Cotrimoxazole reduces systemic inflammation in HIV infection by altering the gut microbiome and immune activation

Claire D. Bourke, Ethan Gough, Godfrey Pimundu, Annie Shonhai, Chipo Berejena, Louise Terry, Lucas Baumard, Naheed Choudhry, Yusuf Karmali, Mutsa Bwakura-Dangarembizi, Victor Musiime, Joseph Lutaakome, Adeodata Kekitiinwa, Kuda Mutasa, Alexander J. Szubert, Moira J. Spyer, Jane R. Deayton, Magdalena Glass, Hyun Min Geum, Claire Pardieu & 6 others Diana M. Gibb, Nigel Klein, Thaddeus J. Edens, A. Sarah Walker, Amee R. Manges, Andrew J. Prendergast

Research output: Contribution to journalArticle

Abstract

Long-term cotrimoxazole prophylaxis reduces mortality and morbidity in HIV infection, but the mechanisms underlying these clinical benefits are unclear. Here, we investigate the impact of cotrimoxazole on systemic inflammation, an independent driver of HIV mortality. In HIV-positive Ugandan and Zimbabwean children receiving antiretroviral therapy, we show that plasma inflammatory markers were lower after randomization to continue (n = 144) versus stop (n = 149) cotrimoxazole. This was not explained by clinical illness, HIV progression, or nutritional status. Because subclinical enteropathogen carriage and enteropathy can drive systemic inflammation, we explored cotrimoxazole effects on the gut microbiome and intestinal inflammatory biomarkers. Although global microbiome composition was unchanged, viridans group Streptococci and streptococcal mevalonate pathway enzymes were lower among children continuing (n = 36) versus stopping (n = 36) cotrimoxazole. These changes were associated with lower fecal myeloperoxidase. To isolate direct effects of cotrimoxazole on immune activation from antibiotic effects, we established in vitro models of systemic and intestinal inflammation. In vitro cotrimoxazole had modest but consistent inhibitory effects on proinflammatory cytokine production by blood leukocytes from HIV-positive (n = 16) and HIV-negative (n = 8) UK adults and reduced IL-8 production by gut epithelial cell lines. Collectively we demonstrate that cotrimoxazole reduces systemic and intestinal inflammation both indirectly via antibiotic effects on the microbiome and directly by blunting immune and epithelial cell activation. Synergy between these pathways may explain the clinical benefits of cotrimoxazole despite high antimicrobial resistance, providing further rationale for extending coverage among people living with HIV in sub-Saharan Africa.

Original languageEnglish (US)
Article numbereaav0537
JournalScience translational medicine
Volume11
Issue number486
DOIs
StatePublished - Apr 3 2019

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Sulfamethoxazole Drug Combination Trimethoprim
HIV Infections
Inflammation
HIV
Microbiota
Epithelial Cells
Anti-Bacterial Agents
Viridans Streptococci
Gastrointestinal Microbiome
Mevalonic Acid
Mortality
Africa South of the Sahara
Random Allocation
Nutritional Status
Interleukin-8
Peroxidase
Leukocytes
Biomarkers
Cytokines
Morbidity

ASJC Scopus subject areas

  • Medicine(all)

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Cotrimoxazole reduces systemic inflammation in HIV infection by altering the gut microbiome and immune activation. / Bourke, Claire D.; Gough, Ethan; Pimundu, Godfrey; Shonhai, Annie; Berejena, Chipo; Terry, Louise; Baumard, Lucas; Choudhry, Naheed; Karmali, Yusuf; Bwakura-Dangarembizi, Mutsa; Musiime, Victor; Lutaakome, Joseph; Kekitiinwa, Adeodata; Mutasa, Kuda; Szubert, Alexander J.; Spyer, Moira J.; Deayton, Jane R.; Glass, Magdalena; Geum, Hyun Min; Pardieu, Claire; Gibb, Diana M.; Klein, Nigel; Edens, Thaddeus J.; Sarah Walker, A.; Manges, Amee R.; Prendergast, Andrew J.

In: Science translational medicine, Vol. 11, No. 486, eaav0537, 03.04.2019.

