High-fat diet feeding exacerbates HIV-1 rectal transmission.

High-fat diet (HFD) is well known to impact various aspects of gut health and has been associated with many diseases and inflammation. However, the impact of HFD feeding on HIV-1 rectal transmission has not yet been well addressed. With an increasing threat of HIV-1 infection in men who have sex with men (MSM), where the rectal route is the primary mode of infection, it is imperative to understand the impact of HFD on gut microbiota and inflammation and consequently, its effect on HIV-1 rectal transmission. Here, we utilized our double humanized bone marrow, liver, thymus (dHu-BLT) mouse model to assess the impact of HFD feeding on the host's susceptibility to HIV-1 rectal transmission. We found that feeding an HFD successfully altered the gut microbial composition within 3 weeks in the dHu-BLT mouse model. In addition, levels of inflammatory mediators, specifically IL-12p70, IP-10, ICAM-1, and fecal calprotectin, were significantly higher in HFD-fed mice compared to control mice on a regular chow diet. We also observed that significantly different inflammatory markers (IL-12p70 and ICAM-1) were negatively correlated with the number of observed ASVs, Shannon diversity, and Faith's diversity in the HFD-fed group. Notably, when repeatedly challenged with a low dose of HIV-1 via a rectal route, mice receiving an HFD were significantly more susceptible to HIV-1 rectal infection than control mice. Together, these results underscore the impact of HFD feeding on the gut microbiota and inflammation and suggest the significance of diet-induced gut microbial dysbiosis and inflammation in promoting viral infection.IMPORTANCEHFD induces gut microbial dysbiosis and inflammation and has been associated with many infections and disease progression; however, its impact on HIV-1 rectal transmission is largely unknown. Given the increasing threat of HIV-1 incidence in men who have sex with men (MSM), it has become crucial to comprehend the impact of factors associated with gut health, like HFD consumption, on host susceptibility to HIV-1 rectal transmission. This is particularly important since anal intercourse remains the primary mode of HIV transmission within the MSM group. In this study, utilizing our unique mouse model, featuring both the human immune system and gut microbiota, we showed that HFD feeding led to gut microbial dysbiosis, induced inflammation, and increased HIV-1 rectal transmission. Collectively, our study highlights the significant impact of HFD on gut microbiota and inflammation and suggests an HFD consumption as a potential risk factor for promoting HIV-1 rectal susceptibility.