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.     

Microbes: possible link between modern lifestyle transition and the rise of metabolic syndrome

The rapid decrease in infectious diseases globally has coincided with an increase in the prevalence of obesity and other components of metabolic syndrome. Insulin resistance is a common feature of metabolic syndrome and can be influenced by genetic and non‐genetic/environmental factors. The emergence of metabolic syndrome epidemics over only a few decades suggests a more prominent role of the latter. Changes in our environment and lifestyle have indeed paralleled the rise in metabolic syndrome. Gastrointestinal tract microbiota, the composition of which plays a significant role in host physiology, including metabolism and energy homeostasis, are distinctly different within the context of metabolic syndrome. Among humans, recent lifestyle‐related changes could be linked to changes in diversity and composition of ‘ancient’ microbiota. Given the co‐adaptation and co‐evolution of microbiota with the immune system over a long period of time, it is plausible that such lifestyle‐related microbiota changes could trigger aberrant immune responses, thereby predisposing an individual to a variety of diseases. Here, we review current evidence supporting a role for gut microbiota in the ongoing rise of metabolic syndrome. We conclude that population‐level shifts in microbiota can play a mediatory role between lifestyle factors and pathogenesis of insulin resistance and metabolic syndrome.     

Variants in genes of innate immunity,appetite control and energy metabolism are associated with host cardiometabolic health and gut microbiota composition

ABSTRACT

Identifying the genetic and non-genetic determinants of obesity and related cardiometabolic dysfunctions is cornerstone for their prevention, treatment, and control. While genetic variants contribute to the cardiometabolic syndrome (CMS), non-genetic factors, such as the gut microbiota, also play key roles. Gut microbiota is intimately associated with CMS and its composition is heritable. However, associations between this microbial community and host genetics are understudied. We contribute filling this gap by genotyping 60 variants in 39 genes of three modules involved in CMS risk, measuring cardiometabolic risk factors, and characterizing gut microbiota in a cohort of 441 Colombians. We hypothesized that CMS risk variants were correlated with detrimental levels of clinical parameters and with the abundance of disease-associated microbes. We found several polymorphisms in genes of innate immunity, appetite control, and energy metabolism that were associated with metabolic dysregulation and microbiota composition; the associations between host genetics and cardiometabolic health were independent of the participants’ gut microbiota, and those between polymorphisms and gut microbes were independent of the CMS risk. Associations were also independent of the host genetic ancestry, diet and lifestyle. Most microbes explaining genetic-microbiota associations belonged to the families Lachnospiraceae and Ruminococcaceae. Multiple CMS risk alleles were correlated with increased abundance of beneficial microbiota, suggesting that the phenotypic outcome of the evaluated variants might depend upon the genetic background of the studied population and its environmental context. Our results provide additional evidence that the gut microbiota is under the host genetic control and present pathways of host–microbe interactions.     

Gut microbiota and non-alcoholic fatty liver disease

BACKGROUND: Non-alcoholic fatty liver disease(NAFLD) is a common disorder with poorly understood pathogenesis. Beyond environmental and genetic factors,cumulative data support the causative role of gut microbiota in disease development and progression.DATA SOURCE: We performed a Pub Med literature search with the following key words: "non-alcoholic fatty liver disease","non-alcoholic steatohepatitis","fatty liver","gut microbiota" and "microbiome",to review the data implicating gut microbiota in NAFLD development and progression.RESULTS: Recent metagenomic studies revealed differences in the phylum and genus levels between patients with fatty liver and healthy controls. While bacteroidetes and firmicutes remain the dominant phyla among NAFLD patients,their proportional abundance and genera detection vary among different studies. New techniques indicate a correlation between the methanogenic archaeon(methanobrevibacter smithii) and obesity,while the bacterium akkermanshia municiphila protects against metabolic syndrome. Among NAFLD patients,small intestinal bacterial overgrowth detected by breath tests might induce gut microbiota and host interactions,facilitating disease development.CONCLUSIONS: There is evidence that gut microbiota participates in NAFLD development through,among others,obesity induction,endogenous ethanol production,inflammatory response triggering and alterations in choline metabolism. Further studies with emerging techniques are needed to further elucidate the microbiome and host crosstalk in NAFLD pathogenesis.     

The therapeutic potential of manipulating gut microbiota in obesity and type 2 diabetes mellitus

Obesity and type 2 diabetes mellitus (T2DM) are attributed to a combination of genetic susceptibility and lifestyle factors. Their increasing prevalence necessitates further studies on modifiable causative factors and novel treatment options. The gut microbiota has emerged as an important contributor to the obesity--and T2DM--epidemic proposed to act by increasing energy harvest from the diet. Although obesity is associated with substantial changes in the composition and metabolic function of the gut microbiota, the pathophysiological processes remain only partly understood. In this review we will describe the development of the adult human microbiome and discuss how the composition of the gut microbiota changes in response to modulating factors. The influence of short-chain fatty acids, bile acids, prebiotics, probiotics, antibiotics and microbial transplantation is discussed from studies using animal and human models. Ultimately, we aim to translate these findings into therapeutic pathways for obesity and T2DM in humans.     

