Gut Microbiota and Type 1 Diabetes

The gut immune system has a key role in the development of autoimmune diabetes, and factors that control the gut immune system are also regulators of beta-cell autoimmunity. Gut microbiota modulate the function of the gut immune system by their effect on the innate immune system, such as the intestinal epithelial cells and dendritic cells, and on the adaptive immune system, in particular intestinal T cells. Due to the immunological link between gut and pancreas, e.g. the shared lymphocyte homing receptors, the immunological changes in the gut are reflected in the pancreas. According to animal studies, changes in gut microbiota alter the development of autoimmune diabetes. This has been demonstrated by antibiotics that induce changes in the gut microbiota. Furthermore, gut-colonizing microbes may modify the incidence of autoimmune diabetes in animal models. Deficient toll-like receptor (TLR) signaling, mediating microbial stimulus in immune cells, prevents autoimmune diabetes, which appears to be dependent on alterations in the intestinal microbiota. Although few studies have been conducted in humans, recent studies suggest that the abundance of Bacteroides and lack of butyrate-producing bacteria in fecal microbiota are associated with beta-cell autoimmunity and type 1 diabetes. It is possible that altered gut microbiota are associated with immunological aberrancies in type 1 diabetes. The changes in gut microbiota could lead to alterations in the gut immune system, such as increased gut permeability, small intestinal inflammation, and impaired tolerance to food antigens, all of which are observed in type 1 diabetes. Poor fitness of gut microbiota could explain why children who develop type 1 diabetes are prone to enterovirus infections, and do not develop tolerance to cow milk antigens. These candidate risk factors of type 1 diabetes may imply an increased risk of type 1 diabetes due to the presence of gut microbiota that do not support health. Despite the complex interaction of microbiota, host, environment, and disease mechanisms, gut microbiota are promising novel targets in the prevention of type 1 diabetes.     

Human Intestinal Microbiota and Type 1 Diabetes

The role of intestinal microbiota in immune-mediated diseases, such as type 1 diabetes, has deservedly received a lot of attention. Evidently, changes in the intestinal microbiota are associated with type 1 diabetes as demonstrated by recent studies. Children with beta-cell autoimmunity have shown low abundance of butyrate-producing bacteria and increase in the abundance of members of the Bacteroidetes phylum in fecal microbiota. These alterations could explain increased gut permeability, subclinical small intestinal inflammation, and dysregulation of oral tolerance in type 1 diabetes. However, these studies do not provide evidence of the causative role of the gut microbiota in the development of beta-cell autoimmunity, yet. In animal models, the composition of gut microbiota modulates the function of both innate and adaptive immunity, and intestinal bacteria are regulators of autoimmune diabetes. Thus, prevention of type 1 diabetes could, in the future, be based on the interventions targeted to the gut microbiota.     

Aryl hydrocarbon receptor

Intestinal homeostasis results from a complex mutualism between gut microbiota and host cells. Defining the molecular network regulating such mutualism is currently of increasing interest, as its deregulation is reported to lead to increased susceptibility to infections, chronic inflammatory bowel diseases and cancer. Until now, the focus has been on the mechanism, by which the composition of indigenous microbiota shapes the immune system. In a recent study, we have shown that dietary compounds have also the ability to affect innate immune system. This regulation involves aryl hydrocarbon receptor (AhR), a sensor of plant-derived phytochemicals, which mediates the maintenance of Retinoic acid related orphan receptor γ t-expressing innate lymphoid cells (RORγt⁺ ILC) in the gut and consequently formation of postnatal lymphoid follicles. Thus, AhR represents the first evidence of a molecular link between diet and immunity at intestinal mucosal surfaces.     

