Colonocyte-Derived Lactate Promotes Enterobacteriaceae Fitness During Non-Infectious Colitis

The interface of the gut microbiota and the host intestine presents ample opportunities for interactions between host and microbe. In homeostatic conditions, these interactions are often beneficial, such as exchange of metabolites or resistance to gastrointestinal pathogens. In disease, however, the perturbation of these complex interactions can exacerbate pathogenesis. In this study, we examine the mechanisms promoting the disruption of normal host-microbe interactions after perturbances induced by helminth infection, antibiotics, and non-infectious colitis. We specifically probe the contribution of metabolism by members of the Enterobacteriaceae family of bacteria, a group known to commonly outgrow during intestinal inflammation. In the example of non-infectious colitis, we further explore metabolic interactions between host and microbe by manipulating host factors that produce metabolites which can be used by the gut microbiota. In our studies with the murine intestinal helminth parasite H. polygyrus, we found that helminth infection exacerbated colitis-associated and antibiotic-associated gut microbiota dysbiosis and worsened disease severity of chemically-induced murine colitis. Though we did not identify the molecular mechanisms underlying the helminth-associated exacerbation, we further explored how Enterobacteriaceae metabolism contributes generally to dysbiosis associated with antibiotic treatment and non-infectious colitis. Using comparative metagenomics, we observed that microbial lactate utilization is elevated during non-infectious chemically-induced colitis. We recapitulated these findings in a genetic model of colitis and found that lactate utilization via the respiratory lactate dehydrogenase LldD enhanced E. coli fitness during intestinal inflammation. We then were able to separate the contributing factors of dysbiosis and inflammation by administering either the antibiotic streptomycin, a low dose of dextran sulfate sodium (DSS), or both together. In this way, we demonstrated that both inflammation and dysbiosis together were required to induce a maximal production of lactate and for E. coli to utilize lactate. With a genetic mouse model lacking lactate dehydrogenase subunit A (LDHA, encoded by Ldha) in its intestinal epithelium, we illustrated that epithelial-derived lactate contributes to the accumulation of lactate during non-infectious colitis, and that epithelial-produced lactate is utilized by the gastrointestinal pathogen Salmonella enterica subspecies Typhimurium during Salmonella infection, another model of intestinal inflammation accompanied by dysbiosis. In all, this study illustrates how metabolic changes in the intestinal epithelium can support the fitness of Enterobacteriaceae during intestinal inflammation and dysbiosis.