Gut microbiome: Linking together obesity,bariatric surgery and associated clinical outcomes under a single focus

Obesity is increasingly prevalent in the post-industrial era, with increased mortality rates. The gut microbiota has a central role in immunological, nutritional and metabolism mediated functions, and due to its multiplexity, it is considered an independent organ. Modern high-throughput sequencing techniques have allowed phylogenetic exploration and quantitative analyses of gut microbiome and improved our current understanding of the gut microbiota in health and disease. Its role in obesity and its changes following bariatric surgery have been highlighted in several studies. According to current literature, obesity is linked to a particular microbiota profile that grants the host an augmented potential for calorie release, while limited diversity of gut microbiome has also been observed. Moreover, bariatric surgery procedures represent effective interventions for sustained weight loss and restore a healthier microbiota, contributing to the observed fat mass reduction and lean mass increase. However, newer evidence has shown that gut microbiota is only partially recovered following bariatric surgery. Moreover, several targets including FGF15/19 (a gut-derived peptide), could be responsible for the favorable metabolic changes of bariatric surgery. More randomized controlled trials and larger prospective studies that include well-defined cohorts are required to better identify associations between gut microbiota, obesity, and bariatric surgery.     

Microbiota of the gastrointestinal tract: Friend or foe?

The gut microbiota is currently considered an external organ of the human body that provides important mechanisms of metabolic regulation and protection. The gut microbiota encodes over 3 million genes, which is approximately 150 times more than the total number of genes present in the human genome. Changes in the qualitative and quantitative composition of the microbiome lead to disruption in the synthesis of key bacterial metabolites, changes in intestinal barrier function, and inflammation and can cause the development of a wide variety of diseases, such as diabetes, obesity, gastrointestinal disorders, cardiovascular issues, neurological disorders and oncological concerns. In this review, I consider issues related to the role of the microbiome in the regulation of intestinal barrier function, its influence on physiological and pathological processes occurring in the body, and potential new therapeutic strategies aimed at restoring the gut microbiome. Herewith, it is important to understand that the gut microbiota and human body should be considered as a single biological system, where change of one element will inevitably affect its other components. Thus, the study of the impact of the intestinal microbiota on health should be considered only taking into account numerous factors, the role of which has not yet been fully elucidated.     

Diagnostics and therapeutic implications of gut microbiota alterations in cardiometabolic diseases

Alterations in gut microbiota composition and its metabolic activity are emerging as one of the most powerful determinants of cardiovascular disease. Although our knowledge of the precise molecular mechanisms by which gut microbiota influences cardiometabolic homeostasis is still limited, a growing body of knowledge has recently been uncovered about the potential modulation of microbiome for cardiovascular diagnostic and therapeutic aspects. The multitude of interactions between the microorganisms inhabiting the digestive tract and the host has been recognized crucial in the development and progression of atherosclerosis, obesity, diabetes and hypertension. Here, we summarize the role of gut microbiota in host physiology as well as in the pathophysiology of the most common cardio-metabolic disorders, discussing the potential therapeutic opportunities offered by interventions aimed at modifying microbiome composition and activity.     

The microbiome and obesity: Is obesity linked to our gut flora?

The human gut is a lush microbial ecosystem containing about 100 trillion microorganisms, whose collective genome, the microbiome, contains 100-fold more genes than the entire human genome. The symbiosis of our extended genome plays a role in host homeostasis and energy extraction from diet. In this article, we summarize some of the studies that have advanced the understanding of the microbiome and its effects on metabolism, obesity, and health. Metagenomic studies demonstrated that certain mixes of gut microbiota may protect or predispose the host to obesity. Furthermore, microbiota transplantation studies in germ-free murine models showed that the efficient energy extraction traits of obese-type gut flora are transmissible. The proposed methods by which the microbiome may contribute to obesity include increasing dietary energy harvest, promoting fat deposition, and triggering systemic inflammation. Future treatments for obesity may involve modulation of gut microbiota using probiotics or prebiotics.     

Role of gut microbiota in cardiovascular diseases

The human gut is colonized by a community of microbiota, primarily bacteria,that exist in a symbiotic relationship with the host. Intestinal microbiota-host interactions play a critical role in the regulation of human physiology.Deleterious changes to the composition of gut microbiota, referred to as gut dysbiosis, has been linked to the development and progression of numerous diseases, including cardiovascular disease(CVD). Imbalances in host-microbial interaction impair homeostatic mechanisms that regulate health and can activate multiple pathways leading to CVD risk factor progression. Most CVD risk factors, including aging, obesity, dietary patterns, and a sedentary lifestyle, have been shown to induce gut dysbiosis. Dysbiosis is associated with intestinal inflammation and reduced integrity of the gut barrier, which in turn increases circulating levels of bacterial structural components and microbial metabolites,including trimethylamine-N-oxide and short-chain fatty acids, that may facilitate the development of CVD. This article reviews the normal function and composition of the gut microbiome, mechanisms leading to the leaky gut syndrome, its mechanistic link to CVD and potential novel therapeutic approaches aimed towards restoring gut microbiome and CVD prevention. As CVD is the leading cause of deaths globally, investigating the gut microbiota as a locus of intervention presents a novel and clinically relevant avenue for future research.     

