Research

Microbial translocation revisited: targeting the endotoxic potential of gut microbes in HIV-infected individuals

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Abstract

OBJECTIVE: Translocation of microbial products such as lipopolysaccharides (LPS) from the gut may contribute to chronic inflammation in HIV-infected individuals. Recent studies indicate that differences in degree of acylation of gut-bacterial derived LPS may explain variable immune effects, with hexa-acylated rather than penta-acylated LPS having pro-inflammatory capacity. We investigated whether the degree of acylation of gut-derived LPS associates with systemic inflammation, and the potential effect of probiotic intervention. METHODS:Gut microbiota profiles from a probiotics intervention were investigated, and validated in a cohort of HIV-infected individuals commencing ART. The PiCRUSt software was used to predict overall functional capacity of the microbiota, and in-house bioinformatics to distinguish between bacteria producing hexa- and penta-acylated LPS. RESULTS AND CONCLUSION: HIV-infected individuals with the highest ratio of pro-inflammatory hexa-acylated LPS- to non-inflammatory penta-acylated LPS-producing bacteria exhibited increased levels of systemic inflammation (neopterin, P < 0.001) and tryptophan catabolism (kynurenine/tryptophan-ratio, P = 0.01), indicating a link between pro-inflammatory LPS, tryptophan catabolism and inflammation. After probiotics for eight weeks, there was a decrease in gram-negative bacteria (P = 0.01), related primarily to a reduction in bacteria producing penta-acylated LPS (P = 0.01), but not hexa-acylated LPS. The reduction in gram-negative bacteria correlated positively with decreased plasma LPS (r = 0.72), mainly related to a reduction in bacteria producing non-inflammatory penta-acylated LPS (r = 0.58). Notably, gut bacteria producing hexa-acylated LPS were outnumbered by penta-acylated LPS with a factor of 25 in HIV-infected individuals. Further studies are warranted to determine whether microbes producing hexa-acylated LPS might be a more relevant trigger of systemic inflammation compared to plasma LPS captured by the existing limulus assay.