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

Nature Microbiology (2026)Cite this article

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Abstract

The gut microbiome of people living with human immunodeficiency virus (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 faecal 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 Bacteroides to Prevotella species in an Israeli cohort and multiple Enterobacteriaceae species including Escherichia coli and Klebsiella quasivariicola in an Ethiopian cohort. We identified correlations between human immunodeficiency virus-related dysbiosis and the extent of systemic immunodeficiency, as proxied by peripheral CD4+ T cell counts. Faecal microbiome transplantation from PLWH with high peripheral CD4+ T cell counts induced colonic epithelium-associated CD4+ T cells in germ-free or antibiotic-treated recipient mice. Impaired epithelium-associated lymphocyte induction in recipients of faecal microbiome transplantation from severely immunodeficient PLWH donors was associated with altered protection from Cryptosporidium parvum infection. Collectively, our results suggest a link between systemic immunodeficiency and associated intestinal dysbiosis in PLWH, resulting in impaired gut mucosal immunity.

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Fig. 1: Israeli cohort of PLWH.
Fig. 2: Metagenomic characterization of the gut microbiome in an Israeli cohort of PLWH.
Fig. 3: Ethiopian cohort of PLWH.
Fig. 4: Metagenomic characterization of the gut microbiome in an Ethiopian cohort of PLWH.
Fig. 5: FMT from PLWH with high but not low CD4+ T cell counts to recipient mice induces colonic epithelium-associated CD4+ T cells.
Fig. 6: Individual bacterial species associated with epithelium-associated CD4+ T cell induction in PLWH.

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Data availability

All shotgun metagenomic and transcriptomic sequencing data analysed in this study are available via the European Nucleotide Archive at https://www.ebi.ac.uk/ena/browser/home under accession number PRJEB81733.

The source data underlying this study are available via Figshare at https://doi.org/10.6084/m9.figshare.30834287 (ref. 65).

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Acknowledgements

We thank the members of the Elinav laboratory, Weizmann Institute of Science, and Microbiome and Cancer Division, DKFZ, for insightful discussions; C. Bar-Nathan for dedicated GF mouse husbandry; and D. Kviatcovsky for help with experiments. We thank R. Nir-Paz and J. Strahilevitz of Hadassah-Hebrew University Medical Center, Jerusalem, Israel, for key help and advice. M. Heinemann was funded by Deutsche Forschungsgemeinschaft (German Research Foundation, 438122637). L.A. received funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie Grant Agreement Number 842203. R.V.-M. was a recipient of a senior postdoctoral fellowship from the Weizmann Institute of Science. H.S. is the incumbent of the Vera Rosenberg Schwartz Research Fellow Chair. J.P. is supported by the Helmholtz Foundation and the DKFZ Hector Cancer Institute at the University Medical Center Mannheim, Germany. E.E. is supported by the Leona M. and Harry B. Helmsley Charitable Trust, Bill and Melinda Gates Foundation, European Research Council, Israel Science Foundation, Israel Ministry of Science and Technology, Israel Ministry of Health, Helmholtz Foundation, European Crohn’s and Colitis Organization, Kenneth Rainin Foundation, Rising Tide Foundation, Lupus Research Alliance, Jose Carreras Foundation, Human Frontiers Science Program, Deutsch-Israelische Projektkooperation, IDSA Foundation, European Union THRIVE consortium (J.P. and E.E., HORIZON-MISS-2023-CANCER) and the Nutriome consortium. E.E. is the incumbent of the Sir Marc and Lady Tania Feldmann Professorial Chair, a Kimmel researcher, a CIFAR fellow and a partner of the Novo Nordisk Foundation Microbiome Health Initiative.

Author information

Author notes

  1. Stavros Bashiardes

    Present address: Department of Molecular Virology, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus

  2. Melina Heinemann

    Present address: Division of Internal Medicine, University Hospital and University Zurich, Zurich, Switzerland

  3. Lorenz Adlung

    Present address: First Department of Medicine, University Medical Center Hamburg-Eppendorf (UKE), Hamburg, Germany

  4. Rafael Valdés-Mas

    Present address: Cima Universidad de Navarra, Pamplona, Spain

  5. These authors contributed equally: Stavros Bashiardes, Melina Heinemann, Lorenz Adlung, Rafael Valdés-Mas, Jemal Ali Mahdi.