Gut dysbiosis and heart failure: navigating the universe within

Alternations in gut microbial composition (i.e. loss of microbial diversity or ‘gut dysbiosis’) have been associated with heart failure with reduced ejection fraction (HFrEF). It has also been suggested that increased chronic low‐level inflammation and immune system dysregulation seen in patients with HFrEF could be related to gut dysbiosis and increased intestinal permeability. Hence, the concept of modulating gut microbial composition with the goal of reducing systemic inflammation and controlling HFrEF progression has generated a substantial interest in the scientific community. However, several challenges to the gut dysbiosis theory remain as the exact gut microbial composition in HFrEF patients in these studies is not the same and a common microbiome linked to HFrEF is not yet established. With the advances in culture independent sequencing techniques it has also become evident that the gut microbiome may be much more diverse than previously believed. Further, various ‘omic’ technologies have enabled us to appreciate the potential role of gut microbial metabolites in various physiological processes in the host. Hence, identification of specific gut microbial metabolites may offer an alternative approach at solving this gut microbiome‐HFrEF puzzle. In the current review, we evaluate the concept of gut symbiosis, the potential role of gut dysbiosis in systemic inflammation and HFrEF, and finally highlight the challenges faced by the gut dysbiosis theory in HFrEF and provide a framework for the possible solutions.     

Gut microbiota and obesity: An opportunity to alter obesity through faecal microbiota transplant (FMT)

Obesity is a global pandemic with immense health consequences for individuals and societies. Multiple factors, including environmental influences and genetic predispositions, are known to affect the development of obesity. Despite an increasing understanding of the factors driving the obesity epidemic, therapeutic interventions to prevent or reverse obesity are limited in their impact. Manipulation of the human gut microbiome provides a new potential therapeutic approach in the fight against obesity. Specific gut bacteria and their metabolites are known to affect host metabolism and feeding behaviour, and dysbiosis of this biosystem may lead to metabolic syndrome. Potential therapies to alter the gut microbiota to treat obesity include dietary changes, supplementation of the diet with probiotic organisms and prebiotic compounds that influence bacterial growth, and the use of faecal microbiota transplant, in which gut microbiota from healthy individuals are introduced into the gut. In this review, we examine the growing scientific evidence supporting the mechanisms by which the human gut microbiota may influence carbohydrate metabolism and obesity, and the various possible therapies that may utilize the gut microbiota to help correct metabolic dysfunction.     

Periodontal treatment and microbiome-targeted therapy in management of periodontitis-related nonalcoholic fatty liver disease with oral and gut dysbiosis

A growing body of evidence from multiple areas proposes that periodontal disease, accompanied by oral inflammation and pathological changes in the microbiome, induces gut dysbiosis and is involved in the pathogenesis of nonalcoholic fatty liver disease (NAFLD). A subgroup of NAFLD patients have a severely progressive form, namely nonalcoholic steatohepatitis (NASH), which is characterized by histological findings that include inflammatory cell infiltration and fibrosis. NASH has a high risk of further progression to cirrhosis and hepatocellular carcinoma. The oral microbiota may serve as an endogenous reservoir for gut microbiota, and transport of oral bacteria through the gastro-intestinal tract can set up a gut microbiome dysbiosis. Gut dysbiosis increases the production of potential hepatotoxins, including lipopolysaccharide, ethanol, and other volatile organic compounds such as acetone, phenol and cyclopentane. Moreover, gut dysbiosis increases intestinal permeability by disrupting tight junctions in the intestinal wall, leading to enhanced translocation of these hepatotoxins and enteric bacteria into the liver through the portal circulation. In particular, many animal studies support that oral administration of Porphyromonas gingivalis, a typical periodontopathic bacterium, induces disturbances in glycolipid metabolism and inflammation in the liver with gut dysbiosis. NAFLD, also known as the hepatic phenotype of metabolic syndrome, is strongly associated with metabolic complications, such as obesity and diabetes. Periodontal disease also has a bidirectional relationship with metabolic syndrome, and both diseases may induce oral and gut microbiome dysbiosis with insulin resistance and systemic chronic inflammation cooperatively. In this review, we will describe the link between periodontal disease and NAFLD with a focus on basic, epidemiological, and clinical studies, and discuss potential mechanisms linking the two diseases and possible therapeutic approaches focused on the microbiome. In conclusion, it is presumed that the pathogenesis of NAFLD involves a complex crosstalk between periodontal disease, gut microbiota, and metabolic syndrome. Thus, the conventional periodontal treatment and novel microbiome-targeted therapies that include probiotics, prebiotics and bacteriocins would hold great promise for preventing the onset and progression of NAFLD and subsequent complications in patients with periodontal disease.     

