Inflammatory diseases of the gastrointestinal tract are frequently associated with dysbiosis, characterized by changes in gut microbial communities that include an expansion of facultative anaerobic ...bacteria of the Enterobacteriaceae family (phylum Proteobacteria). Here we show that a dysbiotic expansion of Enterobacteriaceae during gut inflammation could be prevented by tungstate treatment, which selectively inhibited molybdenum-cofactor-dependent microbial respiratory pathways that are operational only during episodes of inflammation. By contrast, we found that tungstate treatment caused minimal changes in the microbiota composition under homeostatic conditions. Notably, tungstate-mediated microbiota editing reduced the severity of intestinal inflammation in mouse models of colitis. We conclude that precision editing of the microbiota composition by tungstate treatment ameliorates the adverse effects of dysbiosis in the inflamed gut.
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.
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•Genes encoding respiratory pathways are overrepresented in the dysbiotic microbiome•Utilization of microbiota-derived formate enhances E. coli fitness in the inflamed gut•Formate concentrations in the gut are elevated during inflammation-associated dysbiosis•During gut inflammation, formate utilization by E. coli requires oxygen respiration
Intestinal inflammation is associated with changes in the microbiota composition (dysbiosis), such as the expansion of the commensal Enterobacteriaceae population. Hughes and Winter et al. show that utilization of microbiota-derived formate as electron donor and oxygen as terminal electron acceptor contribute to the bloom of Enterobacteriaceae in the inflamed gut.
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.
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•Salmonella Typhimurium (S. Tm) utilizes l-lactate as a nutrient during gut infection•Lactate used by S. Tm during infection is primarily host derived•Depletion of Clostridia from the microbiota alters host metabolism to produce lactate•Oxygen is the terminal electron acceptor for l-lactate utilization by S. Tm
Intestinal infection with Salmonella Typhimurium results in inflammation-induced dysbiosis. Gillis et al. demonstrate that depletion of commensal Clostridia reduces butyrate availability and subsequently alters host metabolism to produce lactate. Lactate oxidation by Salmonella enhances fitness in the gut and allows the pathogen to outcompete the microbiota.
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.
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•During gut colonization, S. Typhimurium performs a complete, oxidative TCA cycle•Host-derived alternative electron acceptors impact S. Tm central metabolism•Uptake of C4-dicarboxylates enhances S. Tm fitness in the inflamed intestine•Utilization of microbiota-derived succinate supports growth of S. Tm in the gut lumen
Spiga et al. show that during colonization of the intestinal lumen, the enteric pathogen S. Typhimurium performs a complete TCA cycle. This oxidative central metabolism enables S. Typhimurium to utilize the microbiota-derived fermentation product succinate as a nutrient and to compete with the microbiota for colonization of the intestinal tract.
serovar Typhimurium induces intestinal inflammation to create a niche that fosters the outgrowth of the pathogen over the gut microbiota. Under inflammatory conditions,
utilizes terminal electron ...acceptors generated as byproducts of intestinal inflammation to generate cellular energy through respiration. However, the electron donating reactions in these electron transport chains are poorly understood. Here, we investigated how formate utilization through the respiratory formate dehydrogenase-N (FdnGHI) and formate dehydrogenase-O (FdoGHI) contribute to gut colonization of
. Both enzymes fulfilled redundant roles in enhancing fitness in a mouse model of
-induced colitis, and coupled to tetrathionate, nitrate, and oxygen respiration. The formic acid utilized by
during infection was generated by its own pyruvate-formate lyase as well as the gut microbiota. Transcription of formate dehydrogenases and pyruvate-formate lyase was significantly higher in bacteria residing in the mucus layer compared to the lumen. Furthermore, formate utilization conferred a more pronounced fitness advantage in the mucus, indicating that formate production and degradation occurred predominantly in the mucus layer. Our results provide new insights into how
adapts its energy metabolism to the local microenvironment in the gut. IMPORTANCE Bacterial pathogens must not only evade immune responses but also adapt their metabolism to successfully colonize their host. The microenvironments encountered by enteric pathogens differ based on anatomical location, such as small versus large intestine, spatial stratification by host factors, such as mucus layer and antimicrobial peptides, and distinct commensal microbial communities that inhabit these microenvironments. Our understanding of how
populations adapt its metabolism to different environments in the gut is incomplete. In the current study, we discovered that
utilizes formate as an electron donor to support respiration, and that formate oxidation predominantly occurs in the mucus layer. Our experiments suggest that spatially distinct
populations in the mucus layer and the lumen differ in their energy metabolism. Our findings enhance our understanding of the spatial nature of microbial metabolism and may have implications for other enteric pathogens as well as commensal host-associated microbial communities.
