Bacterial Encroachment in Metabolic Syndrome: Too Much Togetherness?

s our understanding of the intestinal microbiota’s Astructure, function, regulation, and wide-ranging influence on human health grows, several important roadblocks to therapeutic targeting remain. First is the descriptive nature of most studies to date, which in many cases have documented steady-state phenotypes without investigating cause–effect relationships. Substantive progress is underway in this direction, with a number of investigators beginning to mechanistically address causal relationships using mouse models and direct manipulation or transfer of microbial populations. For example, fecal microbial transplant from patients with inflammatory bowel disease was shown to accelerate or exacerbate intestinal inflammation in genetically-susceptible mice, and mouse models of metabolic syndrome—a collection of symptoms associated with obesity, diabetes, and heart disease—support a role for altered epithelial–microbial interaction in development and progression of this state, at least in rodents. The next major roadblock in translation of discovery, then, is validating the human clinical relevance of mouse models. To somewhat cheekily paraphrase Judah Folkman’s comment in cancer—if you have metabolic syndrome or colitis and you are a mouse, we can probably target your microbiome therapeutically. However, because it is not yet clear how faithfully and completely the mouse þ microbiota holo-organism maps this same partnership in humans, validation and confirmation of rodent results in human clinical specimens is essential. In this issue of Cellular and Molecular Gastroenterology and Hepatology, Chassaing et al address the human relevance of mouse models of metabolic syndrome. In their article, they provide evidence from patient samples that bacterial encroachment—a shrinking of the “bug-free” zone adjacent to the colonic epithelium—is a feature of human metabolic syndrome. Encroachment has been associated with human inflammatory bowel disease and was demonstrated in mouse models of both colitis and metabolic syndrome, but the current study represents the first clear demonstration of the same phenomenon in obese human patients with diabetes. The authors report that in a cohort of 42 individuals ranging from 31 to 74 years of age, the epithelial–bacterial distance (the average width of the sterile mucus layer) was inversely correlated with body mass index, fasting glucose, and hemoglobin A1C levels. Interestingly, in these human patients the primary predictor of encroachment was dysglycemia. Unlike in mouse models in which body mass index and dysglycemia are essentially linked, here it was possible to separate these parameters in the analysis. Examining only obese patients