Modulating the Microbiota as a Therapeutic Intervention for Type 2 Diabetes.
TL;DR: The role of the Gut Microbiota in Type 2 Diabetes (T2D) is discussed in this article, where the causal relationship between microbiota and T2D established using fecal microbiota transplantation (FMT) or probiotic supplementation, and the potential underlying mechanisms such as byproducts of microbial metabolism.
Abstract: Mounting evidence suggested that the gut microbiota has a significant role in the metabolism and disease status of the host. In particular, Type 2 Diabetes (T2D), which has a complex etiology that includes obesity and chronic low-grade inflammation, is modulated by the gut microbiota and microbial metabolites. Current literature supports that unbalanced gut microbial composition (dysbiosis) is a risk factor for T2D. In this review, we critically summarize the recent findings regarding the role of gut microbiota in T2D. Beyond these associative studies, we focus on the causal relationship between microbiota and T2D established using fecal microbiota transplantation (FMT) or probiotic supplementation, and the potential underlying mechanisms such as byproducts of microbial metabolism. These microbial metabolites are small molecules that establish communication between microbiota and host cells. We critically summarize the associations between T2D and microbial metabolites such as short-chain fatty acids (SCFAs) and trimethylamine N-Oxide (TMAO). Additionally, we comment on how host genetic architecture and the epigenome influence the microbial composition and thus how the gut microbiota may explain part of the missing heritability of T2D found by GWAS analysis. We also discuss future directions in this field and how approaches such as FMT, prebiotics, and probiotics supplementation are being considered as potential therapeutics for T2D.
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TL;DR: The digestive tract is replete with complex and diverse microbial communities that are important for the regulation of multiple pathophysiological processes in humans and animals, particularly those involved in the maintenance of intestinal homeostasis, immunity, inflammation, and tumorigenesis.
Abstract: The digestive tract is replete with complex and diverse microbial communities that are important for the regulation of multiple pathophysiological processes in humans and animals, particularly those involved in the maintenance of intestinal homeostasis, immunity, inflammation, and tumorigenesis. The diversity of bile acids is a result of the joint efforts of host and intestinal microflora. There is a bidirectional relationship between the microbial community of the intestinal tract and bile acids in that, while the microbial flora tightly modulates the metabolism and synthesis of bile acids, the bile acid pool and composition affect the diversity and the homeostasis of the intestinal flora. Homeostatic imbalances of bile acid and intestinal flora systems may lead to the development of a variety of diseases, such as inflammatory bowel disease (IBD), colorectal cancer (CRC), hepatocellular carcinoma (HCC), type 2 diabetes (T2DM), and polycystic ovary syndrome (PCOS). The interactions between bile acids and intestinal flora may be (in)directly involved in the pathogenesis of these diseases.
15 citations
TL;DR: In this paper, the relationship between metabolic disorders and inflammatory bowel diseases (IBD) at molecular levels is described, and the authors highlight and summarize the molecular risk factors that may link between the pathogeneses of the two diseases.
Abstract: Despite considerable epidemiological evidence indicating comorbidity between metabolic disorders, such as obesity, type 2 diabetes, and non-alcoholic fatty liver disease, and inflammatory bowel diseases (IBD), such as Crohn’s disease and ulcerative colitis, as well as common pathophysiological features shared by these two categories of diseases, the relationship between their pathogenesis at molecular levels are not well described. Intestinal barrier dysfunction is a characteristic pathological feature of IBD, which also plays causal roles in the pathogenesis of chronic inflammatory metabolic disorders. Increased intestinal permeability is associated with a pro-inflammatory response of the intestinal immune system, possibly leading to the development of both diseases. In addition, dysregulated interactions between the gut microbiota and the host immunity have been found to contribute to immune-mediated disorders including the two diseases. In connection with disrupted gut microbial composition, alterations in gut microbiota-derived metabolites have also been shown to be closely related to the pathogeneses of both diseases. Focusing on these prominent pathophysiological features observed in both metabolic disorders and IBD, this review highlights and summarizes the molecular risk factors that may link between the pathogeneses of the two diseases, which is aimed at providing a comprehensive understanding of molecular mechanisms underlying their comorbidity.
14 citations
TL;DR: A review summarises some of the sources of anthocyanins and their mechanisms and benefits in the treatment of chronic human diseases is presented in this article , which includes non-commercialised native plants from around the world and agri-waste containing Anthocyanin.
