source data_NMICROBIOL-24124010E

The gut microbiome of people living with HIV (PLWH) has been characterized but its role in influencing host immunity and associated clinical features are unclear. Here, we used shotgun metagenomics to characterize the fecal microbiome of two geographically-distinct cohorts of PLWH and healthy controls in Israel and Ethiopia. We uncovered disease-specific, geographically divergent microbial patterns including a shift from <i>Bacteroides</i> to <i>Prevotella</i> species in an Israeli cohort, and multiple multiple Enterobacteriaceae species including <i>Escherichia coli</i> and <i>Klebsiella quasivariicola</i> species in an Ethiopian cohort. We identified correlations between HIV-related dysbiosis and the extent of systemic immunodeficiency, as proxied by peripheral CD4+ T cell counts. Fecal microbiome transplantation (FMT) from PLWH with high peripheral CD4+ T cells induced colonic epithelium-associated CD4+ T cells in germ-free or antibiotic-treated recipient mice. Impaired epithelium-associated lymphocyte induction in FMT recipients from severely immunodeficient PLWH donors was associated with altered protection from <i>Cryptosporidium parvum</i> infection. Collectively, our results suggest a link between systemic immunodeficiency and associated intestinal dysbiosis in PLWH, resulting in impaired gut mucosal immunity