Aryl hydrocarbon receptor: A molecular link between postnatal lymphoid follicle formation and diet

Intestinal homeostasis results from a complex mutualism between gut microbiota and host cells. Defining the molecular network regulating such mutualism is currently of increasing interest, as its deregulation is reported to lead to increased susceptibility to infections, chronic inflammatory bowel diseases and cancer. Until now, the focus has been on the mechanism, by which the composition of indigenous microbiota shapes the immune system. In a recent study, we have shown that dietary compounds have also the ability to affect innate immune system. This regulation involves aryl hydrocarbon receptor (AhR), a sensor of plant-derived phytochemicals, which mediates the maintenance of Retinoic acid related orphan receptor γ t-expressing innate lymphoid cells (RORγt⁺ ILC) in the gut and consequently formation of postnatal lymphoid follicles. Thus, AhR represents the first evidence of a molecular link between diet and immunity at intestinal mucosal surfaces.     

Diabetes,obesity and gut microbiota

The gut microbiota composition has been associated with several hallmarks of metabolic syndrome (e.g., obesity, type 2 diabetes, cardiovascular diseases, and non-alcoholic steatohepatitis). Growing evidence suggests that gut microbes contribute to the onset of the low-grade inflammation characterising these metabolic disorders via mechanisms associated with gut barrier dysfunctions. Recently, enteroendocrine cells and the endocannabinoid system have been shown to control gut permeability and metabolic endotoxaemia. Moreover, targeted nutritional interventions using non-digestible carbohydrates with prebiotic properties have shown promising results in pre-clinical studies in this context, although human intervention studies warrant further investigations. Thus, in this review, we discuss putative mechanisms linking gut microbiota and type 2 diabetes. These data underline the advantage of investigating and changing the gut microbiota as a therapeutic target in the context of obesity and type 2 diabetes.     

短链脂肪酸在2型糖尿病发病机制中的作用

短链脂肪酸(SCFA)是由肠道菌群发酵膳食纤维产生的代谢产物,饮食结构变化通过改变肠道菌群结构与功能,影响SCFA的产生.近来研究发现,SCFA通过调节胃肠道激素分泌、胰岛素敏感性及糖、脂代谢,参与了2型糖尿病的发生、发展.对SCFA的深入研究,为阐明2型糖尿病发病机制及其预防和治疗提供了新的思路和靶点.     

Alterations of the gut microbiota in coronavirus disease 2019 and its therapeutic potential

The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) poses a serious threat to global health. SARS-CoV-2 infects host cells primarily by binding to angiotensin-converting enzyme 2, which is coexpressed in alveolar type 2 cells and gut epithelial cells. It is known that COVID-19 often presents with gastrointestinal symptoms and gut dysbiosis, mainly characterized by an increase in opportunistic pathogens and a decrease in beneficial commensal bacteria. In recent years, multiple studies have comprehensively explored gut microbiota alterations in COVID-19 and highlighted the clinical correlation between dysbiosis and COVID-19. SARS-CoV-2 causes gastrointestinal infections and dysbiosis mainly through fecal-oral transmission and the circulatory and immune pathways. Studies have shown that the gut microbiota and its metabolites can regulate the immune response and modulate antiviral effects. In addition, the gut microbiota is closely related to gastrointestinal symptoms, such as diarrhea, a common gastrointestinal symptom among COVID-19. Therefore, the contribution of the gut microbiota in COVID-19 should not be overlooked. Strategies targeting the gut microbiota via probiotics, prebiotics and fecal microbiota transplantation should be considered to treat this patient population in the future. However, the specific alterations and mechanisms as well as the contributions of gut microbiota in COVID-19 should be urgently further explored.     

Does the gut microbiota have a role in type 1 diabetes? Early evidence from humans and animal models of the disease

Despite years of appreciating the potential role of environment to influence the pathogenesis of type 1 diabetes, specific agents or mechanisms serving in such a capacity remain ill defined. This is exceedingly disappointing as the identification of factors capable of modulating the disease, either as triggers or regulators of the autoimmune response underlying type 1 diabetes, would not only provide clues as to why the disorder develops but, in addition, afford opportunities for improved biomarkers of disease activity and the potential to design novel therapeutics capable of disease abatement. Recent improvements in sequencing technologies, combined with increasing appreciation of the role of innate and mucosal immunity in human disease, have stirred strong interest in what is commonly referred to as the ‘gut microbiota’. The gut (or intestinal) microbiota is an exceedingly complex microenvironment that is intimately linked with the immune system, including the regulation of immune responses. After evaluating evidence supporting a role for environment in type 1 diabetes, this review will convey current notions for contributions of the gut microbiota to human health and disease, including information gleaned from studies of humans and animal models for this autoimmune disorder.     

