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

Abstract

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.

Effect of Stopping Cotrimoxazole Preventive Therapy on Microbial Translocation and Inflammatory Markers Among Human Immunodeficiency Virus–Infected Ugandan Adults on Antiretroviral Therapy: The COSTOP Trial Immunology Substudy

“…A direct anti-inflammatory effect of cotrimoxazole in vitro, suppressing the TNF-α and IL-6 response to LPS or zymosan in whole blood or the release of IL-8 by Caco-2 epithelial cell lines treated with IL-1β, was shown recently by Bourke et al [18]. Increased plasma IL-6, CRP, and TNF-α, but not sCD14, were observed after CPT discontinuation [18]. Alternatively, while microbial resistance to cotrimoxazole is widespread, cotrimoxazole might be altering the composition of the intestinal microbiome.…”

“…Our finding of similar levels of plasma LPS in the CPT as in the placebo arm suggests that microbial translocation is similar in both arms, leaving the question of what might be causing the increase of inflammatory markers in the placebo arm. A direct anti-inflammatory effect of cotrimoxazole in vitro, suppressing the TNF-α and IL-6 response to LPS or zymosan in whole blood or the release of IL-8 by Caco-2 epithelial cell lines treated with IL-1β, was shown recently by Bourke et al [18]. Increased plasma IL-6, CRP, and TNF-α, but not sCD14, were observed after CPT discontinuation [18].…”

“…Alternatively, while microbial resistance to cotrimoxazole is widespread, cotrimoxazole might be altering the composition of the intestinal microbiome. In the Anti-Retroviral Research for Watoto (ARROW) study, suppression of abundance and function of gut-resident streptococci (not LPS producers) were described in Zimbabwean HIV-infected children continuing CPT, while global effects on gut microbiome were not observed and LPS-producing Enterobacteriaceae were not affected or even increased [18]. Fecal myeloperoxidase, a marker of intestinal inflammation, was lower in children continuing CPT [18].…”

“…In the Anti-Retroviral Research for Watoto (ARROW) study, suppression of abundance and function of gut-resident streptococci (not LPS producers) were described in Zimbabwean HIV-infected children continuing CPT, while global effects on gut microbiome were not observed and LPS-producing Enterobacteriaceae were not affected or even increased [18]. Fecal myeloperoxidase, a marker of intestinal inflammation, was lower in children continuing CPT [18]. Thus, studies in children and adults show anti-inflammatory effects of CPT not involving changes in plasma endotoxin.…”

Rezidivprophylaxe bei okulärer Toxoplasmose

“…Welche Folgen diese Veränderungen haben, ist weitgehend unbekannt. Andererseits wurde bei Kindern mit HIV-Infektion ein positiver Einfluss auf den Krankheitsverlauf gesehen, da die Cotrimoxazol-Therapie die entzündliche Aktivität im Darm und im Blut deutlich reduzierte [50,51]. Konkrete Untersuchungen bei Patienten mit OT und Langzeitprophylaxe und deren Auswirkungen auf das Mikrobiom gibt es bislang nicht.…”