Gut microbiota and obesity: Role in aetiology and potential therapeutic target

Obesity is epidemic; chronic energy surplus is clearly important in obesity development but other factors are at play. Indigenous gut microbiota are implicated in the aetiopathogenesis of obesity and obesity-related disorders. Evidence from murine models initially suggested a role for the gut microbiota in weight regulation and the microbiota has been shown to contribute to the low grade inflammation that characterises obesity. The microbiota and its metabolites mediate some of the alterations of the microbiota–gut–brain axis, the endocannabinoid system, and bile acid metabolism, found in obesity-related disorders. Modulation of the gut microbiota is an attractive proposition for prevention or treatment of obesity, particularly as traditional measures have been sub-optimal     

Nutrition,the gut microbiome and the metabolic syndrome

Metabolic syndrome is a lifestyle disease, determined by the interplay of genetic and environmental factors. Obesity is a significant risk factor for development of the metabolic syndrome, and the prevalence of obesity is increasing due to changes in lifestyle and diet. Recently, the gut microbiota has emerged as an important contributor to the development of obesity and metabolic disorders, through its interactions with environmental (e.g. diet) and genetic factors. Human and animal studies have shown that alterations in intestinal microbiota composition and shifts in the gut microbiome towards increased energy harvest are associated with an obese phenotype. However, the underlying mechanisms by which gut microbiota affects host metabolism still need to be defined.In this review we discuss the complexity surrounding the interactions between diet and the gut microbiota, and their connection to obesity. Furthermore, we review the literature on the effects of probiotics and prebiotics on the gut microbiota and host metabolism, focussing primarily on their anti-obesity potential.     

Targeting gut microbiota in obesity: effects of prebiotics and probiotics

At birth, the human colon is rapidly colonized by gut microbes. Owing to their vast number and their capacity to ferment nutrients and secrete bioactive compounds, these gastrointestinal microbes act as an environmental factor that affects the host's physiology and metabolism, particularly in the context of obesity and its related metabolic disorders. Experiments that compared germ-free and colonized mice or analyzed the influence of nutrients that qualitatively change the composition of the gut microbiota (namely prebiotics) showed that gut microbes induce a wide variety of host responses within the intestinal mucosa and thereby control the gut's barrier and endocrine functions. Gut microbes also influence the metabolism of cells in tissues outside of the intestines (in the liver and adipose tissue) and thereby modulate lipid and glucose homeostasis, as well as systemic inflammation, in the host. A number of studies describe characteristic differences between the composition and/or activity of the gut microbiota of lean individuals and those with obesity. Although these data are controversial, they suggest that specific phyla, classes or species of bacteria, or bacterial metabolic activities could be beneficial or detrimental to patients with obesity. The gut microbiota is, therefore, a potential nutritional and pharmacological target in the management of obesity and obesity-related disorders.     

RETRACTED ARTICLE: Gut microbiota and related diseases: clinical features

Intestinal microbiota is essential for gut homeostasis. Specifically, the microorganisms inhabiting the gut lumen interact with the intestinal immune system, supply key nutrients for the major components of the gut wall, and modulate energy metabolism. Host–microbiome interactions can be either beneficial or deleterious, driving gastrointestinal lymphoid tissue activities and shaping gut wall structures. This overview briefly focuses on the potential role played by abnormalities in gut microbiota and relative responses of the gastrointestinal tract in the determination of important pathological conditions such as the irritable bowel syndrome, inflammatory bowel diseases and colorectal cancer.     

Novel Players in Inflammatory Bowel Disease Pathogenesis

Technological and conceptual advances in inflammatory bowel disease research have uncovered new mechanisms that contribute to the pathogenesis of these disorders. It is becoming increasingly clear that the microbiota of the gut and the response of intestinal cells to that microbiota can initiate or contribute to intestinal inflammation. Evidence from genetic studies have identified IBD-associated genes implicated in autophagy and innate sensing of microbes. These genes also play key roles in the homeostasis of a cell type that stands at the interface of host-microbial interaction – the Paneth cell. Here we discuss recent findings that underscore the importance of the microbiome, Paneth cells and autophagy in inflammatory bowel disease.     