Gut Microbiota in Metabolic-associated Fatty Liver Disease and in Other Chronic Metabolic Diseases

The gut microbiome plays a key role in the health-disease balance in the human body. Although its composition is unique for each person and tends to remain stable throughout lifetime, it has been shown that certain bacterial patterns may be determining factors in the onset of certain chronic metabolic diseases, such as type 2 diabetes mellitus (T2DM), obesity, metabolic-associated fatty liver disease (MAFLD), and metabolic syndrome. The gut-liver axis embodies the close relationship between the gut and the liver; disturbance of the normal gut microbiota, also known as dysbiosis, may lead to a cascade of mechanisms that modify the epithelial properties and facilitate bacterial translocation. Regulation of gut microbiota is fundamental to maintaining gut integrity, as well as the bile acids composition. In the present review, we summarize the current knowledge regarding the microbiota, bile acids composition and their association with MAFLD, obesity, T2DM and metabolic syndrome.     

肠道菌群和心血管疾病的免疫调节

心血管疾病是人类健康的第一杀手,发病率和死亡率逐年增加。数万亿微生物寄居于人类肠道,在心血管疾病及其相关的代谢、免疫反应中发挥着至关重要的作用。先天性和适应性免疫机制都参与了心血管疾病的发生发展,菌群组分和代谢产物可调节巨噬细胞、淋巴细胞等免疫细胞的分化及功能,并通过循环系统影响机体免疫稳态。本文将通过肠道菌群及其代谢产物与免疫系统的相互作用,讨论肠道菌群与心血管疾病发展之间潜在的免疫机制,为预防和治疗心血管疾病提供新思路。     

Understanding the role of the gut ecosystem in diabetes mellitus

Diabetes mellitus is a type of metabolic disorder whereby patients are unable to regulate glycemia. It is currently a worldwide public health issue, and is a burden to society because of its disabling and common complications. Diabetes is multifactorial, and also induces the onset of other diseases. In the present report, we review the labyrinth encompassing the gut microbiota and gut microbiota‐derived metabolites in type 1 diabetes and type 2 diabetes pathogenesis. There have been exceptional improvements in deoxyribonucleic acid sequencing and mass spectrometry technologies throughout these past years, and these have allowed the comprehensive collection of information on our unique gut ecosystem. We would like to advocate incorporating metagenome and metabolome information for a comprehensive perspective of the complex interrelationships between the gut environment, host metabolism and diabetes pathogenesis. We hope that with this improved understanding we would be able to provide exciting novel therapeutic approaches to engineer an ideal gut ecosystem for optimal health.     

Programming of host metabolism by the gut microbiota

The human gut harbors a vast ensemble of bacteria that has co-evolved with the human host and performs several important functions that affect our physiology and metabolism. The human gut is sterile at birth and is subsequently colonized with bacteria from the mother and the environment. The complexity of the gut microbiota is increased during childhood, and adult humans contain 150-fold more bacterial genes than human genes. Recent advances in next-generation sequencing technology and mechanistic testing in gnotobiotic mice have identified the gut microbiota as an environmental factor that contributes to obesity. Germ-free mice are protected against developing diet-induced obesity and the underlying mechanisms whereby the gut microbiota contributes to host metabolism are beginning to be clarified. The obese phenotype is associated with increased microbial fermentation and energy extraction; however, other microbially modulated mechanisms contribute to disease progression as well. The gut microbiota has profound effects on host gene expression in the enterohepatic system, including genes involved in immunity and metabolism. For example, the gut microbiota affects expression of secreted proteins in the gut, which modulate lipid metabolism in peripheral organs. In addition, the gut microbiota is also a source of proinflammatory molecules that augment adipose inflammation and macrophage recruitment by signaling through the innate immune system. TLRs (Toll-like receptors) are integral parts of the innate immune system and are expressed by both macrophages and epithelial cells. Activation of TLRs in macrophages dramatically impairs glucose homeostasis, whereas TLRs in the gut may alter the gut microbial composition that may have profound effects on host metabolism. Accordingly, reprogramming the gut microbiota, or its function, in early life may have beneficial effects on host metabolism later in life.     

