Inflammasomes in health, dysbiosis, and disease  — ASN Events

Inflammasomes in health, dysbiosis, and disease  (#S-11)

Richard Flavell 1
  1. Department of Immunobiology and Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT, USA

Dysregulation of the immune system and host-microbiota interaction has been associated with the development of metabolic diseases such as obesity and diabetes. Recent studies in our lab have elucidated the important function of inflammasomes as steady-state sensors and regulators of the gut microbiota. Mice with disrupted inflammasome pathway have been shown to develop a colitogenic microbial community, which resulted in exacerbation of chemical-induced colitis and diet-induced steatohepatitis. As increasing evidence has demonstrated the profound effect of intestinal microbiome on host metabolism, the goal of this study was to examine the role of inflammasome-regulated microbiota in the pathogenesis of obesity and associated metabolic disorders. Notably, we found that mice lacking the inflammasome adaptor ASC developed increased adiposity and impaired glucose tolerance on regular chow. When fed with a high fat diet (HFD), mice lacking ASC, NLRP6, caspase-1 or IL-18 all manifested exacerbated obesity, adiposity and insulin resistance. 16S-rRNA based metagenomic analysis demonstrated an altered fecal microbial composition in HFD-fed ASC KO mice. Cross-fostering to WT mothers and antibiotic treatment diminished the aberrant microbiota in ASC KO mice and abrogated their metabolic phenotype. Together, these data suggest that the inflammasomes play a critical role in regulating energy metabolism via modulation of the gut microbiome.  The relationship between the mucosal immune system, host metabolism and the microbiome will be discussed.