  6. These authors jointly supervised this work: Hila Elinav, Eran Elinav.

Authors and Affiliations

  1. Department of Systems Immunology, Weizmann Institute of Science, Rehovot, Israel

    Stavros Bashiardes, Melina Heinemann, Lorenz Adlung, Rafael Valdés-Mas, Jemal Ali Mahdi, Samuel P. Nobs, Timur Tuganbaev, Takahiro Yamada, Max Horn, Uria Mor, Yotam Cohen, Muhammed Dervis Arslan, Shahar Molina, Maya Zur, Shimrit Eliyahu-Miller, Aurélie Bukimer, Sara Federici, Mally Dori-Bachash, Nira Amar, Hagit Shapiro, Ido Amit & Eran Elinav

  2. Department of Microbiology, Immunology and Genetics, Ben-Gurion University of the Negev, Beer Sheba, Israel

    Jemal Ali Mahdi & Zvi Bentwich

  3. Division of Biochemistry, Keio University, Minato, Japan

    Takahiro Yamada

  4. Hadassah AIDS Center, Clinical Microbiology & Infectious Diseases Department, Hadassah-Hebrew University Medical Center, Jerusalem, Israel

    Sarah Israel, Maya Korem, Yonatan Oster, Karen Olshtain-Pops, Efrat Orenbuch-Harroch & Hila Elinav

  5. Hebrew University Faculty of Medicine, Jerusalem, Israel

    Sarah Israel, Maya Korem, Yonatan Oster, Karen Olshtain-Pops, Efrat Orenbuch-Harroch & Hila Elinav

  6. Faculty of Medicine, Inonu University, Malatya, Turkey

    Muhammed Dervis Arslan

  7. Allergy, Clinical Immunology and HIV Unit, Kaplan Medical Center, Rehovot, Israel

    Daniel Elbirt

  8. Tel-Aviv Sourasky Medical Center, Crusaid Kobler AIDS Center, Tel Aviv, Israel

    Ronit Cohen-Poradosu & Dan Turner

  9. Gray Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

    Ronit Cohen-Poradosu & Dan Turner

  10. Department of Gastroenterology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel

    Tiberiu Hershcovici & Elez Vainer

  11. Department of Veterinary Resources, Weizmann Institute of Science, Rehovot, Israel

    Noa Stettner & Alon Harmelin

  12. Department of Internal Medicine, Collage of Health Sciences, Mekelle University, Mekelle, Ethiopia

    Hailay Gebremeskel & Yazezew Kebede

  13. Division of Microbiome and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany

    Sabine Schmidt, Arunraj Dhamodaran, Jens Puschhof & Eran Elinav

  14. School of Medicine, Faculty of Medicine and Health Sciences, Tel Aviv University, Tel Aviv, Israel

    Niv Zmora

  15. Research Center for Digestive Tract and Liver Diseases, Tel Aviv Sourasky Medical Center, Tel Aviv University, Tel Aviv, Israel

    Niv Zmora

Authors
  1. Stavros Bashiardes
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  2. Melina Heinemann
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  3. Lorenz Adlung
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  4. Rafael Valdés-Mas
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  5. Jemal Ali Mahdi
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  6. Samuel P. Nobs
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  7. Timur Tuganbaev
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  15. Karen Olshtain-Pops
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  17. Muhammed Dervis Arslan
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  18. Shahar Molina
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  19. Maya Zur
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  21. Aurélie Bukimer
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  23. Mally Dori-Bachash
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  24. Nira Amar
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  25. Daniel Elbirt
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  26. Ronit Cohen-Poradosu
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  27. Dan Turner
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  28. Tiberiu Hershcovici
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  29. Elez Vainer
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  30. Noa Stettner
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  31. Alon Harmelin
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  32. Hailay Gebremeskel
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  33. Yazezew Kebede
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  34. Sabine Schmidt
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  35. Niv Zmora
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  36. Arunraj Dhamodaran
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  39. Hagit Shapiro
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  40. Ido Amit
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  41. Hila Elinav
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  42. Eran Elinav
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Contributions