Triggering Akkermansia with dietary polyphenols: A new weapon to combat the metabolic syndrome?

The gut and its bacterial colonizers are now well characterized as key players in whole-body metabolism, opening new avenues of research and generating great expectation for new treatments against obesity and its cardiometabolic complications. As diet is the main environmental factor affecting the gut microbiota, it has been suggested that fruits and vegetables, whose consumption is strongly associated with a healthy lifestyle, may carry phytochemicals that could help maintain intestinal homeostasis and metabolic health. We recently demonstrated that oral administration of a cranberry extract rich in polyphenols prevented diet-induced obesity and several detrimental features of the metabolic syndrome in association with a remarkable increase in the abundance of the mucin-degrading bacterium Akkermansia in the gut microbiota of mice. This addendum provides an extended discussion in light of recent discoveries suggesting a mechanistic link between polyphenols and Akkermansia, also contemplating how this unique microorganism may be exploited to fight the metabolic syndrome.     

Insulin resistance,adipose depots and gut: Interactions and pathological implications

This review article focuses on the many metabolic actions of insulin at the level of muscle, liver and adipose tissue. In terms of pathogenetic mechanisms, the condition of insulin resistance is complex, as multiple genetic and environmental factors, among which an increasingly sedentary lifestyle associated with high-fat diet, mutually interact according to variable patterns in time in any given individual. It is well recognized that obesity (in particular abdominal obesity) favours the development of insulin resistance. Here we evaluate the impact of obesity and ectopic fat accumulation (visceral and hepatic) on insulin resistance at the level of different target organs, i.e., muscle, liver and adipose tissue. The roles of the gut and the liver, in particular of bile acids and gut microflora, are also discussed as possible determinants of energy balance and glucose metabolism.     

Gut microbiota in obesity

Obesity is a major global health problem determined by heredity and environment, and its incidence is increasing yearly. In recent years, increasing evidence linking obesity to the gut microbiota has been reported. Gut microbiota management has become a new method of obesity treatment. However, the complex interactions among genetics, environment, the gut microbiota, and obesity remain poorly understood. In this review, we summarize the characteristics of the gut microbiota in obesity, the mechanism of obesity induced by the gut microbiota, and the influence of genetic and environmental factors on the gut microbiota and obesity to provide support for understanding the complex relationship between obesity and microbiota. At the same time, the prospect of obesity research related to the gut microbiota is proposed.     

Do nutrient–gut–microbiota interactions play a role in human obesity,insulin resistance and type 2 diabetes?

The current obesity and type 2 diabetes pandemics have causes beyond changes in eating and exercise habits against a susceptible genetic background. Gut bacteria seem to additionally contribute to the differences in body weight, fat distribution, insulin sensitivity and glucose‐ and lipid‐metabolism. Data, mostly derived from preclinical studies, suggest that gut microbiota play an important role in conditions such as obesity, diabetes, metabolic syndrome and non‐alcoholic fatty liver disease. Regulation of energy uptake from the gut, by digesting otherwise indigestible common polysaccharides in our diet, production or activation of signalling molecules involved in host metabolism, modification of gut permeability, the release of gut hormones and inflammation, are among the mechanisms by which gut microbiota may influence the host cardiometabolic phenotype. Recent evidence suggests that quantitative and qualitative differences in gut microbiota exist between lean and obese, and between diabetic and non‐diabetic individuals. Modification of the gut microbiota composition and/or its biochemical capacity by specific dietary or pharmacological interventions may favourably affect host metabolism. Large‐scale intervention trials, investigating the potential benefit of prebiotics and probiotics in improving cardiometabolic health in high‐risk populations, are eagerly awaited.     

Gut microbial adaptation to dietary consumption of fructose,artificial sweeteners and sugar alcohols: implications for host–microbe interactions contributing to obesity

The Western diet, comprised of highly refined carbohydrates and fat but reduced complex plant polysaccharides, has been attributed to the prevalence of obesity. A concomitant rise in the consumption of fructose and sugar substitutes such as sugar alcohols, artificial sweeteners, even rare sugars, has mirrored this trend, as both probable contributor and solution to the epidemic. Acknowledgement of the gut microbiota as a factor involved in obesity has sparked much controversy as to the cause and consequence of this relationship. Dietary intakes are a known modulator of gut microbial phylogeny and metabolic activity, frequently exploited to stimulate beneficial bacteria, promoting health benefits. Comparably little research exists on the impact of ‘unconscious’ dietary modulation on the resident commensal community mediated by increased fructose and sugar substitute consumption. This review highlights mechanisms of potential host and gut microbial fructose and sugar substitute metabolism. Evidence is presented suggesting these sugar compounds, particularly fructose, condition the microbiota, resulting in acquisition of a westernized microbiome with altered metabolic capacity. Disturbances in host–microbe interactions resulting from fructose consumption are also explored.     

