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

Long-term cotrimoxazole prophylaxis reduces mortality and morbidity in HIV infection but the mechanisms underlying these sustained 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 Zimbabwan 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. Since sub-clinical enteropathogen carriage and enteropathy can drive systemic inflammation, we explored the impact of cotrimoxazole on the gut microbiome and biomarkers of intestinal inflammation. Although global microbiome community composition was unchanged, viridans group Streptococci and streptococcal mevalonate pathway enzymes were lower among children who continued (n=36) versus stopped (n=36) cotrimoxazole. These changes were associated with lower fecal myeloperoxidase. To isolate direct effects of cotrimoxazole on immune activation from its antibiotic properties, we established in vitro models of systemic and intestinal inflammation. In vitro cotrimoxazole treatment had modest but consistent inhibitory effects on pro-inflammatory cytokine production by blood leukocytes from HIV-positive (n=16) and HIV-negative (n=8) U.K. adults. It also reduced IL-8 production by inflamed gut epithelial cell lines. Together, these data 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.