Low nadir CD4+ T-cell counts predict gut dysbiosis in HIV-1 infection

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

doi:10.1038/s41385-018-0083-7

Abstract

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.

Highlights

In settings with adequate access to antiretroviral therapy (ART), the main clinical problems of people living with human immunodeficiency virus (HIV)-1 (PLWH) derive either from late HIV-1 diagnosis[1,2] or from premature aging.[3,4] Up to one-third of all HIV-1-related deaths in Western countries can be attributed to late HIV-1 diagnosis.[5]
HIV-1-infected subjects were recruited from two tertiary HIV-1 clinics in Barcelona, Spain
Most HIV-1-negative controls were enrolled from a prospective cohort of HIV-negative MSM who attend quarterly medical and counseling visits at a community-based center in Barcelona.[44,45]

Summary

Introduction

In settings with adequate access to antiretroviral therapy (ART), the main clinical problems of people living with human immunodeficiency virus (HIV)-1 (PLWH) derive either from late HIV-1 diagnosis[1,2] or from premature aging.[3,4] Up to one-third of all HIV-1-related deaths in Western countries can be attributed to late HIV-1 diagnosis.[5] Low nadir CD4+ T-cell counts are a major risk factor for developing AIDS- and non-AIDS-defining illnesses,[6,7,8] bacterial infections,[9] ART failure,[5] and suboptimal immune reconstitution with ART.[10,11] Premature aging involves the precocious development of type 2 diabetes, dyslipidemia, cardiovascular diseases, osteoporosis, and frailty syndrome.[4] In PLWH, such illnesses have been linked to chronic inflammation, immune activation, and endotoxemia.[4,12,13,14] In non-HIV-infected subjects, they have been related to shifts in the gut microbiome associated with reduced microbial gene richness.[15,16,17,18,19,20]

Methods

Results

Conclusion