Gut microbiota and diabetes: from pathogenesis to therapeutic perspective

Abstract

More than several hundreds of millions of people will be diabetic and obese over the next decades in front of which the actual therapeutic approaches aim at treating the consequences rather than causes of the impaired metabolism. This strategy is not efficient and new paradigms should be found. The wide analysis of the genome cannot predict or explain more than 10-20% of the disease, whereas changes in feeding and social behavior have certainly a major impact. However, the molecular mechanisms linking environmental factors and genetic susceptibility were so far not envisioned until the recent discovery of a hidden source of genomic diversity, i.e., the metagenome. More than 3 million genes from several hundreds of species constitute our intestinal microbiome. First key experiments have demonstrated that this biome can by itself transfer metabolic disease. The mechanisms are unknown but could be involved in the modulation of energy harvesting capacity by the host as well as the low-grade inflammation and the corresponding immune response on adipose tissue plasticity, hepatic steatosis, insulin resistance and even the secondary cardiovascular events. Secreted bacterial factors reach the circulating blood, and even full bacteria from intestinal microbiota can reach tissues where inflammation is triggered. The last 5 years have demonstrated that intestinal microbiota, at its molecular level, is a causal factor early in the development of the diseases. Nonetheless, much more need to be uncovered in order to identify first, new predictive biomarkers so that preventive strategies based on pre- and probiotics, and second, new therapeutic strategies against the cause rather than the consequence of hyperglycemia and body weight gain.

Fig. 1

Multiple-sited impact of gut microbiota on whole host metabolism. Gut microbes have been shown or proposed to have an impact on adipose tissue and liver fat storage, skeletal muscle energy metabolism, fat liver metabolism and hepatic steatosis, atherosclerosis and cardiovascular diseases (CVD), tissue lipid composition in the retina lens, periodontitis, behavior and motor activity, and enteroendocrine metabolism. The precise bacteria involved remained to be determined and should be the basis of present and future discoveries

Fig. 2

The inflammatory burn: gut microbiota dysbiosis and the origin of metabolic impairments. The origin of metabolic diseases is multifactorial but the impact of deleterious feeding habits is certainly the major factor responsible. This directly modifies intestinal ecology and we first showed that upon an increased intestinal permeability it led to an increased circulating concentration of LPS from Gram-negative bacteria of intestinal origin [3, 82] called metabolic endotoxemia. The inflammatory factors LPS and other bacterial fragments can translocate toward target tissues such as the blood, the liver, and the adipose depots or the arterial wall to interfere with cells from the immune system to generate the chronic low-grade inflammation required for the development of metabolic and cardiovascular diseases

Fig. 3

Therapy strategies challenging gut microbes. The discovery of the role of intestinal microbiota on the control of metabolic diseases opens numerous therapeutic strategies such as prebiotics, probiotics, and immune modulation. It also allows the generation of biomarker strategies to set predictive profiles, to classify and to stratify the patients and the corresponding metabolic and cardiovascular diseases