Abstract: Anthocyanins are mainly purple-coloured phenolic compounds of plant origin that as secondary metabolites are important in plant survival. Understanding their health benefits in humans requires sourcing these unstable compounds in sufficient quantities at a reasonable cost, which has led to improved methods of extraction. Dark-coloured fruits, cereals and vegetables are current sources of these compounds. The range of potential sustainable sources is much larger and includes non-commercialised native plants from around the world and agri-waste containing anthocyanins. In the last 5 years, there have been significant advances in developing the therapeutic potential of anthocyanins in chronic human diseases. Anthocyanins exert their beneficial effects through improvements in gut microbiota, oxidative stress and inflammation, and modulation of neuropeptides such as insulin-like growth factor-1. Their health benefits in humans include reduced cognitive decline; protection of organs such as the liver, as well as the cardiovascular system, gastrointestinal tract and kidneys; improvements in bone health and obesity; and regulation of glucose and lipid metabolism. This review summarises some of the sources of anthocyanins and their mechanisms and benefits in the treatment of chronic human diseases.
12 citations
TL;DR: The use of the type 2 diabetes drug metformin is a promising treatment for this comorbidity because, in addition to its hypoglycemic action, it can increase amount of intestinal bacteria that induce regulatory T cell response.
Abstract: Coronavirus disease 2019, or COVID-19, is a major challenge facing scientists worldwide. Alongside the lungs, the system of organs comprising the GI tract is commonly targeted by COVID-19. The dysbiotic modulations in the intestine influence the disease severity, potentially due to the ability of the intestinal microbiota to modulate T lymphocyte functions, i.e., to suppress or activate T cell subpopulations. The interplay between the lungs and intestinal microbiota is named the gut–lung axis. One of the most usual comorbidities in COVID-19 patients is type 2 diabetes, which induces changes in intestinal microbiota, resulting in a pro-inflammatory immune response, and consequently, a more severe course of COVID-19. However, changes in the microbiota in this comorbid pathology remain unclear. Metformin is used as a medication to treat type 2 diabetes. The use of the type 2 diabetes drug metformin is a promising treatment for this comorbidity because, in addition to its hypoglycemic action, it can increase amount of intestinal bacteria that induce regulatory T cell response. This dual activity of metformin can reduce lung damage and improve the course of the COVID-19 disease.
11 citations
TL;DR: The combination of physiology and computational modeling of microbiota metabolism will drive the diagnosis and treatment of T2D patients in a personalized way and present computational approaches for disentangling the metabolic activity underlying host-microbiota codependence.
Abstract: ABSTRACT The association between the physio-pathological variables of type 2 diabetes (T2D) and gut microbiota composition suggests a new avenue to track the disease and improve the outcomes of pharmacological and non-pharmacological treatments. This enterprise requires new strategies to elucidate the metabolic disturbances occurring in the gut microbiome as the disease progresses. To this end, physiological knowledge and systems biology pave the way for characterizing microbiota and identifying strategies in a move toward healthy compositions. Here, we dissect the recent associations between gut microbiota and T2D. In addition, we discuss recent advances in how drugs, diet, and exercise modulate the microbiome to favor healthy stages. Finally, we present computational approaches for disentangling the metabolic activity underlying host-microbiota codependence. Altogether, we envision that the combination of physiology and computational modeling of microbiota metabolism will drive us to optimize the diagnosis and treatment of T2D patients in a personalized way.
10 citations
References
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TL;DR: It is demonstrated through metagenomic and biochemical analyses that changes in the relative abundance of the Bacteroidetes and Firmicutes affect the metabolic potential of the mouse gut microbiota and indicates that the obese microbiome has an increased capacity to harvest energy from the diet.
Abstract: The worldwide obesity epidemic is stimulating efforts to identify host and environmental factors that affect energy balance. Comparisons of the distal gut microbiota of genetically obese mice and their lean littermates, as well as those of obese and lean human volunteers have revealed that obesity is associated with changes in the relative abundance of the two dominant bacterial divisions, the Bacteroidetes and the Firmicutes. Here we demonstrate through metagenomic and biochemical analyses that these changes affect the metabolic potential of the mouse gut microbiota. Our results indicate that the obese microbiome has an increased capacity to harvest energy from the diet. Furthermore, this trait is transmissible: colonization of germ-free mice with an 'obese microbiota' results in a significantly greater increase in total body fat than colonization with a 'lean microbiota'. These results identify the gut microbiota as an additional contributing factor to the pathophysiology of obesity.
10,126 citations
TL;DR: It is shown that the relative proportion of Bacteroidetes is decreased in obese people by comparison with lean people, and that this proportion increases with weight loss on two types of low-calorie diet.
