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The intestinal epithelium separates host tissue and gut-associated microbial communities. During inflammation, the host releases reactive oxygen and nitrogen species as an antimicrobial response. The impact of these radicals on gut microbes is incompletely understood. We discovered that the cryptic appBCX genes, predicted to encode a cytochrome bd-II oxidase, conferred a fitness advantage for E. coli in chemical and genetic models of non-infectious colitis. This fitness advantage was absent in mice that lacked epithelial NADPH oxidase 1 (NOX1) activity. In laboratory growth experiments, supplementation with exogenous hydrogen peroxide enhanced E. coli growth through AppBCX-mediated respiration in a catalase-dependent manner. We conclude that epithelial-derived reactive oxygen species are degraded in the gut lumen, which gives rise to molecular oxygen that supports the aerobic respiration of E. coli. This work illustrates how epithelial host responses intersect with gut microbial metabolism in the context of gut inflammation.

During short-lived perturbations, such as inflammation, the gut microbiota exhibits resilience and reverts to its original configuration. Although microbial access to the micronutrient iron is decreased during colitis, pathogens can scavenge iron by using siderophores. How commensal bacteria acquire iron during gut inflammation is incompletely understood. Curiously, the human commensal Bacteroides thetaiotaomicron does not produce siderophores but grows under iron-limiting conditions using enterobacterial siderophores. Using RNA-seq, we identify B. thetaiotaomicron genes that were upregulated during Salmonella-induced gut inflammation and were predicted to be involved in iron uptake. Mutants in the xusABC locus (BT2063-2065) were defective for xenosiderophore-mediated iron uptake in vitro. In the normal mouse gut, the XusABC system was dispensable, while a xusA mutant colonized poorly during colitis. This work identifies xenosiderophore utilization as a critical mechanism for B. thetaiotaomicron to sustain colonization during inflammation and suggests a mechanism of how interphylum iron metabolism contributes to gut microbiota resilience.

During Salmonella-induced gastroenteritis, mucosal inflammation creates a niche that favors the expansion of the pathogen population over the microbiota. Here, we show that Salmonella Typhimurium infection was accompanied by dysbiosis, decreased butyrate levels, and substantially elevated lactate levels in the gut lumen. Administration of a lactate dehydrogenase inhibitor blunted lactate production in germ-free mice, suggesting that lactate was predominantly of host origin. Depletion of butyrate-producing Clostridia, either through oral antibiotic treatment or as part of the pathogen-induced dysbiosis, triggered a switch in host cells from oxidative metabolism to lactate fermentation, increasing both lactate levels and Salmonella lactate utilization. Administration of tributyrin or a PPARγ agonist diminished host lactate production and abrogated the fitness advantage conferred on Salmonella by lactate utilization. We conclude that alterations of the gut microbiota, specifically a depletion of Clostridia, reprogram host metabolism to perform lactate fermentation, thus supporting Salmonella infection.

The mucosal inflammatory response induced by Salmonella serovar Typhimurium creates a favorable niche for this gut pathogen. Conventional wisdom holds that S. Typhimurium undergoes an incomplete tricarboxylic acid (TCA) cycle in the anaerobic mammalian gut. One change during S. Typhimurium-induced inflammation is the production of oxidized compounds by infiltrating neutrophils. We show that inflammation-derived electron acceptors induce a complete, oxidative TCA cycle in S. Typhimurium, allowing the bacteria to compete with the microbiota for colonization. A complete TCA cycle facilitates utilization of the microbiota-derived fermentation product succinate as a carbon source. S. Typhimurium succinate utilization genes contribute to efficient colonization in conventionally raised mice, but provide no growth advantage in germ-free mice. Mono-association of gnotobiotic mice with Bacteroides, a major succinate producer, restores succinate utilization in S. Typhimurium. Thus, oxidative central metabolism enables S. Typhimurium to utilize a variety of carbon sources, including microbiota-derived succinate.

Intestinal inflammation is frequently associated with an alteration of the gut microbiota, termed dysbiosis, which is characterized by a reduced abundance of obligate anaerobic bacteria and an expansion of facultative Proteobacteria such as commensal E. coli. The mechanisms enabling the outgrowth of Proteobacteria during inflammation are incompletely understood. Metagenomic sequencing revealed bacterial formate oxidation and aerobic respiration to be overrepresented metabolic pathways in a chemically induced murine model of colitis. Dysbiosis was accompanied by increased formate levels in the gut lumen. Formate was of microbial origin since no formate was detected in germ-free mice. Complementary studies using commensal E. coli strains as model organisms indicated that formate dehydrogenase and terminal oxidase genes provided a fitness advantage in murine models of colitis. In vivo, formate served as electron donor in conjunction with oxygen as the terminal electron acceptor. This work identifies bacterial formate oxidation and oxygen respiration as metabolic signatures for inflammation-associated dysbiosis.

Many infectious diseases involve polymicrobial infections, which are characterized by synergistic interactions between different microorganisms colonizing a host. In this issue of Cell Host & Microbe, Keogh et al. (2016) show that Enterococcus faecalis promotes Escherichia coli biofilm formation in low-iron conditions, thus facilitating polymicrobial growth.