Dysbiosis-Associated Changes in Host Metabolism Produce Lactate to Support Enterobacterial Expansion During Inflammation

The lumen of the gastrointestinal tract is heavily colonized by microbes, termed the gut microbiota. Under normal conditions, fermentative anaerobes constitute the majority of the gut microbiota. However, during inflammation there is a change in the nutritional environment of the gut that enables the outgrowth of facultative aerobic Enterobacteriaceae through respiratory metabolism. Salmonella enterica serovar Typhimurium (S. Tm) is a pathogenic member of the Enterobacteriaceae family that benefits from inflammation. We found that S. Tm uses lactate as a nutrient during infection, which maximizes colonization of the gut. During S. Tm infection, a profound change in the microbial community of the gut occurs. In particular, butyrate-producing Clostridia species are depleted. Butyrate is the preferred substrate for β-oxidation by intestinal epithelial cells (IEC). In the absence of butyrate, IEC perform a fermentative metabolism that produces lactate as a waste product. Lactate is then used in conjunction with oxygen as a terminal electron acceptor to support growth of S. Tm in the murine gut lumen. We next investigated the regulation of lactate utilization in S. Tm. We found that the lactate utilization genes (lldPRD), were inducible by electron acceptors and L-lactate. The transcriptional response to L-lactate was coordinated by the regulatory protein LldR, which maximized colonization of the murine gut. Under anaerobic conditions, lldPRD expression was repressed by the two-component system ArcAB. Commensal members of the Enterobacteriaceae family also expand during non-infectious colitis. We investigated whether lactate was also produced during non-infectious colitis and if commensal Enterobacteriaceae could use this nutrient. Butyrate was depleted and lactate was abundant in a murine model of colitis. Metagenomic sequencing demonstrated that lactate dehydrogenase genes were more abundant in the microbiome of inflamed mice than control mice. We next began to characterize putative lactate dehydrogenases in E. coli. We identified several putative lactate dehydrogenases, however, their role in E. coli fitness requires further study. In conclusion, we identified an important host-derived nutrient that promotes S. Tm fitness during infection and may serve as a nutrient for commensal Enterobacteriaceae during non-infectious colitis. This illustrates the importance of nutrient acquisition for Enterobacteriaceae during inflammatory colonization of the gut.