UCSF

The mammalian gut bacterial microbiome is increasingly recognized as a vital immune organ. Numerous studies in murine models implicate the gut bacterial microbiome not only as being required for the induction and maintenance of various important cellular mediators of immunity, but also as being capable of initiating and/or exacerbating states of chronic inflammation in the gut and the periphery. HIV infection and subsequent disease progression is driven by chronic inflammation, and is concomitantly characterized by a disruption within many mucosal cellular compartments involved in regulating gut microbial community composition, including Paneth cells, macrophages, dendritic cells, and Th17 cells. Previous work from our laboratory has shown a link between Th17 cell depletion and activity of the immunomodulatory enzyme indoleamine 2,3-dioxygenase (IDO1), which produces molecules known as kynurenines that can directly inhibit differentiation of Th17 cells in vitro and in vivo. However, a putative interaction between the gut microbiome and the constellation of immune disruptions in HIV, including chronic inflammation and mucosal immune disruption (perhaps involving the IDO1 pathway), had not yet been described. We hypothesized that HIV infection is associated with a shift in gut microbiome composition, and that this shift could potentiate further mucosal immune disruptions and the chronic inflammation that drives HIV disease progression.

We profiled the gut mucosal-adherent microbiome of 32 human subjects at varying stages of HIV disease. We found that the microbiomes of untreated, infected individuals was significantly different from those that were uninfected, and the extent to which this microbiome differed was proportionally related to markers of chronic inflammation and mucosal immune disruption (IDO1 activity). Furthermore, we found that some gut bacterial taxa that were enriched in HIV infection correlated strongly and positively with IDO1 activity, and representative members of the top such correlate could directly produce kynurenines in vitro. We further sought to identify gut-resident bacteria that may inhibit IDO1 activity, and longitudinally profiled 12 rhesus macaques before and after SIV infection toward that end. We found that fecal abundance of Lactobacillus was negatively correlated with IDO1 activity, and macaques given a Lactobacillus-containing probiotic exhibited diminished IDO1 activity as measured in peripheral blood.