The environment within: how gut microbiota may influence metabolism and body composition

Obesity, diabetes and consequently atherosclerotic vascular disease have become major health and public health issues worldwide. The increasing and staggering prevalence of obesity might not only be explained by nutritional habits or the reduction of energy expenditure through decreased physical activity. In addition, recent studies have focused on intestinal microbiota as environmental factors that increase energy yield from diet, regulate peripheral metabolism and thereby increase body weight. Obesity is associated with substantial changes in composition and metabolic function of gut microbiota, but the pathophysiological processes driving this bidirectional relationship have not been fully elucidated. This review discusses the relationships between the following: composition of gut microbiota, energy extracted from diet, synthesis of gut hormones involved in energy homeostasis, production of butyrate and the regulation of fat storage.     

The gut microbiota,environment and diseases of modern society

The human gut microbiota is a complex community that provides important metabolic functions to the host. Consequently, alterations in the gut microbiota have been associated with the pathogenesis of several human diseases associated with a disturbance in metabolism, particularly those that have been increasing in incidence over the last several decades including obesity, diabetes and atherosclerosis. In this review, we explore how advances in deep DNA sequencing technology have provided us a greater understanding of the factors that influence that composition of the gut microbiota and its possible links to the pathogenesis of these diseases.     

The gut microbiota, environment and diseases of modern society

The human gut microbiota is a complex community that provides important metabolic functions to the host. Consequently, alterations in the gut microbiota have been associated with the pathogenesis of several human diseases associated with a disturbance in metabolism, particularly those that have been increasing in incidence over the last several decades including obesity, diabetes and atherosclerosis. In this review, we explore how advances in deep DNA sequencing technology have provided us a greater understanding of the factors that influence that composition of the gut microbiota and its possible links to the pathogenesis of these diseases.     

Gut Microbiota as a Modulator of Cardiometabolic Risk: Mechanisms and Therapeutic Implications

Obesity-related disorders result from the combination of genetic susceptibility and environmental factors, including gut microbiota. Evidence from animal models provides insight into several mechanisms underlying the interaction between microbiome and host metabolic and inflammatory responses, such as increased energy harvest from the diet, regulation of intestinal transit rate and mucosal barrier function, modulation of fatty acid metabolism, and lipopolysaccharide-induced activation of Toll-like receptor-4 inflammatory pathway. In humans, gut microbiota alterations could link high energy intake and obesity-related cardiometabolic disorders; the composition of intestinal microflora of obese patients differs from that of lean subjects and microbiota manipulation through prebiotic/probiotics or microbial transplantation can affect post-prandial endotoxinemia levels and glucose metabolism. We discuss mechanisms connecting gut microbiota to obesity-related diseases and potential therapeutic applications.     

Microbiome response to diet: focus on obesity and related diseases

Numerous studies in humans and animal models describe disturbances of the gut microbial ecosystem associated with adiposity and hallmarks of the metabolic syndrome, including hepatic and cardiovascular diseases. The manipulation of the microbiome, which is largely influenced by the diet, appears as an innovative therapeutic tool to prevent or control obesity and related diseases. This review describes the impact of nutrients on the gut microbiota composition and/or function and when available, the consequences on host physiology. A special emphasis is made on the contribution of bacterial-derived metabolites in the regulation of key gut functions that may explain their systemic effect.

     

Involvement of gut microbiota in the development of low-grade inflammation and type 2 diabetes associated with obesity

Obesity is associated with metabolic alterations related to glucose homeostasis and cardiovascular risk factors. These metabolic alterations are associated with low-grade inflammation that contributes to the onset of these diseases. We and others have provided evidence that gut microbiota participates in whole-body metabolism by affecting energy balance, glucose metabolism, and low-grade inflammation associated with obesity and related metabolic disorders. Recently, we defined gut microbiota-derived lipopolysaccharide (LPS) (and metabolic endotoxemia) as a factor involved in the onset and progression of inflammation and metabolic diseases. In this review, we discuss mechanisms involved in the development of metabolic endotoxemia such as the gut permeability. We also discuss our latest discoveries demonstrating a link between the gut microbiota, endocannabinoid system tone, leptin resistance, gut peptides (glucagon-like peptide-1 and -2), and metabolic features. Finally, we will introduce the role of the gut microbiota in specific dietary treatments (prebiotics and probiotics) and surgical interventions (gastric bypass).     

