Microbial metabolites in health and disease: Navigating the unknown in search of function.

The gut microbiota has been implicated in the development of a number of chronic gastrointestinal and systemic diseases. These include inflammatory bowel diseases, irritable bowel syndrome, and metabolic (i.e. obesity, non-alcoholic fatty liver disease, and diabetes) and neurological diseases. The advanced understanding of host-microbe interactions has largely been due to new technologies such as 16S rRNA sequencing to identify previously unknown microbial communities and, more importantly, their functional characteristics through metagenomic sequencing and other multi-omic technologies, such as metatranscriptomics, metaproteomics, and metabolomics. Given the vast array of newly acquired knowledge in the field and technological advances, it is expected that mechanisms underlying several disease states involving the interactions between microbes, their metabolites, and the host will be discovered. The identification of these mechanisms will allow for the development of more precise therapies to prevent or manage chronic disease. This review discusses the functional characterization of the microbiome, highlighting the advances in identifying bioactive microbial metabolites that have been directly linked to gastrointestinal and peripheral diseases.

Activation of bile acid signaling improves metabolic phenotypes in high-fat diet-induced obese mice.

The metabolic benefits induced by gastric bypass, currently the most effective treatment for morbid obesity, are associated with bile acid (BA) delivery to the distal intestine. However, mechanistic insights into BA signaling in the mediation of metabolic benefits remain an area of study. The bile diversion () mouse model, in which the gallbladder is anastomosed to the distal jejunum, was used to test the specific role of BA in the regulation of glucose and lipid homeostasis. Metabolic phenotype, including body weight and composition, glucose tolerance, energy expenditure, thermogenesis genes, total BA and BA composition in the circulation and portal vein, and gut microbiota were examined. BD improves the metabolic phenotype, which is in accord with increased circulating primary BAs and regulation of enterohormones. BD-induced hypertrophy of the proximal intestine in the absence of BA was reversed by BA oral gavage, but without influencing BD metabolic benefits. BD-enhanced energy expenditure was associated with elevated TGR5, D2, and thermogenic genes, including UCP1, PRDM16, PGC-1α, PGC-1ß, and PDGFRα in epididymal white adipose tissue (WAT) and inguinal WAT, but not in brown adipose tissue. BD resulted in an altered gut microbiota profile (i.e., Firmicutes bacteria were decreased, Bacteroidetes were increased, and Akkermansia was positively correlated with higher levels of circulating primary BAs). Our study demonstrates that enhancement of BA signaling regulates glucose and lipid homeostasis, promotes thermogenesis, and modulates the gut microbiota, which collectively resulted in an improved metabolic phenotype.

Western diets, gut dysbiosis, and metabolic diseases: Are they linked?

Obesity afflicts 36.5% of the US population and 600 million individuals world-wide. Thus, it is imperative to understand the risk factors underlying metabolic disease including diet, activity level, sleep, and genetics. Another key contributory factor is the gut microbiota given its widely reported role in the development of metabolic disease. The gut microbiota, particularly its structure and function, is heavily influenced by Western style diets rich in a complex mixture of fats and high in simple sugars. In this review, the profound impact of obesity and Western diets on the gut microbiota will be illustrated, and the following research questions will be addressed: 1) to what extent do high fat diets (HFDs) alter community membership and function and does this depend upon the amount or type of fat consumed?, 2) how rapidly do dietary shifts alter gut microbial communities?, 3) are these alterations sustained or can the microbiome recover from dietary stress?, 4) how does diet drive host-microbe interactions leading to obesity?, and 5) what can be done to restore the detrimental impact of HFD on the gut microbiota? The goal of this review is to address these questions by parsing out the effects and underlying mechanisms of how Western diets impact the gut microbiota and host. By doing so, potential avenues for further exploration and strategies for microbiome-based interventions to prevent or treat diet-induced obesity may become more apparent.

The Gut Microbiota: The Gateway to Improved Metabolism.

Obesity is an emerging global epidemic with profound challenges to world health care economies and societies. Traditional approaches to fighting obesity have not shown promise in promoting a decline in obesity prevalence. The gut microbiota is becoming widely appreciated for its role in regulating metabolism and thus represents a target for new therapies to combat obesity and associated comorbidities. This article provides an overview of altered microbial community structure in obesity, dietary impact on the gut microbiota, host-microbe interactions contributing to the disease, and improvements in microbial assemblage after bariatric surgery and with therapies targeting the gut microbiome.