Yogurt-sourced probiotic bacteria alleviate shrimp tropomyosin-induced allergic mucosal disorders,potentially through microbiota and metabolism modifications

BackgroundShrimp tropomyosin (TM) is a major food allergen that may cause serious allergic responses, lactic acid-producing bacteria (LAPB) are believed to alleviate food allergy, but the mechanisms have not been fully clarified. The aim of this work is to investigate the mechanisms of LAPB in ameliorating food allergy-induced intestinal mucosal disorders and to investigate whether or not these disorders occur by the regulation of gut microbiota and metabolism.MethodsA TM allergy BALB/c mouse model was established, and two LAPB strains, Bifidobacterium longum (Bi) and Bacillus coagulans (Bc), were used for oral treatment in sensitized mice. The allergic mucosal disorders were assessed by histological analysis and ELISAs. Additionally, microbiota and metabolic modifications were determined by 16S rRNA gene amplicon sequencing and GC-TOF-MS, respectively.ResultsYSPB administration suppressed TM-induced intestinal mucosal disorders, restored allergenic Th2 cell over-polarization and dysbiosis, and regulated gut arginine and proline metabolism pathways. Statistical analysis suggested the metabolites aspartate and arginine, as well as several commensal flora groups, to be the critical mediators in the process.ConclusionsThese data demonstrated the correlation between allergic mucosal disorder, T cell subtype differentiation, gut microbiota composition and intestinal metabolism especially the arginine and proline metabolism pathways. We also revealed the significant effects of LAPB in ameliorating food allergy and maintaining the mucosal ecosystem. This study confirmed the efficiency of LAPB in relieving food allergy, provided Bi and Bc as the potential treatment approaches, and suggested amino acid metabolism pathways might be the novel targets for potential clinical applications.     

The normal intestinal microbiota

PURPOSE OF REVIEW: Long neglected and considered a difficult ecosystem to study, several developments have recently converged to renew interest in studying the normal gut microbiota. These include molecular methods of studying the microbiota, improved understanding of host-microbe interactions in health and disease, and the potential for therapeutic manipulation of the microbiota. This review focuses on the most recent work in these areas. RECENT FINDINGS: Host-microbe signaling in the gut is critical for normal development and homeostasis of the gastrointestinal mucosa. The molecular basis of these interactions promises new therapeutic strategies for various disorders. Particularly noteworthy has been the emergence of evidence for the role of enteric bacterial metabolism in the pathogenesis of disorders ranging from functional and inflammatory bowel diseases to human obesity. Metagenomic and metabolomic profiling of the microbiota, although at an early stage, has demonstrated the range and complexity of the gut ecosystem and cast insights into several diseases. The molecular basis of host-microbe dialogue and the mechanisms by which the host contains enteric bacteria within the lumen has immediate relevance to infectious and chronic inflammatory bowel disease. SUMMARY: Improved understanding of the normal gut microbiota has made the therapeutic manipulation of the gut ecosystem a valid and realistic future prospect.     

Pathophysiological mechanisms underlying gastrointestinal symptoms in patients with COVID-19

Gastrointestinal (GI) symptoms, such as diarrhea, abdominal pain, vomiting, and anorexia, are frequently observed in patients with coronavirus disease 2019 (COVID-19). However, the pathophysiological mechanisms connecting these GI symptoms to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections remain elusive. Previous studies indicate that the entry of SARS-CoV-2 into intestinal cells leads to downregulation of angiotensin converting enzyme 2 (ACE2) receptors resulting in impaired barrier function. While intestinal ACE2 functions as a chaperone for the amino acid transporter B0AT1, the B0AT1/ACE2 complex within the intestinal epithelium acts as a regulator of gut microbiota composition and function. Alternations to the B0AT1/ACE2 complex lead to microbial dysbiosis through increased local and systemic immune responses. Previous studies have also suggested that altered serotonin metabolism may be the underlying cause of GI disorders involving diarrhea. The findings of elevated plasma serotonin levels and high fecal calprotectin in COVID-19 patients with diarrhea indicate that the viral infection evokes a systemic inflammatory response that specifically involves the GI. Interestingly, the elevated proinflammatory cytokines correlate with elevated serotonin and fecal calprotectin levels further supporting the evidence of GI inflammation, a hallmark of functional GI disorders. Moreover, the finding that rectal swabs of COVID-19 patients remain positive for SARS-CoV-2 even after the nasopharynx clears the virus, suggests that viral replication and shedding from the GI tract may be more robust than that of the respiratory tract, further indicating fecal-oral transmission as another important route of viral spread. This review summarized the evidence for pathophysiological mechanisms (impaired barrier function, gut inflammation, altered serotonin metabolism and gut microbiota dysbiosis) underlying the GI symptoms in patients with COVID-19.     

Frailty and the gut

Frailty, which is a syndrome that encompasses losses in physical, psychological and social domains, is responsible for enhanced vulnerability to endogenous and/or exogenous stressors. Frailty is a public health problem for an ageing society; however, it is poorly understood and often under-recognised in clinical settings. In particular, the impact of frailty on either intestinal functions, i.e. immune response, permeability, and absorption, or gut microbiota composition is as yet mostly unexplored. A better comprehension of the intestinal dysfunction occurring in the elderly would help in clarifying the mechanisms predisposing frail patients to a higher risk of infectious or inflammatory events. Moreover, recent evidence suggests that senescence-induced perturbations of the gut–brain axis are involved in the neuroinflammation process, thus raising the hypothesis that preserving gut permeability and preventing frailty-related changes in the microbiota composition might reduce the susceptibility to develop neurodegenerative disorders. In this review, we highlight the current insights concerning the relationship between frailty, intestinal functions, microbiota, and gut–brain axis.     

