Abstract and Introduction
Abstract
The gut microbiota affects numerous biological functions throughout the body and its characterisation has become a major research area in biomedicine. Recent studies have suggested that gut bacteria play a fundamental role in diseases such as obesity, diabetes and cardiovascular disease. Data are accumulating in animal models and humans suggesting that obesity and type 2 diabetes (T2D) are associated with a profound dysbiosis. First human metagenome-wide association studies demonstrated highly significant correlations of specific intestinal bacteria, certain bacterial genes and respective metabolic pathways with T2D. Importantly, especially butyrate-producing bacteria such as Roseburia intestinalis and Faecalibacterium prausnitzii concentrations were lower in T2D subjects. This supports the increasing evidence, that butyrate and other short-chain fatty acids are able to exert profound immunometabolic effects. Endotoxaemia, most likely gut-derived has also been observed in patients with metabolic syndrome and T2D and might play a key role in metabolic inflammation. A further hint towards an association between microbiota and T2D has been derived from studies in pregnancy showing that major gut microbial shifts occurring during pregnancy affect host metabolism. Interestingly, certain antidiabetic drugs such as metformin also interfere with the intestinal microbiota. Specific members of the microbiota such as Akkermansia muciniphila might be decreased in diabetes and when administered to murines exerted antidiabetic effects. Therefore, as a 'gut signature' becomes more evident in T2D, a better understanding of the role of the microbiota in diabetes might provide new aspects regarding its pathophysiological relevance and pave the way for new therapeutic principles.
Introduction
The human intestinal tract contains a unique group of micro-organisms that is, the microbiota consisting of numerous bacteria, archaea and viruses. All these micro-organisms generate a biomass of more than 1.5 kg and their combined genomes (ie, microbiome) exceed the human genome more than 100-fold. Whereas earlier studies have mainly proposed that these genes may encode functions which generally direct pathways favouring, for example, the digestion of complex carbohydrates or the development of innate and adaptive immunity, recent evidence suggests that the microbiota may have key functions in regulating metabolic pathways in health and in disease. The introduction of culture-independent, high-throughput sequencing technologies has allowed in the last years to increase the understanding of the complexity and diversity of the microbiota. In contrast, the majorities of the more than 1000 assumed bacterial species still cannot be cultured and therefore remain poorly characterised with respect to their biological functions.
The origin of chronic inflammatory processes observed in metabolic disorders is still a matter of debate. The recent obesity epidemic is a driving force for the worldwide increasing incidence of type 2 diabetes (T2D) as more than 80% of patients with T2D are overweight. Obesity-induced insulin resistance is the dominant underlying pathophysiological factor. As insulin resistance and metabolic inflammation are frequently observed in parallel, research in the past decade has tried to connect these two phenomena. It is widely accepted that the aetiology of insulin resistance is complex and involves various pathways. It is, however, also increasingly established that inflammatory pathways are critically involved in the evolution of insulin resistance. Overnutrition and certain diets could represent major starting points as they might alter the gut microbiota, lead to changes in lipid metabolism, hepatic steatosis and finally systemic inflammation. It remains, however, unclear at which sites inflammatory processes are initiated and the GI tract with its significantly altered microbiota could reflect one of the early events in these disorders.
An altered microbiota in metabolic disease might allow to initiate inflammatory processes. Such an altered microbiota might act 'locally' and via an impaired mucosal barrier act systemically. In support of such a concept, it has been recently demonstrated that patients with metabolic syndrome and T2D exhibit a remarkable endotoxaemia. This is in accordance with the recently proposed concept of 'metabolic infection', where parts of the intestinal microbiota might affect systemic including adipose tissue inflammation. In various disorders such as IBD or obesity a 'microbiotal signature' has been identified. In this article we will discuss the current evidence for a potential role of the gut microbiota in the pathophysiology of T2D.