculated to the liver from the gut. However, gut bacteria are capable of deconjugating primary bile acids hindering their recirculation. The primary deconjugated bile acids are further metabolised by gut bacteria to secondary bile acids. Secondary bile acids bind to the G protein-coupled receptor TGR5, which results in increased energy expenditure in muscles and GLP1 secretion in the enteroendocrine L-cells, both of which lead to improved insulin sensitivity.
- Besides, microbiota-dependent changes in gut tight-junction proteins, endocannabinoid system and intestinal alkaline phosphatase activity may be also involved in altered intestinal permeability and the pathogenesis of insulin resistance.
Gut microbiota helps harvesting energy from the diet and increases lipogenesis. By several mechanisms:
- It was found that gut microbiota conventionalisation results in a doubling of the density of capillaries in the small intestinal villus epithelium, thereby helping to promote intestinal monosaccharide absorption.
- Gut microbiota promote hepatic de novo lipogenesis through the expression of several key enzymes such as aceyl-CoA carboxylase (ACC) and fatty acid synthase (FAS).
- Gut microbiota promote fat storage through increasing the enzyme lipoprotein lipase (LPL) activity (as a consequence of suppressing the Fasting-Induced Adipose Factor (FIAF) in the gut).
- The microbiota also impacts muscle metabolism and consequently influences the regulation of insulin resistance. In response to a high-fat diet, the gut microbiota inhibit AMP-activated kinase dependent fatty acid oxidation.
The metabolic impact of the complex interaction between gut microbiota and the host has driven interest in manipulating microbiota in order to develop new therapeutic targets for T2DM.
The composition and functional capabilities of the human gut microbiota rapidly adapt to changes in macronutrient content of the diet. Also, evidence for the existence of a modulating effect of physical activity on the gut microbiota is accumulating.
Antibiotic treatment is another method of gut microbiota modulation. And, bariatric surgery promotes evident changes in intestinal bacterial composition. These changes could reinforce the beneficial effects of the surgical intervention on host’s appetite and insulin sensitivity.
Changing gut microbiota by the mean of prebiotics protects against high-fat diet induced metabolic endotoxemia and the development of metabolic disorders. Prebiotic treatment increases Bifidobacterium-spp., decreases plasma LPS levels and improved insulin sensitivity, steatosis, and normalized low-grade inflammation. Also, the modulation of gut microbiota by prebiotics treatment modulates the endogenous production of gut peptides associated with energy homeostasis.
Probiotics may be involved in the maintenance of a healthier gut microbiota, and have also been identified as effective adjuvants in insulin resistance therapies. Probiotic consumption increases the number of bifidobacteria, and increased expression of adhesion proteins reduces intestinal permeability, impairing the activation of TLR4 by LPS. Probiotics influence the enteric immune system through the production of IgA or the induction of anti-inflammatory molecules such as Il10. Also, probiotics have been shown to improve the absorption of antioxidants and reduce post-prandial lipid concentrations, actions directly related to oxidative stress.
Fecal microbiota transplantation raised interest in the therapeutic effect of fecal transplantation in metabolic syndrome and T2DM. The main principle of fecal transplant is the possibility of this procedure to replace pathogenic microbes by beneficial communities, thus restoring the gut microbiota balance and enabling the cure of the disease.
Other data
| Title | The Role Of Gut Microbiota In The Development Of Type 2 Diabetes Mellitus | Other Titles | دور الكائنات الدقيقة بالقناه الهضمية فى الاصابة بداء السكرى من النوع الثانى | Authors | Nesma Ali Ibrahim | Issue Date | 2016 |
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