When specific gut microbes reveal a possible link between hepatic steatosis and adipose tissue

Abstract

The gut microbiota is considered as a factor involved in the regulation of numerous metabolic pathways by impacting different functions of the host. Among these regulations, the influence of gut microbes on energy homeostasis is of particular interest because it has been suggested to be a driving force in the pathogenesis of metabolic diseases associated with obesity (such as insulin resistance, diabetes, cardiovascular disease, and non-alcoholic fatty liver disease (NAFLD)) [1,2]. Intestinal microbes have developed a mutualistic relationship with their host and can influence physiological systems by modulating gut motility, intestinal barrier homeostasis, nutrient absorption, fat distribution, and liver fat accumulation [3,4]. The relationship between changes in gut microbiota and the development and progression of liver disease has been known for over fifty years. Endotoxemia and gut-derived toxins are suggested to have causative roles in the onset and progression of liver inflammation and damage in chronic liver diseases [5]. Similar to the mechanisms underlying metabolic endotoxemia (i.e., increased blood lipopolysaccharides (LPS) levels) and inflammation described in our previous work [6], intestinal bacterial overgrowth, gut leakiness and increased endotoxin absorption have all been associated with hepatic fat accumulation and inflammation (NAFLD and non-alcoholic steatohepatitis (NASH)) in both rodents and human patients [7–9]. However, the role of specific bacteria, metabolites coming from the gut microbiota or both remained to be demonstrated. In NAFLD patients changes in tight junction protein expression and distribution are suggested as critical factors in the impairment of gut barrier function and subsequent alterations in gut permeability [10]. As a consequence, metabolic endotoxemia exposes the liver to gut-derived toxins resulting in the release of numerous pro-inflammatory cytokines that ultimately lead to hepatic injury and fibrosis [11]. However, although previous studies have shown that the treatment with antibiotics or loss of endotoxins receptors (Toll-like receptor-(TLR) 4) significantly attenuates the development of hepatic steatosis in mice [12,13], it has also been suggested that other TLRs than TLR4 contributed to the onset of NAFLD [14]. In light of these recent