Research ArticleHIV

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

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Science Translational Medicine  03 Apr 2019:
Vol. 11, Issue 486, eaav0537
DOI: 10.1126/scitranslmed.aav0537

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Cotrimoxazole curbs inflammation

Prophylactic antibiotics are used in HIV-endemic areas and have been shown to reduce mortality and morbidity. Using samples from a clinical trial where HIV-positive children were randomized to continue or stop cotrimoxazole, Bourke et al. examined potential mechanisms behind these protective effects. They observed decreases of certain types of Streptococcus in the gut and decreased systemic inflammatory markers in children who continued treatment. Treatment of primary samples from HIV-infected adults or a gut epithelial cell line revealed that cotrimoxazole dampened inflammatory cytokine production. Their results showcase how this antibiotic interacts with the gut microbiome and the immune system to alter the inflammatory response with beneficial outcomes.

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.

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