During
serovar Typhimurium infection, host inflammation alters the metabolic environment of the gut lumen to favor the outgrowth of the pathogen at the expense of the microbiota. Inflammation-driven ...changes in host cell metabolism lead to the release of l-lactate and molecular oxygen from the tissue into the gut lumen.
utilizes lactate as an electron donor in conjunction with oxygen as the terminal electron acceptor to support gut colonization. Here, we investigated transcriptional regulation of the respiratory l-lactate dehydrogenase LldD
and in mouse models of
infection. The two-component system ArcAB repressed transcription of l-lactate utilization genes under anaerobic conditions
The ArcAB-mediated repression of
transcription was relieved under microaerobic conditions. Transcription of
was induced by l-lactate but not d-lactate. A mutant lacking the regulatory protein LldR failed to induce
transcription in response to l-lactate. Furthermore, the
mutant exhibited reduced transcription of l-lactate utilization genes and impaired fitness in murine models of infection. These data provide evidence that the host-derived metabolites oxygen and l-lactate serve as cues for
to regulate lactate oxidation metabolism on a transcriptional level.
Intestinal inflammation disrupts the microbiota composition leading to an expansion of Enterobacteriaceae family members (dysbiosis). Associated with this shift in microbiota composition is a ...profound change in the metabolic landscape of the intestine. It is unclear how changes in metabolite availability during gut inflammation impact microbial and host physiology.
We investigated microbial and host lactate metabolism in murine models of infectious and non-infectious colitis. During inflammation-associated dysbiosis, lactate levels in the gut lumen increased. The disease-associated spike in lactate availability was significantly reduced in mice lacking the lactate dehydrogenase A subunit in intestinal epithelial cells. Commensal E. coli and pathogenic Salmonella, representative Enterobacteriaceae family members, utilized lactate via the respiratory L-lactate dehydrogenase LldD to increase fitness. Furthermore, mice lacking the lactate dehydrogenase A subunit in intestinal epithelial cells exhibited lower levels of inflammation in a model of non-infectious colitis.
The release of lactate by intestinal epithelial cells during gut inflammation impacts the metabolism of gut-associated microbial communities. These findings suggest that during intestinal inflammation and dysbiosis, changes in metabolite availability can perpetuate colitis-associated disturbances of microbiota composition. Video Abstract.
The composition of gut-associated microbial communities changes during intestinal inflammation, including an expansion of Enterobacteriaceae populations. The mechanisms underlying microbiota changes ...during inflammation are incompletely understood. Here, we analyzed previously published metagenomic datasets with a focus on microbial hydrogen metabolism. The bacterial genomes in the inflamed murine gut and in patients with inflammatory bowel disease contained more genes encoding predicted hydrogen-utilizing hydrogenases compared to communities found under non-inflamed conditions. To validate these findings, we investigated hydrogen metabolism of
a representative Enterobacteriaceae, in mouse models of colitis.
mutants lacking hydrogenase-1 and hydrogenase-2 displayed decreased fitness during colonization of the inflamed cecum and colon. Utilization of molecular hydrogen was in part dependent on respiration of inflammation-derived electron acceptors. This work highlights the contribution of hydrogenases to alterations of the gut microbiota in the context of non-infectious colitis.
During peripheral immune activation caused by an infection or an inflammatory condition, the innate immune response signals to the brain and causes an up-regulation of central nervous system (CNS) ...cytokine production. Central actions of proinflammatory cytokines, in particular IL-1β, are pivotal for the induction of fever and fatigue. In the present study, the influence of peripheral chronic joint inflammatory disease in rheumatoid arthritis (RA) on CNS inflammation was investigated. Intrathecal interleukin (IL)-1β concentrations were markedly elevated in RA patients compared with controls or with patients with multiple sclerosis. Conversely, the anti-inflammatory IL-1 receptor antagonist and IL-4 were decreased in RA cerebrospinal fluid (CSF). Tumor necrosis factor and IL-6 levels in the CSF did not differ between patients and controls. Concerning IL-1β, CSF concentrations in RA patients were higher than in serum, indicating local production in the CNS, and there was a positive correlation between CSF IL-1β and fatigue assessments. Next, spinal inflammation in experimental arthritis was investigated. A marked increase of IL-1β, IL-18, and tumor necrosis factor, but not IL-6 mRNA production, in the spinal cord was observed, coinciding with increased arthritis scores in the KBxN serum transfer model. These data provide evidence that peripheral inflammation such as arthritis is associated with an immunological activation in the CNS in both humans and mice, suggesting a possible therapeutic target for centrally affecting conditions as fatigue in chronic inflammatory diseases, for which to date there are no specific treatments.
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