Obesity,fatty liver disease and intestinal microbiota

Nonalcoholic fatty liver disease(NAFLD) is a chronic liver disorder that is increasing in prevalence with the worldwide epidemic of obesity. NAFLD is the hepatic manifestation of the metabolic syndrome. The term NAFLD describes a spectrum of liver pathology ranges from simple steatosis to steatosis with inflammation nonalcoholic steatohepatitis and even cirrhosis. Metabolic syndrome and NAFLD also predict hepatocellular carcinoma. Many genetic and environmental factors have been suggested to contribute to the development of obesity and NAFLD, but the exact mechanisms are not known. Intestinal ecosystem contains trillions of microorganisms including bacteria, Archaea, yeasts and viruses. Several studies support the relationship between the intestinal microbial changes and obesity and also its complications, including insulin resistance and NAFLD. Given that the gut and liver are connected by the portal venous system, it makes the liver more vulnerable to translocation of bacteria, bacterial products, endotoxins or secreted cytokines. Altered intestinal microbiota(dysbiosis) may stimulate hepatic fat deposition through several mechanisms: regulation of gut permeability, increasing low-grade inflammation, modulation of dietary choline metabolism, regulation of bile acid metabolism and producing endogenous ethanol. Regulation of intestinal microbial ecosystem by diet modifications or by using probiotics and prebiotics as a treatment for obesity and its complications might be the issue of further investigations.     

Gut microbiota imbalance and colorectal cancer

The gut microbiota acts as a real organ. The symbiotic interactions between resident micro-organisms and the digestive tract highly contribute to maintain the gut homeostasis. However, alterations to the microbiome caused by environmental changes(e.g., infection, diet and/or lifestyle) can disturb this symbiotic relationship and promote disease, such as inflammatory bowel diseases and cancer. Colorectal cancer is a complex association of tumoral cells, non-neoplastic cells and a large amount of micro-organisms, and the involvement of the microbiota in colorectal carcinogenesis is becoming increasingly clear. Indeed, many changes in the bacterial composition of the gut microbiota have been reported in colorectal cancer, suggesting a major role of dysbiosis in colorectal carcinogenesis. Some bacterial species have been identified and suspected to play a role in colorectal carcinogenesis, such as Streptococcus bovis, Helicobacter pylori, Bacteroides fragilis, Enterococcus faecalis, Clostridium septicum, Fusobacterium spp. and Escherichia coli. The potential pro-carcinogenic effects of these bacteria are now better understood. In this review, we discuss the possible links between the bacterial microbiota and colorectal carcinogenesis, focusing on dysbiosis and the potential pro-carcinogenic properties of bacteria, such as genotoxicity and other virulence factors, inflammation, host defenses modulation, bacterial derived metabolism, oxidative stress and anti-oxidative defenses modulation. We lastly describe how bacterial microbiota modifications could represent novel prognosis markers and/or targets for innovative therapeutic strategies.     

Gut microbiota and host metabolism in liver cirrhosis

The gut microbiota has the capacity to produce a diverse range of compounds that play a major role in regulatingthe activity of distal organs and the liver is strategically positioned downstream of the gut. Gut microbiota linked compounds such as short chain fatty acids, bile acids, choline metabolites, indole derivatives, vitamins, polyamines, lipids, neurotransmitters and neuroactive compounds, and hypothalamic-pituitary-adrenal axis hormones have many biological functions. This review focuses on the gut microbiota and host metabolism in liver cirrhosis. Dysbiosis in liver cirrhosis causes serious complications, such as bacteremia and hepatic encephalopathy, accompanied by small intestinal bacterial overgrowth and increased intestinal permeability. Gut dysbiosis in cirrhosis and intervention with probiotics and synbiotics in a clinical setting is reviewed and evaluated. Recent studies have revealed the relationship between gut microbiota and host metabolism in chronic metabolic liver disease, especially, non-alcoholic fatty liver disease, alcoholic liver disease, and with the gut microbiota metabolic interactions in dysbiosis related metabolic diseases such as diabetes and obesity. Recently, our understanding of the relationship between the gut and liver and how this regulates systemic metabolic changes in liver cirrhosis has increased. The serum lipid levels of phospholipids, free fatty acids, polyunsaturated fatty acids, especially, eicosapentaenoic acid, arachidonic acid, and docosahexaenoic acid have significant correlations with specific fecal flora in liver cirrhosis. Many clinical and experimental reports support the relationship between fatty acid metabolism and gut-microbiota. Various blood metabolome such as cytokines, amino acids, and vitamins are correlated with gut microbiota in probioticstreated liver cirrhosis patients. The future evaluation of the gut-microbiota-liver metabolic network and the intervention of these relationships using probiotics, synbiotics, and prebiotics, with sufficient nutrition could aid the development of treatments and prevention for liver cirrhosis patients.     

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.