Abstract: Two groups of beneficial bacteria are dominant in the human gut, the Bacteroidetes and the Firmicutes. Here we show that the relative proportion of Bacteroidetes is decreased in obese people by comparison with lean people, and that this proportion increases with weight loss on two types of low-calorie diet. Our findings indicate that obesity has a microbial component, which might have potential therapeutic implications.
7,550 citations
TL;DR: By combining the rationale of pro- and prebiotics, the concept of synbiotics is proposed to characterize some colonic foods with interesting nutritional properties that make these compounds candidates for classification as health-enhancing functional food ingredients.
Abstract: Because the human gut microbiota can play a major role in host health, there is currently some interest in the manipulation of the composition of the gut flora towards a potentially more remedial community. Attempts have been made to increase bacterial groups such as Bifidobacterium and Lactobacillus that are perceived as exerting health-promoting properties. Probiotics, defined as microbial food supplements that beneficially affect the host by improving its intestinal microbial balance, have been used to change the composition of colonic microbiota. However, such changes may be transient, and the implantation of exogenous bacteria therefore becomes limited. In contrast, prebiotics are nondigestible food ingredients that beneficially affect the host by selectively stimulating the growth and/or activity of one or a limited number of bacterial species already resident in the colon, and thus attempt to improve host health. Intake of prebiotics can significantly modulate the colonic microbiota by increasing the number of specific bacteria and thus changing the composition of the microbiota. Nondigestible oligosaccharides in general, and fructooligosaccharides in particular, are prebiotics. They have been shown to stimulate the growth of endogenous bifidobacteria, which, after a short feeding period, become predominant in human feces. Moreover, these prebiotics modulate lipid metabolism, most likely via fermentation products. By combining the rationale of pro- and prebiotics, the concept of synbiotics is proposed to characterize some colonic foods with interesting nutritional properties that make these compounds candidates for classification as health-enhancing functional food ingredients.
7,232 citations
TL;DR: Analysis of the microbiota of genetically obese ob/ob mice, lean ob/+ and wild-type siblings, and their ob/+ mothers, all fed the same polysaccharide-rich diet, indicates that obesity affects the diversity of the gut microbiota and suggests that intentional manipulation of community structure may be useful for regulating energy balance in obese individuals.
Abstract: We have analyzed 5,088 bacterial 16S rRNA gene sequences from the distal intestinal (cecal) microbiota of genetically obese ob/ob mice, lean ob/+ and wild-type siblings, and their ob/+ mothers, all fed the same polysaccharide-rich diet. Although the majority of mouse gut species are unique, the mouse and human microbiota(s) are similar at the division (superkingdom) level, with Firmicutes and Bacteroidetes dominating. Microbial-community composition is inherited from mothers. However, compared with lean mice and regardless of kinship, ob/ob animals have a 50% reduction in the abundance of Bacteroidetes and a proportional increase in Firmicutes. These changes, which are division-wide, indicate that, in this model, obesity affects the diversity of the gut microbiota and suggest that intentional manipulation of community structure may be useful for regulating energy balance in obese individuals.
5,365 citations
TL;DR: In this article, the authors found that conventionalization of adult germ-free C57BL/6 mice with a normal microbiota harvested from the distal intestine (cecum) of conventionally raised animals produces a 60% increase in body fat content and insulin resistance within 14 days despite reduced food intake.
Abstract: New therapeutic targets for noncognitive reductions in energy intake, absorption, or storage are crucial given the worldwide epidemic of obesity. The gut microbial community (microbiota) is essential for processing dietary polysaccharides. We found that conventionalization of adult germ-free (GF) C57BL/6 mice with a normal microbiota harvested from the distal intestine (cecum) of conventionally raised animals produces a 60% increase in body fat content and insulin resistance within 14 days despite reduced food intake. Studies of GF and conventionalized mice revealed that the microbiota promotes absorption of monosaccharides from the gut lumen, with resulting induction of de novo hepatic lipogenesis. Fasting-induced adipocyte factor (Fiaf), a member of the angiopoietin-like family of proteins, is selectively suppressed in the intestinal epithelium of normal mice by conventionalization. Analysis of GF and conventionalized, normal and Fiaf knockout mice established that Fiaf is a circulating lipoprotein lipase inhibitor and that its suppression is essential for the microbiota-induced deposition of triglycerides in adipocytes. Studies of Rag1-/- animals indicate that these host responses do not require mature lymphocytes. Our findings suggest that the gut microbiota is an important environmental factor that affects energy harvest from the diet and energy storage in the host. Data deposition: The sequences reported in this paper have been deposited in the GenBank database (accession nos. AY 667702--AY 668946).
5,221 citations