Gut microbiome in primary sclerosing cholangitis: A review

Primary sclerosing cholangitis(PSC) is a chronic cholestatic liver disease characterized by biliary inflammation and stricturing. Exploration of the pathogenesis of PSC in light of its association with inflammatory bowel disease(IBD) and the "gut-liver" axis is an emerging area of interest. A growing number of studies have begun to elucidate the role of the gut microbiota, its metabolites and its influence on host immune responses in the development of PSC and PSCIBD. Studies of the fecal microbiota have highlighted enriched levels of certain species, including Veillonella, Streptococcus and Enterococcus, among others. A heightened immune response to enteric dysbiosis and bacterial translocation have also been implicated. For example, Klebsiella pneumoniae strains derived from gnotobiotic mice transplanted with PSC-IBD microbiota were found to induce pore formation in human intestinal epithelial cells and enhanced Th17 responses. Gut microbes have additionally been hypothesized to be implicated in PSC pathogenesis through their role in the synthesis of various metabolites,including bile acids(BAs), which function as signaling molecules with important gut and hepatic effects. An expanded knowledge of the gut microbiome as it relates to PSC offers critical insight into the development of microbe-altering therapeutic interventions, such as antibiotics, nutritional interventions and fecal microbial transplantation. Some of these have already shown some preliminary evidence of benefit. Despite exciting progress in the field, much work remains to be done; areas that are particularly lacking include functional characterization of the microbiome and examination of pediatric populations. In this review, we summarize studies that have investigated the microbiome in PSC and PSC-IBD as well as putative mechanisms, including the potential role of metabolites, such as BAs. We then briefly review the evidence for interventions with microbe-altering properties for treating PSC.     

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.     

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.     

Mikrobiom,Adipositas und Energiestoffwechsel

Background

The gut microbiome has emerged as a key player in the modulation of the immune system and metabolism. Changes in the composition of the gut microbial ecosystems have been reported to be associated with metabolic diseases but also with the development and progression of cardiovascular diseases, inflammatory bowel disease, certain types of cancer and psychiatric diseases.

Objective

The role of the gut microbiome in the pathophysiology of obesity and type 2 diabetes, and treatment approaches based thereon are discussed.

Microbiome and pathophysiology

The pathophysiology in humans is not entirely understood. Studies in mice suggest a strong causal link between changes in the microbiome and the development of metabolic diseases. Potential mechanisms how the microbiome is linked to diseases of the host include signaling through lipopolysaccharides from gram-negative bacteria and interactions with the host immune system, fermentation of indigestible fiber to short chain fatty acids, modulation of bile acids, and bile acid signaling. Interactions between gut microbiota, its products, and the immune system may lead to an increased gut permeability resulting in visceral fat and liver inflammation with subsequent systemic subclinical inflammation (leaky gut hypothesis). Moreover, host-specific factors and environmental factors have been discussed to have a role.

Conclusion

Increasing knowledge in this area could contribute to the treatment of obesity and type 2 diabetes with fecal or targeted microbiota transplantation.

     

The human gut microbiome: Implications for future health care

In their intestine, humans possess an “extended genome” of millions of microbial genes—the microbiome. Because this complex symbiosis influences host metabolism, physiology, and gene expression, it has been proposed that humans are complex biologic “superorganisms.” Advances in microbiologic analysis and systems biology are now beginning to implicate the gut microbiome in the etiology of localized intestinal diseases such as the irritable bowel syndrome, inflammatory bowel disease, and colon cancer. These approaches also suggest possible links between the gut and previously unassociated systemic conditions such as type 2 diabetes and obesity. The elucidation of the intestinal microbiome is therefore likely to underpin future disease prevention strategies, personalized health care regimens, and the development of novel therapeutic interventions. This review summarizes the research that is defining our understanding of the intestinal microbiome and highlights future areas of research in gastroenterology and human health in which the intestinal microbiome will play a significant role.     

