Evaluating Causality of Gut Microbiota in Obesity and Diabetes in Humans

Abstract

The pathophysiology of obesity and obesity-related diseases such as type 2 diabetes mellitus (T2DM) is complex and driven by many factors. One of the most recently identified factors in development of these metabolic pathologies is the gut microbiota. The introduction of affordable, high-throughput sequencing technologies has substantially expanded our understanding of the role of the gut microbiome in modulation of host metabolism and (cardio)metabolic disease development. Nevertheless, evidence for a role of the gut microbiome as a causal, driving factor in disease development mainly originates from studies in mouse models: data showing causality in humans are scarce. In this review, we will discuss the quality of evidence supporting a causal role for the gut microbiome in the development of obesity and diabetes, in particular T2DM, in humans. Considering overlap in potential mechanisms, the role of the gut microbiome in type 1 diabetes mellitus will also be addressed. We will elaborate on factors that drive microbiome composition in humans and discuss how alterations in microbial composition or microbial metabolite production contribute to disease development. Challenging aspects in determining causality in humans will be postulated together with strategies that might hold potential to overcome these challenges. Furthermore, we will discuss means to modify gut microbiome composition in humans to help establish causality and discuss systems biology approaches that might hold the key to unravelling the role of the gut microbiome in obesity and T2DM.

Butyrate protects against high‐fat diet‐induced atherosclerosis via up‐regulating ABCA1 expression in apolipoprotein E‐deficiency mice

“…Atherosclerosis has long been recognized as a complex pathological process involving both dysregulated lipid metabolism and chronic inflammation. Recently, a growing amount of evidence from both animal and human studies has highlighted the essential role of intestinal microbiota in modulating various metabolic diseases, such as obesity, type 2 diabetes and atherosclerotic CVD, by affecting energy balance and inhibiting inflammation (Koren et al, ; Meijnikman, Gerdes, Nieuwdorp, & Herrema, ). The gut microbe‐derived metabolite trimethylamine N‐oxide (TMAO) has been shown to promote atherosclerosis and thrombotic vascular disease in mouse models (Tang & Hazen, ) and is clinically relevant in human CVD (Brown & Hazen, ).…”

Association between blood microbiome and type 2 diabetes mellitus: A nested case‐control study

“…“Balanced” gut microbiota is critical to maintain the host energy and metabolism equilibrium. Moreover, microbial dysbiosis in the human gut has been recognized as an important risk factor for the development of obesity‐related diseases, including hypertension and T2DM . During the past two decades, accumulative evidence has demonstrated that enteric bacterial products (eg lipopolysaccharides [LPS]) could cross the impaired intestinal barrier to reach peripheral circulation and contributed to the low‐grade chronic inflammatory state .…”

From germ theory to germ therapy

“…Dysbiosis can represent a change in the numbers of microbes or a change in the diversity of the microbiota that may be related to certain diseases and health conditions. In this section, we highlight a few of the recent findings on the role of the microbiota in particular diseases or conditions, but we cannot touch on all of the emerging findings in a multitude of other diseases, including but not limited to autoimmune disease, colorectal cancer, liver disease, and diabetes …”

“…The precise mechanisms underlying this association are still under investigation. Bacterial metabolites and bacteria‐derived components such as short chain fatty acids and bile acids can regulate human metabolism by influencing the expression of important metabolic regulatory peptides . Host life style, exercise, diet, and hygiene preferences, and medication change the composition of the gut microbiota.…”