Gut butyrate is associated with enhanced cytomegalovirus IE1 gene expression in a pregnancy-associated context

Human cytomegalovirus (HCMV) reactivates in the breast milk of seropositive women during lactation, yet the mechanisms governing this process remain poorly defined. The gut microbiota shapes host immunity and has been implicated in the control of latent viral infections. Short-chain fatty acids (SCFAs), particularly butyrate, are microbial metabolites that can influence viral latency and gene expression. Here, we investigated the potential contribution of gut butyrate to CMV immediate-early 1 (IE1) gene expression in the context of pregnancy. To examine the association between dietary alterations in the intestinal microbial and metabolic environment and CMV IE1 expression, mice were fed either a high-fiber diet (HFD) or a low-fiber diet (LFD). MCMV IE1 gene expression was assessed in pregnant and non-pregnant animals by quantifying IE1 transcripts. Cecal SCFA levels and microbial populations were also analyzed. In parallel, the effect of individual SCFAs on MCMV IE1 gene expression was examined in experimentally infected fibroblasts. MCMV IE1 expression was not detected in non-pregnant mice. In contrast, MCMV IE1 expression was detected in pregnant mice, with higher IE1 mRNA levels in mammary and colonic tissues of HFD-fed mice than in LFD-fed mice. HFD feeding was also associated with increased cecal butyrate concentrations and an enrichment of heat-tolerant anaerobic bacteria. Consistently, butyrate enhanced MCMV IE1 mRNA expression in MCMV-infected fibroblasts in vitro . Together, these findings suggest that pregnancy provides a permissive host context for MCMV IE1 gene expression and that microbiota-derived butyrate may act as a modulatory factor that amplifies CMV gene expression. These findings support a potential link between dietary alterations in the intestinal microbial and metabolic environment and CMV gene expression in the pregnancy-associated host environment.