S.B., M. Heinemann, L.A. and R.V.-M. designed, performed, analysed and interpreted the experiments and wrote the paper. J.A.M. headed, coordinated and analysed human trials and experiments. S.B., M. Heinemann, L.A., R.V.-M. and J.A.M. equally contributed to the work. Y.C. and U.M. helped with the computational aspects and provided critical insights. S.P.N., T.T., T.Y., M. Heinemann, M.D.A., S.F., N.A., Z.B., A.D., J.P., I.A. and N.Z. provided critical insights or helped with the experiments. N.S. and H.S. coordinated the key animal experimentation. M.Z., A.B. and S.E.-M. coordinated human trials and handled human data and sample collection. S.I., M.K., Y.O., K.O.-P., E.O.-H., D.E., R.C.-P., D.T., T.H., H.G., Y.K. and E.V. headed the clinical trials, shared samples and metadata, and provided key experimental insights. M.D.-B., S.M. and S.S. performed sample processing and next-generation DNA sequencing. A.H. performed histopathological scoring. H.E. and E.E. conceived the study, supervised the participants, interpreted the experiments and wrote the paper.

Corresponding authors

Correspondence to Hila Elinav or Eran Elinav.

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Competing interests

E.E. is an advisor to Purposebio and Zoe in topics unrelated to this work. The other authors declare no competing interests.

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Nature Microbiology thanks Namita Rout and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Extended data

Extended Data Table 1 Characteristics of donors used in FMT experiments
Full size table
Extended Data Table 2 Characteristics of donors used in Cryptosporidium infection experiments
Full size table

Extended Data Fig. 1 Table summarizing the characteristics of the Israeli study cohort living with HIV.

aIf more than one sample was provided before initiation of ART, only the first sample was chosen and numeric parameters are related to the time the first sample was collected. bIf more than one sample was provided during ART, only the last sample was chosen, and numeric parameters are related to the time the last sample was collected. cViral load was undetectable in 2 samples from untreated individuals and in 48 samples from individuals on ART. Data are given as median (IQR) or n (%). ART, antiretroviral treatment; HC, healthy control; MSM, men who have sex with men; PLWH, people living with human immunodeficiency virus; IDU, injection drug use; F, female; M, male.

Source data

Extended Data Fig. 2 Characterization of the gut microbiome in an Israeli cohort of PLWH by shotgun metagenomic sequencing.

(a) Differential species abundance between untreated PLWH and HC, controlling for mode of transmission. Wald test with FDR correction (DESeq2). Dashed lines: p adjusted of 0.05. Differentially abundant species are shown in color according to disease status; black, non-differentially abundant species. (b) Differential species abundance between PLWH on ART and HC, controlling for mode of transmission. Wald test with FDR correction (DESeq2). Dashed lines: p adjusted of 0.05. Differentially abundant species are shown in color according to disease status; black, non-differentially abundant species. (c–d) Alpha diversity analysis comparing untreated PLWH, PLWH on ART, and HC, as shown in Fig. 2a and Fig. 2c, was repeated after excluding individuals with MSM behavior. Two-sided Mann-Whitney test (p = 0.0165). (c) Simpson’s diversity index comparing untreated PLWH (n = 46) and HC (n = 20); values are plotted as mean ± SEM. (d) Simpson’s diversity index comparing PLWH on ART (n = 42) and HC (n = 20); values are plotted as mean ± SEM. (e) Linear model showing the association between CD4⁺ T cell counts and blood CRP levels in PLWH (simple linear regression, p < 0.019). (f) Pairwise comparison of the Simpson’s index between untreated PLWH and PLWH on ART (n = 55/group). Wilcoxon matched-pairs signed rank test. Plotted values represent mean ± SEM. (g) PCoA of pairwise comparison between untreated PLWH and PLWH on ART. PERMANOVA. (h) Pairwise comparison of differential species abundance between untreated PLWH and PLWH on ART, controlling for patientID. Wald test with FDR correction (DESeq2). Dashed lines: p adjusted of 0.05. Differentially abundant species are shown in color according to the group of PLWH; black, non-differentially abundant species. For pairwise comparisons, the first blood and stool sample collected before initiation of ART and the last blood and stool sample collected during ART were compared. (i–j) Differential viral species abundance between (i) untreated PLWH and (j) PLWH on ART compared to HC, controlling for mode of transmission. Wald test with FDR correction (DESeq2). Differentially abundant viral species are colored according to disease status; non-significant species are shown in black. * p < 0.05; ART, antiretroviral treatment; HC, healthy controls; PCoA, principal coordinate analysis; PC, principal component; PLWH, people living with human immunodeficiency virus; Padj, adjusted P value.

