Bacterial Microbiome of Foreskin Tissue, Impact of Short-course PrEP, and Relation to Host Inflammation

HIV pre-exposure prophylaxis (PrEP) is effective at preventing HIV acquisition, but its impact on the microbiome of the penis has not been described. As part of the CHAPS randomized clinical trial, we sequenced a segment of the bacterial 16S rRNA gene from foreskin tissue collected during surgical penile circumcision of 144 adolescents in South Africa and Uganda after randomization to placebo, emtricitabine with tenofovir disoproxil fumarate, or emtricitabine with tenofovir alafenamide. We found a large proportion of Corynebacterium in addition to other anaerobic species. Cutibacterium acnes was more abundant among participants from South Africa than Uganda, though this made no difference in surgical recovery. We did not find a difference in bacterial populations by treatment received nor bacterial taxa that were differentially abundant between participants who received placebo versus active drug. Using RNAseq libraries from the same participants, we found generally negative correlations between the relative abundance of bacterial taxa and the expression of genes downstream of the innate response to bacteria and regulation of the inflammatory response. When participants were divided into two clusters based on bacterial community composition, these clusters were also distinguished by high and low bacterial diversity. Random forest classification showed higher expression of NFATC3 and SELENOS and lower expression of STAP1 and NLRP6 in the higher diversity group compared to the lower. Our results show no difference in the tissue microbiome of the foreskin in the different PrEP arms versus placebo. Bacterial taxa were largely inversely correlated with gene expression, consistent with non-inflammatory colonization. Importance We found that a short course of oral medicine to prevent HIV was not associated with a difference in the bacterial community of the foreskin of the penis. Previous studies found increased inflammation with certain anaerobic bacteria from swabs taken under the foreskin, but we found that higher relative abundances of the bacteria were correlated with lower expression of inflammatory genes. Understanding the relationship between bacteria and inflammation in the penis will help us to understand how interventions like penile circumcision reduce the risk of acquiring sexually transmitted infections such as HIV. ### Competing Interest Statement The authors have declared no competing interest.