Regulation of host metabolism and immunity by the gut microbiome

During recent years, central roles of the gut microbiome in metabolic and immunological diseases have been uncovered, and multiple studies have shown that bacterial-derived components shape host physiology and immune responses via direct cellular interactions. The intestinal immune system is crucial for the induction of effective immune responses against invading pathogens while simultaneously being vital for maintenance of homeostatic conditions. This balancing act requires a tightly regulated system that might be influenced by bacterial metabolites such as butyrate, since reduced frequencies of butyrate-producing species associate with various lifestyle-associated disorders.

In the present work, we used systems biology approaches to understand how bacterial components may associate with metabolic disease and mediate phenotypic shifts in pro-inflammatory immune cells. First, we developed a computational framework for identifying bacteria that produce specific endotoxin variants with opposing immunological effects in metagenomic fecal samples. This framework was used to identify the endotoxin variant distribution amongst bacteria in the gut microbiome of Danes and Chinese with obesity and type 2 diabetes. We show for the first time that species producing pro-inflammatory endotoxin variants are vastly underrepresented in the gut microbiome compared to species producing non-inflammatory endotoxin and we identify country-specific gram-negative bacterial modules associated with insulin resistance. Second, we show that when the short-chain fatty acid butyrate is present under proinflammatory conditions, it induces a phenotypic switch in monocyte-derived dendritic cells to promote homeostasis through a potent inhibition of a type 1 immune response and induction of tissue-sustaining transcriptional programs. Collectively, these studies give insight into how intestinal microbes can affect their human host in a context-specific manner.