Impaired gut microbiota-mediated short-chain fatty acid production precedes morbidity and mortality in people with HIV
Irini Sereti,
Myrthe L. Verburgh,
Jacob Gifford,
Alice Lo,
Anders Boyd,
Eveline Verheij,
Aswin Verhoeven,
Ferdinand W.N.M. Wit,
Maarten F. Schim van der Loeff,
Martin Giera,
Neeltje A. Kootstra,
Peter Reiss,
Ivan Vujkovic-Cvijin
Affiliations
Irini Sereti
HIV Pathogenesis Section, Laboratory of Immunoregulation, NIAID/NIH, Rockville, MD, USA; Amsterdam Institute for Global Health and Development, Amsterdam, the Netherlands
Myrthe L. Verburgh
Amsterdam University Medical Centers, University of Amsterdam, Infectious Diseases, Amsterdam, the Netherlands; Amsterdam Institute for Infection and Immunity, Amsterdam, the Netherlands; Amsterdam Institute for Global Health and Development, Amsterdam, the Netherlands
Jacob Gifford
Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA; Karsh Division of Gastroenterology & Hepatology, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA; F. Widjaja Inflammatory Bowel Disease Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
Alice Lo
Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA; Karsh Division of Gastroenterology & Hepatology, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA; F. Widjaja Inflammatory Bowel Disease Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
Anders Boyd
Amsterdam University Medical Centers, University of Amsterdam, Infectious Diseases, Amsterdam, the Netherlands; Amsterdam Institute for Infection and Immunity, Amsterdam, the Netherlands; HIV Monitoring Foundation, Amsterdam, the Netherlands; Public Health Service of Amsterdam, Infectious Diseases, Amsterdam, the Netherlands
Eveline Verheij
Amsterdam University Medical Centers, University of Amsterdam, Infectious Diseases, Amsterdam, the Netherlands; Amsterdam Institute for Infection and Immunity, Amsterdam, the Netherlands; Amsterdam Institute for Global Health and Development, Amsterdam, the Netherlands
Aswin Verhoeven
Leiden University Medical Center, Center for Proteomics & Metabolomics, Leiden, the Netherlands
Ferdinand W.N.M. Wit
Amsterdam University Medical Centers, University of Amsterdam, Infectious Diseases, Amsterdam, the Netherlands; Amsterdam Institute for Infection and Immunity, Amsterdam, the Netherlands; HIV Monitoring Foundation, Amsterdam, the Netherlands
Maarten F. Schim van der Loeff
Amsterdam University Medical Centers, University of Amsterdam, Infectious Diseases, Amsterdam, the Netherlands; Amsterdam Institute for Infection and Immunity, Amsterdam, the Netherlands; Public Health Service of Amsterdam, Infectious Diseases, Amsterdam, the Netherlands
Martin Giera
Leiden University Medical Center, Center for Proteomics & Metabolomics, Leiden, the Netherlands
Neeltje A. Kootstra
Amsterdam Institute for Infection and Immunity, Amsterdam, the Netherlands; Amsterdam UMC, University of Amsterdam, Experimental Immunology, Amsterdam, the Netherlands
Peter Reiss
Amsterdam University Medical Centers, University of Amsterdam, Infectious Diseases, Amsterdam, the Netherlands; Amsterdam Institute for Infection and Immunity, Amsterdam, the Netherlands; Amsterdam Institute for Global Health and Development, Amsterdam, the Netherlands; Amsterdam University Medical Centers, University of Amsterdam, Department of Global Health, Meibergdreef 9, Amsterdam, the Netherlands
Ivan Vujkovic-Cvijin
Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA; Karsh Division of Gastroenterology & Hepatology, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA; F. Widjaja Inflammatory Bowel Disease Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA; Corresponding author
Summary: Antiretroviral therapy (ART) has dramatically lengthened lifespan among people with HIV (PWH), but this population experiences heightened rates of inflammation-related comorbidities. HIV-associated inflammation is linked with an altered microbiome; whether such alterations precede inflammation-related comorbidities or occur as their consequence remains unknown. We find that ART-treated PWH exhibit depletion of gut-resident bacteria that produce short-chain fatty acids (SCFAs)—crucial microbial metabolites with anti-inflammatory properties. Prior reports establish that fecal SCFA concentrations are not depleted in PWH. We find that gut-microbiota-mediated SCFA production capacity is better reflected in serum than in feces and that PWH exhibit reduced serum SCFA, which associates with inflammatory markers. Leveraging stool and serum samples collected prior to comorbidity onset, we find that HIV-specific microbiome alterations precede morbidity and mortality in ART-treated PWH. Among these microbiome alterations, reduced microbiome-mediated conversion of lactate to propionate precedes mortality in PWH. Thus, gut microbial fiber/lactate conversion to SCFAs may modulate HIV-associated comorbidity risk.