Gut microbiota-derived metabolites as key mucosal barrier modulators in obesity

A significant breakthrough in the field of obesity research was the demonstration that an obese phenotype could be manipulated by modulating the gut microbiota. An important next step is to elucidate a human-relevant “map’’ of microbiota-host interactions that regulate the metabolic health of the host. An improved understanding of this crosstalk is a prerequisite for optimizing therapeutic strategies to combat obesity. Intestinal mucosal barrier dysfunction is an important contributor to metabolic diseases and has also been found to be involved in a variety of other chronic inflammatory conditions, including cancer, neurodegeneration, and aging. The mechanistic basis for intestinal barrier dysfunction accompanying metabolic disorders remains poorly understood. Understanding the molecular and cellular modulators of intestinal barrier function will help devise improved strategies to counteract the detrimental systemic consequences of gut barrier breakage. Changes in the composition and function of the gut microbiota, i.e., dysbiosis, are thought to drive obesity-related pathogenesis and may be one of the most important drivers of mucosal barrier dysfunction. Many effects of the microbiota on the host are mediated by microbiota-derived metabolites. In this review, we focus on several relatively well-studied microbial metabolites that can influence intestinal mucosal homeostasis and discuss how they might affect metabolic diseases. The design and use of microbes and their metabolites that are locally active in the gut without systemic side effects are promising novel and safe therapeutic modalities for metabolic diseases.     

Gut microbiota and nonalcoholic fatty liver disease

Recent evidence has linked obesity and the metabolic syndrome with gut dysbiota. The precise mechanisms underlying that association are not entirely understood; however, microbiota can enhance the extraction of energy from diet and regulate whole-body metabolism towards increased fatty acids uptake from adipose tissue and shift lipids metabolism from oxidation to de novo production. Obesity and high fat diet relate to a specific gut microbiota, which is enriched in Firmicutes and with less Bacterioidetes. Microbiota can also play a role in the development of hepatic steatosis, necroinflammation and fibrosis. In fact, some studies have shown an association between small intestinal bacterial overgrowth, increased intestinal permeability and nonalcoholic steatohepatitis (NASH). That association is, in part, due to increased endotoxinaemia and activation of the Toll-like receptor-4 signaling cascade. Preliminary data on probiotics suggest a potential role in NASH treatment, however randomized controlled clinical trials are still lacking.     

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.     

The canine gastrointestinal microbiota: early studies and research frontiers

ABSTRACT

The canine gut microbiota is a complex microbial population that is potentially related to metabolism, immunologic activity and gastrointestinal (GI) diseases. Early studies revealed that the canine gut microbiota was dynamic, and bacterial populations in the adjacent gut segments were similar, with anaerobes predominating. Metagenomics analysis revealed that nutrient contents in the diet modulated bacterial populations and metabolites in the canine gut. Further research revealed significant correlations between dietary factors and canine gut core microbiomes. Canine GI diseases are closely correlated with gut microbiota dysbiosis and metabolic disorders. Probiotic-related therapies can effectively treat canine GI diseases. Recent studies have revealed that the canine gut microbiota is similar to the human gut microbiota, and dietary factors affect both. Studying canine intestinal microorganisms enables clarifying changes in the canine intestinal bacteria under different conditions, simulating human diseases in dog models, and conducting in-depth studies of the interactions between intestinal bacteria and disease.     

Modulation of the gut microbiota by metformin improves metabolic profiles in aged obese mice

The gut microbiota is a contributing factor in obesity-related metabolic disorders. The effect of metformin on the gut microbiota has been reported; however, the relationship between the gut microbiota and the mechanism of action of metformin in elderly individuals is unclear. In this study, the effect of metformin on the gut microbiota was investigated in aged obese mice. The abundance of the genera Akkermansia, Bacteroides, Butyricimonas, and Parabacteroides was significantly increased by metformin in mice fed a high-fat diet. Metformin treatment decreased the expression of IL-1β and IL-6 in epididymal fat, which was correlated with the abundance of various bacterial genera. In addition, both fecal microbiota transplantation from metformin-treated mice and extracellular vesicles of Akkermansia muciniphila improved the body weight and lipid profiles of the mice. Our findings suggest that modulation of the gut microbiota by metformin results in metabolic improvements in aged mice, and that these effects are associated with inflammatory immune responses.     