Research output: Contribution to journalArticle

Bourke, CD, Gough, E, Pimundu, G, Shonhai, A, Berejena, C, Terry, L, Baumard, L, Choudhry, N, Karmali, Y, Bwakura-Dangarembizi, M, Musiime, V, Lutaakome, J, Kekitiinwa, A, Mutasa, K, Szubert, AJ, Spyer, MJ, Deayton, JR, Glass, M, Geum, HM, Pardieu, C, Gibb, DM, Klein, N, Edens, TJ, Sarah Walker, A, Manges, AR & Prendergast, AJ 2019, 'Cotrimoxazole reduces systemic inflammation in HIV infection by altering the gut microbiome and immune activation', Science translational medicine, vol. 11, no. 486, eaav0537. https://doi.org/10.1126/scitranslmed.aav0537
Bourke, Claire D. ; Gough, Ethan ; Pimundu, Godfrey ; Shonhai, Annie ; Berejena, Chipo ; Terry, Louise ; Baumard, Lucas ; Choudhry, Naheed ; Karmali, Yusuf ; Bwakura-Dangarembizi, Mutsa ; Musiime, Victor ; Lutaakome, Joseph ; Kekitiinwa, Adeodata ; Mutasa, Kuda ; Szubert, Alexander J. ; Spyer, Moira J. ; Deayton, Jane R. ; Glass, Magdalena ; Geum, Hyun Min ; Pardieu, Claire ; Gibb, Diana M. ; Klein, Nigel ; Edens, Thaddeus J. ; Sarah Walker, A. ; Manges, Amee R. ; Prendergast, Andrew J. / Cotrimoxazole reduces systemic inflammation in HIV infection by altering the gut microbiome and immune activation. In: Science translational medicine. 2019 ; Vol. 11, No. 486.
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AU - Bourke, Claire D.

AU - Gough, Ethan

AU - Pimundu, Godfrey

AU - Shonhai, Annie

AU - Berejena, Chipo

AU - Terry, Louise

AU - Baumard, Lucas

AU - Choudhry, Naheed

AU - Karmali, Yusuf

AU - Bwakura-Dangarembizi, Mutsa

AU - Musiime, Victor

AU - Lutaakome, Joseph

AU - Kekitiinwa, Adeodata

AU - Mutasa, Kuda

AU - Szubert, Alexander J.

AU - Spyer, Moira J.

AU - Deayton, Jane R.

AU - Glass, Magdalena

AU - Geum, Hyun Min

AU - Pardieu, Claire

AU - Gibb, Diana M.

AU - Klein, Nigel

AU - Edens, Thaddeus J.

AU - Sarah Walker, A.

AU - Manges, Amee R.

AU - Prendergast, Andrew J.

PY - 2019/4/3

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N2 - Long-term cotrimoxazole prophylaxis reduces mortality and morbidity in HIV infection, but the mechanisms underlying these clinical benefits are unclear. Here, we investigate the impact of cotrimoxazole on systemic inflammation, an independent driver of HIV mortality. In HIV-positive Ugandan and Zimbabwean children receiving antiretroviral therapy, we show that plasma inflammatory markers were lower after randomization to continue (n = 144) versus stop (n = 149) cotrimoxazole. This was not explained by clinical illness, HIV progression, or nutritional status. Because subclinical enteropathogen carriage and enteropathy can drive systemic inflammation, we explored cotrimoxazole effects on the gut microbiome and intestinal inflammatory biomarkers. Although global microbiome composition was unchanged, viridans group Streptococci and streptococcal mevalonate pathway enzymes were lower among children continuing (n = 36) versus stopping (n = 36) cotrimoxazole. These changes were associated with lower fecal myeloperoxidase. To isolate direct effects of cotrimoxazole on immune activation from antibiotic effects, we established in vitro models of systemic and intestinal inflammation. In vitro cotrimoxazole had modest but consistent inhibitory effects on proinflammatory cytokine production by blood leukocytes from HIV-positive (n = 16) and HIV-negative (n = 8) UK adults and reduced IL-8 production by gut epithelial cell lines. Collectively we demonstrate that cotrimoxazole reduces systemic and intestinal inflammation both indirectly via antibiotic effects on the microbiome and directly by blunting immune and epithelial cell activation. Synergy between these pathways may explain the clinical benefits of cotrimoxazole despite high antimicrobial resistance, providing further rationale for extending coverage among people living with HIV in sub-Saharan Africa.

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