Role of gut microbiota,bile acids and their cross‐talk in the effects of bariatric surgery on obesity and type 2 diabetes

Type 2 diabetes mellitus is becoming increasingly prevalent worldwide, and has become one of the greatest threats to global health. Bariatric surgery was initially designed to achieve weight loss, and subsequently was noted to induce improvements or remission of type 2 diabetes. Currently, these bariatric operations, such as Roux‐en‐Y gastric bypass and sleeve gastrectomy, are the most effective procedures for the treatment of obesity and type 2 diabetes mellitus worldwide. However, the specific mechanism mediating the beneficial effects of metabolic surgery has remained largely unknown. Those mechanical explanations, such as restriction and malabsorption, are challenged by accumulating evidence from human and animal models of these procedures, which points to the weight‐independent factors, such as hormones, bile acids, gut microbiota, nervous system and other potential underlying mechanisms. A growing body of evidence suggests that gut microbiota are associated with the development of several metabolic disorders, and bile acids and FXR signaling are important for the metabolic benefits of bariatric surgery. Given the close relationship between bacteria and bile acids, it is reasonable to propose that microbiota–bile acid interactions play a role in the mechanisms underlying the effects of metabolic surgery.     

Bile acids and microbes in metabolic disease

Bile acids (BAs) serve as physiological detergents that enable the intestinal absorption and transportation of nutrients, lipids and vitamins. BAs are primarily produced by humans to catabolize cholesterol and play crucial roles in gut metabolism, microbiota habitat regulation and cell signaling. BA-activated nuclear receptors regulate the enterohepatic circulation of BAs which play a role in energy, lipid, glucose, and drug metabolism. The gut microbiota plays an essential role in the biotransformation of BAs and regulates BAs composition and metabolism. Therefore, altered gut microbial and BAs activity can affect human metabolism and thus result in the alteration of metabolic pathways and the occurrence of metabolic diseases/syndromes, such as diabetes mellitus, obesity/hypercholesterolemia, and cardiovascular diseases. BAs and their metabolites are used to treat altered gut microbiota and metabolic diseases. This review explores the increasing body of evidence that links alterations of gut microbial activity and BAs with the pathogenesis of metabolic diseases. Moreover, we summarize existing research on gut microbes and BAs in relation to intracellular pathways pertinent to metabolic disorders. Finally, we discuss how therapeutic interventions using BAs can facilitate microbiome functioning and ease metabolic diseases.     

Effects of gut microbiota on obesity and atherosclerosis via modulation of inflammation and lipid metabolism

Recent studies have revealed a close relationship between inflammatory and metabolic pathways, and inflammation is now recognized to have a major role in obesity and metabolic diseases such as insulin resistance and atherosclerosis. The human body is home to a large number of distinct microbial communities, with the densest population in the distal gut (the gut microbiota). Bacteria have long been known to activate inflammatory pathways, and recent data demonstrate that the gut microbiota may affect lipid metabolism and function as an environmental factor that influences the development of obesity and related diseases. Here, we review how the gut microbiota may affect metabolic diseases by activating the innate immune system.     

Effect of antibiotics on gut microbiota,glucose metabolism and body weight regulation: a review of the literature

Gut bacteria are involved in a number of host metabolic processes and have been implicated in the development of obesity and type 2 diabetes in humans. The use of antibiotics changes the composition of the gut microbiota and there is accumulating evidence from observational studies for an association between exposure to antibiotics and development of obesity and type 2 diabetes. In the present paper, we review human studies examining the effects of antibiotics on body weight regulation and glucose metabolism and discuss whether the observed findings may relate to alterations in the composition and function of the gut microbiota.     

