Alterations in the gut microbiome by HIV-1 infection or a high-fat diet associates with systemic immune activation and inflammation in double humanized-BLT mice

Abstract

9Background 10 While the translatability of gut microbiome studies utilizing animal models to humans has proven 11 difficult, studying the gut microbiome directly in humans is also challenging due to the existence of many 12 confounding variables. Therefore, we utilized double humanized mice, which have both an engrafted 13 stable human-like gut microbiome and functional human immune system. With this model, we were able 14 to determine the in vivo impact of HIV-1 infection or a high-fat diet (HFD) on gut human microbiome 15 composition, and its relationship with human immune cell activation and systemic inflammation. 17 Results 18Surgery was performed on NSG mice to create humanized bone-marrow, liver, thymus mice (hu-mice). In 19 order to create double hu-mice, the hu-mice were treated with broad spectrum antibiotics to deplete 20 murine gut bacteria and subsequently transplanted with human fecal material from healthy human donors. 21We characterized 262 fecal samples from hu-mice, double hu-mice, and human fecal donors to determine 22 the impact of HIV-1 infection or HFD on the gut microbiome and systemic immune activation and 23 inflammation. We found that HIV-1 infection altered the human-like gut microbiome of double hu-mice, 24 which was associated with decreased human CD4 T cells and increased systemic inflammation and 25 2 immune activation. Further, using a HFD we induced gut microbial dysbiosis in double hu-mice which 26 corresponded with increased systemic immune activation and inflammation.