Vaccine therapy for dysbiosis-related diseases

Progress in genomic analysis has resulted in the proposal that the intestinal microbiota is a crucial environmental factor in the development of multifactorial diseases, such as obesity, diabetes, rheumatoid arthritis, and inflammatory bowel diseases represented by Crohn's disease and ulcerative colitis. Dysregulated gut microbiome contributes to the pathogenesis of such disorders; however, there are few effective treatments for controlling only disease-mediating bacteria. Here, we review current knowledge about the intestinal microbiome in health and disease,and discuss a regulatory strategy using a parenteral vaccine with emulsified curdlan and CpG oligodeoxynucleotides, which we have recently developed.Unlike other conventional injectable immunizations, our vaccine contributes to the induction of antigen-specific systemic and mucosal immunity. This vaccine strategy can prevent infectious diseases such as Streptococcus pneumoniae infection, and control metabolic symptoms mediated by intestinal bacteria(e.g.Clostridium ramosum) by induction of high titers of antigen-specific IgA at target mucosal sites. In the future, our vaccination approach could be an effective therapy for common infectious diseases and dysbiosis-related disorders that have been difficult to control so far.     

Inflammation,microbiome and colorectal cancer disparity in African-Americans: Are there bugs in the genetics?

Dysregulated interactions between host inflammation and gut microbiota over the course of life increase the risk of colorectal cancer (CRC). While environmental factors and socio-economic realities of race remain predominant contributors to CRC disparities in African-Americans (AAs), this review focuses on the biological mediators of CRC disparity, namely the under-appreciated influence of inherited ancestral genetic regulation on mucosal innate immunity and its interaction with the microbiome. There remains a poor understanding of mechanisms linking immune-related genetic polymorphisms and microbiome diversity that could influence chronic inflammation and exacerbate CRC disparities in AAs. A better understanding of the relationship between host genetics, bacteria, and CRC pathogenesis will improve the prediction of cancer risk across race/ethnicity groups overall.     

盐、肠道微生物群及其代谢产物和血压水平的关系研究进展

随着人们对高血压的深入了解,越来越多的证据表明高血压患者的血压水平与钠盐关系密切。肠道微生物群由细菌、古菌、真菌、原生动物和病毒等构成,也被称为肠道菌群,肠道菌群及其代谢产物作为当前高血压的热门研究方向,其在钠盐与血压之间扮演了重要的角色。过量钠盐能够改变肠道菌群类群和比例,影响机体炎症水平和代谢水平等因素可能是高血压的发生和发展的机制。控制钠盐摄入是一项低成本且有效的血压控制方式。本文就钠盐、肠道菌群和高血压之间的复杂关系进行综述,希望能够为高血压的预防、治疗和控制提供理论支持。     

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.     

Microbiota in obesity: interactions with enteroendocrine,immune and central nervous systems

Western diets, with high consumption of simple sugars and saturated fats, contribute to the rise in the prevalence of obesity. It now seems clear that high‐fat diets cause obesity, at least in part, by modifying the composition and function of the microorganisms that colonize in the gastrointestinal tract, the microbiota. The exact pathways by which intestinal microbiota contribute to obesity remain largely unknown. High‐fat diet‐induced alterations in intestinal microbiota have been suggested to increase energy extraction, intestinal permeability and systemic inflammation while decreasing the capability to generate obesity‐suppressing short‐chain fatty acids. Moreover, by increasing systemic inflammation, microglial activation and affecting vagal nerve activity, ‘obese microbiota’ indirectly influence hypothalamic gene expression and promote overeating. Because the potential of intestinal microbiota to induce obesity has been recognized, multiple ways to modify its composition and function are being investigated to provide novel preventive and therapeutic strategies against diet‐induced obesity.     

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     

Weight‐loss interventions and gut microbiota changes in overweight and obese patients: a systematic review

Imbalances in the gut microbiota, the bacteria that inhabit the intestines, are central to the pathogenesis of obesity. This systematic review assesses the association between the gut microbiota and weight loss in overweight/obese adults and its potential manipulation as a target for treating obesity. This review identified 43 studies using the keywords ‘overweight’ or ‘obesity’ and ‘microbiota’ and related terms; among these studies, 17 used dietary interventions, 11 used bariatric surgery and 15 used microbiota manipulation. The studies differed in their methodologies as well as their intervention lengths. Restrictive diets decreased the microbiota abundance, correlated with nutrient deficiency rather than weight loss and generally reduced the butyrate producers Firmicutes, Lactobacillus sp. and Bifidobacterium sp. The impact of surgical intervention depended on the given technique and showed a similar effect on butyrate producers, in addition to increasing the presence of the Proteobacteria phylum, which is related to changes in the intestinal absorptive surface, pH and digestion time. Probiotics differed in strain and duration with diverse effects on the microbiota, and they tended to reduce body fat. Prebiotics had a bifidogenic effect and increased butyrate producers, likely due to cross‐feeding interactions, contributing to the gut barrier and improving metabolic outcomes. All of the interventions under consideration had impacts on the gut microbiota, although they did not always correlate with weight loss. These results show that restrictive diets and bariatric surgery reduce microbial abundance and promote changes in microbial composition that could have long‐term detrimental effects on the colon. In contrast, prebiotics might restore a healthy microbiome and reduce body fat.