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Extended Data Fig. 3 Table summarizing the characteristics of the Ethiopian study cohort living with HIV.

ART, antiretroviral treatment; HC, healthy controls; PLWH, people living with human immunodeficiency virus.

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Extended Data Fig. 4 Characterization of the gut microbiome in an Ethiopian cohort of PLWH by shotgun metagenomic sequencing and gating strategy for IEL CD4+ T cells after FMT to recipient mice.

(a) Heatmap of microbial species enriched or decreased in PLWH and healthy household controls from Ethiopia. (b) Gating strategy for IEL CD4 + T cells. TCRb, T Cell Receptor Beta chain; DAPI, 4′,6-diamidino-2-phenylindole; HC, healthy controls; PLWH, people living with human immunodeficiency virus.

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Extended Data Fig. 5 Fecal microbiome transplantation from PLWH to recipient mice.

(a-e) FMT experiments including different human donors (related to Fig. 5). Fecal samples from PLWH with low ( < 200 µl−1) or high ( ≥ 500 µl−1) peripheral blood CD4+  T cells and HC were transplanted into mice. As control, PBS was gavaged. (a) Frequency of intestinal epithelium-associated CD4⁺ T cells among all live epithelium-associated cells in two pooled experiments (Low, n = 12; High, n = 11). Data are presented as mean values +/- SEM. (p = 0.0439). (b-e) Measured fractions of CD4+ T cells in different compartments were normalized to the PBS group: colonic Lamina propria (p = 0.0005; PBS, n = 3; Low, n = 5; High, n = 3; b), small intestine Lamina propria (PBS, n = 3; Low, n = 5; High, n = 3; c), spleen (p = 0.0247; PBS, n = 3; Low, n = 5; High, n = 3; d) and blood (PBS, n = 4; Low, n = 3; High, n = 4, HC, n = 4; e). Data are presented as median values +/- IQR. (f-h) Measurement of the small intestinal length (Low, n = 8; High, n = 7; f), transit time by the fraction of Evans blue 30 minutes after gavage of Evans blue Low, n = 8; High, n = 7; g) and gut permeability by the amount of FITC-dextran detected in the peripheral blood three hours upon oral gavage of FITC dextran (Low, n = 16; High, n = 16; h). Box plots show the median, interquartile range, and minimum/maximum values. Two-sided unpaired t-test. ns, not significant; * p < 0.05; *** p < 0.001. HC, healthy controls; FITC, Fluorescein isothiocyanate; ns, not significant; PBS, phosphate-buffered saline; SI, small intestine; high, PLWH with high peripheral blood CD4+ T cells ( ≥ 500 µl−1); low, PLWH with low peripheral blood CD4+ T cells ( < 200 µl−1).

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Extended Data Fig. 6 Characterization of gene expression profiles in rectal biopsies in an Israeli cohort of PLWH and microbial profiles from stool samples of FMT- and PBS-treated mice.

(a) Study design. PLWH with low ( < 200 µl−1) and high ( ≥ 500 µl−1) peripheral blood CD4+ T cells and HC underwent endoscopy. A rectal biopsy for bulk RNA sequencing was collected. (b) Principal component analysis (PC) of transcriptomic profiles between the three groups. (c) Differentially expressed genes between the low and high group. Wald test with FDR correction (DESeq2). Dashed lines: p adjusted of 0.05. Differentially abundant genes are shown in color; black, non-differentially abundant genes. (d) PC analysis of microbial profiles from stool samples of FMT-treated mice and PBS-treated controls from two independent experiments. HC, healthy controls; high, PLWH with high peripheral blood CD4+ T cells ( ≥ 500 µl−1); low, PLWH with low peripheral blood CD4+ T cells ( < 200 µl−1); ns, not significant; PC, principal component; FC, fold change; PLWH, people living with human immunodeficiency virus; FMT, fecal microbiome transplantation; PBS, phosphate-buffered saline; Padj, adjusted P value.

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Bashiardes, S., Heinemann, M., Adlung, L. et al. Human immunodeficiency virus-associated gut microbiome impacts systemic immunodeficiency and susceptibility to opportunistic gut infection. Nat Microbiol (2026). https://doi.org/10.1038/s41564-025-02253-8

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