Human immunodeficiency virus-associated gut microbiome impacts systemic immunodeficiency and susceptibility to opportunistic gut infection.

Shotgun metagenomics revealed geographically divergent, HIV-specific microbial patterns in two distinct cohorts of PLWH.

• Two geographically distinct cohorts were studied: one in Israel and one in Ethiopia, along with healthy controls in each location.
• The Israeli cohort showed a shift from Bacteroides to Prevotella species in PLWH.
• The Ethiopian cohort showed enrichment of multiple Enterobacteriaceae species including Escherichia coli and Klebsiella quasivariicola in PLWH.
• Faecal microbiome characterization was performed using shotgun metagenomics.

HIV-related gut dysbiosis was correlated with the extent of systemic immunodeficiency as proxied by peripheral CD4+ T cell counts.

• Correlations were identified between HIV-related dysbiosis and peripheral CD4+ T cell counts across PLWH.
• Peripheral CD4+ T cell counts were used as a proxy for systemic immunodeficiency.
• This relationship was observed across geographically distinct cohorts in Israel and Ethiopia.

Faecal microbiome transplantation (FMT) from PLWH with high peripheral CD4+ T cell counts induced colonic epithelium-associated CD4+ T cells in recipient mice.

• FMT was performed using germ-free or antibiotic-treated recipient mice.
• Donors with high peripheral CD4+ T cell counts were able to induce colonic epithelium-associated CD4+ T cells in recipients.
• FMT from severely immunodeficient PLWH donors resulted in impaired epithelium-associated lymphocyte induction in recipients.
• This experiment causally linked the donor microbiome composition to gut mucosal immune outcomes in the recipient.

Impaired epithelium-associated lymphocyte induction following FMT from severely immunodeficient PLWH was associated with altered protection from Cryptosporidium parvum infection.

• Recipient mice that received FMT from severely immunodeficient PLWH donors showed impaired colonic epithelium-associated CD4+ T cell induction.
• This impairment was associated with altered protection from the opportunistic gut pathogen Cryptosporidium parvum.
• The finding suggests the microbiome of severely immunodeficient PLWH is insufficient to support normal mucosal immune defense against opportunistic infection.

The study suggests a link between systemic immunodeficiency and associated intestinal dysbiosis in PLWH, resulting in impaired gut mucosal immunity.

• The authors describe a bidirectional or linked relationship between systemic CD4+ T cell depletion and gut microbial dysbiosis.
• Impaired gut mucosal immunity was demonstrated functionally through reduced epithelium-associated CD4+ T cell induction and susceptibility to Cryptosporidium parvum.
• The study used both human cohort data and mouse FMT experiments to support this conclusion.
• Geographically divergent dysbiosis patterns converged on a common functional outcome of impaired mucosal immunity.