Yolanda Guillén, Marc Noguera-Julian, Javier Rivera, Maria Casadellà, Alexander S Zevin, Muntsa Rocafort, Mariona Parera, Cristina Rodríguez, Marçal Arumí, Jorge Carrillo, Beatriz Mothe, Carla Estany, Josep Coll, Isabel Bravo, Cristina Herrero, Jorge Saz, Guillem Sirera, Ariadna Torrella, Jordi Navarro, Manuel Crespo, Eugènia Negredo, Christian Brander, Julià Blanco, Maria Luz Calle, Nichole R Klatt, Bonaventura Clotet, Roger Paredes

Human immunodeficiency virus (HIV)-1 infection causes severe gut and systemic immune damage, but its effects on the gut microbiome remain unclear. Previous shotgun metagenomic studies in HIV-negative subjects linked low-microbial gene counts (LGC) to gut dysbiosis in diseases featuring intestinal inflammation. Using a similar approach in 156 subjects with different HIV-1 phenotypes, we found a strong, independent, dose-effect association between nadir CD4+ T-cell counts and LGC. As in other diseases involving intestinal inflammation, the gut microbiomes of subjects with LGC were enriched in gram-negative Bacteroides, acetogenic bacteria and Proteobacteria, which are able to metabolize reactive oxygen and nitrogen species; and were depleted in oxygen-sensitive methanogenic archaea and sulfate-reducing bacteria. Interestingly, subjects with LGC also showed increased butyrate levels in direct fecal measurements, consistent with enrichment in Roseburia intestinalis despite reductions in other butyrate producers. The microbiomes of subjects with LGC were also enriched in bacterial virulence factors, as well as in genes associated with beta-lactam, lincosamide, tetracycline, and macrolide resistance. Thus, low nadir CD4+ T-cell counts, rather than HIV-1 serostatus per se, predict the presence of gut dysbiosis in HIV-1 infected subjects. Such dysbiosis does not display obvious HIV-specific features; instead, it shares many similarities with other diseases featuring gut inflammation.