Gut microbiota and obesity

The human gut hosts more than 100 trillion microorganisms, encompassing thousands of species. In adults, Bacteroidetes and Firmicutes are the most prevalent phyla. Experimental data in animal and observational studies in obese patients suggest that obesity is associated with substantial changes in the composition and metabolic function of the gut microbiota. The initial findings linked obesity with the decreased relative proportion of Bacteroidetes to Firmicutes. There are some authors who suggest that probiotics and prebiotics can modulate obesity-host metabolism in obesity and obesity-related disorders.     

Physiology and pathophysiology of liver lipid metabolism

Liver lipid metabolism and its modulation are involved in many pathologic conditions, such as obesity, non-alcoholic fatty liver disease, diabetes mellitus, atherosclerosis and cardiovascular disease. Metabolic disorders seem to share a similar background of low-grade chronic inflammation, even if the pathophysiological mechanisms leading to tissue and organ damage have not been completely clarified yet. The accumulation of neutral lipids in the liver is now recognized as a beneficial and protective mechanism; on the other hand, lipoperoxidation is involved in the development and progression of non-alcoholic steatohepatitis. The role of the gut microbiota in liver lipid metabolism has been the object of recent scientific investigations. It is likely that the gut microbiota is involved in a complex metabolic modulation and the translocation of gut microflora may also contribute to maintaining the low-grade inflammatory status of metabolic syndrome. Therefore, lipid metabolism pathology has vague limits and complex mechanisms, and the knowledge of these is essential to guide diagnostic and therapeutic decisions.     

First victim,later aggressor: How the intestinal microbiota drives the pro-inflammatory effects of dietary emulsifiers?

The intestinal tract is inhabited by a large and diverse community of bacteria, collectively referred to as the gut microbiota. Composed of 500–1000 distinct species, the intestinal microbiota plays an important role in immunity and metabolism. However, alterations in its composition are associated with a variety of inflammatory diseases including obesity, diabetes, and inflammatory bowel disease (IBD). Among many other factors, our diet impacts microbiota composition and function, in either beneficial or detrimental ways. In this addendum, we will discuss our recent findings on how dietary emulsifying agents can directly and detrimentally impact the microbiota, leading to inflammatory diseases and cancer.     

Metagenomics: key to human gut microbiota

The human gastrointestinal tract harbors the most complex human microbial ecosystem (intestinal microbiota). The comprehensive genome of these microbial populations (intestinal microbiome) is estimated to have a far greater genetic potential than the human genome itself. Correlations between changes in composition and activity of the gut microbiota and common disorders, such as inflammatory bowel diseases, obesity, diabetes, and atopic diseases, have been proposed, increasing the interest of the scientific community in this research field. In this perspective, a comprehensive and detailed view of the human gut microbiota, in terms of phylogenetic composition as well as genetic and metabolic potential, is essential to understand the dynamics and possible mechanisms of the cause/effect relationships between gut microbiota and pathology. Metagenomics has emerged as one of the most powerful sequence-driven approaches to study the composition and the genetic potential of this complex ecosystem, and efforts in this direction have been smoothed by the implementation of next generation sequencing platforms. Here, we highlight the potential of the newest high-throughput, culture-independent approaches for the characterization of the human gut microbiome in health and disease. Recent and promising results in this field are presented, underlining the perspectives and future research direction of human gut microbial ecology.     

便秘状态下肠道菌群变化对脂代谢的影响

肠道菌群的稳定在维持机体健康中发挥重要作用,当便秘引起肠道菌群失衡时,它通过干扰胆汁酸(bile acids,BAs)的合成影响脂质消化、吸收过程;肠道菌群代谢物短链脂肪酸(short chain fatty acids,SCFAs)减少可破坏肠道黏膜屏障的完整性,且SCFAs的受体不能被激活,此外,氧化三甲胺(trimethylamine oxide,TMAO)产生量增多影响脂质代谢过程中关键酶的表达,进一步影响脂质转运、清除过程.本文就便秘状态下肠道菌群通过BAs、SCFAs、TMAO的变化介导脂代谢紊乱的机制作一综述.     

Intestinal microbiota and type 2 diabetes: From mechanism insights to therapeutic perspective

The incidence of type 2 diabetes (T2DM) is rapidly increasing worldwide. However, the pathogenesis of T2DM has not yet been well explained. Recent evidence suggests that the intestinal microbiota composition is associated with obesity and T2DM. In this review, we provide an overview about the mechanisms underlying the role of intestinal microbiota in the pathogenesis of T2DM. There is clear evidence that the intestinal microbiota influences the host through its effect on body weight, bile acid metabolism, proinflammatory activity and insulin resistance, and modulation of gut hormones. Modulating gut microbiota with the use of probiotics, prebiotics, antibiotics, and fecal microbiota transplantation may have benefits for improvement in glucose metabolism and insulin resistance in the host. Further studies are required to increase our understanding of the complex interplay between intestinal microbiota and the host with T2DM. Further studies may be able to boost the development of new effective therapeutic approaches for T2DM.