The intestinal microbiota and chronic disorders of the gut

Mucosal surfaces of the gut are colonized by large numbers of heterogeneous bacteria that contribute to intestinal health and disease. In genetically susceptible individuals, a 'pathogenic community' may arise, whereby abnormal gut flora contributes to alterations in the mucosa and local immune system leading to gastrointestinal disease. These diseases include enteric infections, such as Clostridium difficile infection, small intestinal bacterial overgrowth, functional gastrointestinal disorders (including IBS), IBD and colorectal cancer. Prebiotics, probiotics and synbiotics (a combination of prebiotics and probiotics) have the capacity to reverse pathologic changes in gut flora and local immunity. Intestinal health and disease need to be thoroughly characterized to understand the interplay between the indigenous microbiota, the immune system and genetic host factors. This Review provides a broad overview of the importance of the intestinal microbiota in chronic disorders of the gut.     

The gut microbiota and metabolic disease: current understanding and future perspectives

The human gut microbiota has been studied for more than a century. However, of nonculture‐based techniques exploiting next‐generation sequencing for analysing the microbiota, development has renewed research within the field during the past decade. The observation that the gut microbiota, as an environmental factor, contributes to adiposity has further increased interest in the field. The human microbiota is affected by the diet, and macronutrients serve as substrates for many microbially produced metabolites, such as short‐chain fatty acids and bile acids, that may modulate host metabolism. Obesity predisposes towards type 2 diabetes and cardiovascular disease. Recently, it has been established that levels of butyrate‐producing bacteria are reduced in patients with type 2 diabetes, whereas levels of Lactobacillus sp. are increased. Recent data suggest that the reduced levels of butyrate‐producing bacteria might be causally linked to type 2 diabetes. Bariatric surgery, which promotes long‐term weight loss and diabetes remission, alters the gut microbiota in both mice and humans. Furthermore, by transferring the microbiota from postbariatric surgery patients to mice, it has been demonstrated that an altered microbiota may contribute to the improved metabolic phenotype following this intervention. Thus, greater understanding of alterations of the gut microbiota, in combination with dietary patterns, may provide insights into how the gut microbiota contributes to disease progression and whether it can be exploited as a novel diagnostic, prognostic and therapeutic target.     

Fasting intervention and its clinical effects on the human host and microbiome

Experimental trials in organisms ranging from yeast to humans have shown that various forms of reducing food intake (caloric restriction) appear to increase both overall and healthy lifespan, delaying the onset of disease and slowing the progression of biomarkers of aging. The gut microbiota is considered one of the key environmental factors strongly contributing to the regulation of host health. Perturbations in the composition and activity of the gut microbiome are thought to be involved in the emergence of multiple diseases. Indeed, many studies investigating gut microbiota have been performed and have shown strong associations between specific microorganisms and metabolic diseases including overweight, obesity, and type 2 diabetes mellitus as well as specific gastrointestinal disorders, neurodegenerative diseases, and even cancer. Dietary interventions known to reduce inflammation and improve metabolic health are potentiated by prior fasting. Inversely, birth weight differential host oxidative phosphorylation response to fasting implies epigenetic control of some of its effector pathways. There is substantial evidence for the efficacy of fasting in improving insulin signaling and blood glucose control, and in reducing inflammation, conditions for which, additionally, the gut microbiota has been identified as a site of both risk and protective factors. Accordingly, human gut microbiota, both in symbiont and pathobiont roles, have been proposed to impact and mediate some health benefits of fasting and could potentially affect many of these diseases. While results from small-N studies diverge, fasting consistently enriches widely recognized anti-inflammatory gut commensals such as Faecalibacterium and other short-chain fatty acid producers, which likely mediates some of its health effects through immune system and barrier function impact.     

γ-氨基丁酸能信号系统与胰岛素抵抗

γ-氨基丁酸(GABA)是一种重要的抑制性神经递质,研究发现,除了神经系统外,GABA还广泛分布于脂肪、肝脏、肌肉等对胰岛素敏感的组织。GABA可通过对糖脂代谢、炎性反应、免疫应答、肠道菌群等途径的调控,增强外周组织胰岛素信号转导,从而改善胰岛素抵抗,为2型糖尿病的防治提供了新的方向。