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Intestinal Paneth cells limit bacterial invasion by secreting antimicrobial proteins, including lysozyme. However, invasive pathogens can disrupt the Golgi apparatus, interfering with secretion and compromising intestinal antimicrobial defense. Here we show that during bacterial infection, lysozyme is rerouted via secretory autophagy, an autophagy-based alternative secretion pathway. Secretory autophagy was triggered in Paneth cells by bacteria-induced endoplasmic reticulum (ER) stress, required extrinsic signals from innate lymphoid cells, and limited bacterial dissemination. Secretory autophagy was disrupted in Paneth cells of mice harboring a mutation in autophagy gene Atg16L1 that confers increased risk for Crohn’s disease in humans. Our findings identify a role for secretory autophagy in intestinal defense and suggest why Crohn’s disease is associated with genetic mutations that affect both the ER stress response and autophagy.

About the Authors: Savannah J. Taylor * E-mail: Sebastian.Winter@UTSouthwestern.edu (SEW); Savannah.Taylor@UTSouthwestern.edu (SJT) Affiliation: Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America ORCID logo http://orcid.org/0000-0003-2136-6063 Sebastian E. Winter * E-mail: Sebastian.Winter@UTSouthwestern.edu (SEW); Savannah.Taylor@UTSouthwestern.edu (SJT) Affiliation: Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America ORCID logo http://orcid.org/0000-0003-1532-9178 Introduction Infection with nontyphoidal Salmonella strains, such as Salmonella enterica serovar Typhimurium (S. Typhimurium) commonly causes foodborne bacterial gastroenteritis. In a process dependent on Toll-like receptor 4 (TLR4) signaling [6], S. Typhimurium also drives macrophages to increase hemophagocytosis or consumption of erythrocytes (red blood cells) and leukocytes (white blood cells) [5], creating a population of hemophagocytic macrophages with M2-like properties. S. Typhimurium utilizes inflammation-derived electron acceptors and exploits host energy metabolism The gut microbiota protects the intestinal lumen from invasion by enteric pathogens, a phenomenon termed colonization resistance. In the absence of butyrate, the host epithelium switches its metabolism to anaerobic lactate fermentation [18]. Since lactate fermentation does not consume oxygen, oxygen from the blood stream diffuses into the gut lumen [19, 21].

Tungstate inhibits molybdenum-cofactor-dependent microbial respiratory pathways and shows potential as a selective treatment for microbial imbalances that occur during inflammation of the gastrointestinal tract. Countering colon inflammation Expansion of facultative anaerobic bacteria of the Enterobacteriaceae family in the gut is associated with dysbiosis—an imbalance in the microbiota—and inflammatory bowel disease. Sebastian Winter and colleagues show that tungstate treatment, which selectively inhibits molybdenum-cofactor-dependent microbial respiratory pathways that operate only during episodes of inflammation, mitigates inflammation in mouse models of colitis without causing any compositional alterations to the gut microbiota. This is a promising strategy for precision therapy of the microbiota in response to inflammatory disorders, but future work is needed to determine whether similar approaches could be relevant in humans. Inflammatory diseases of the gastrointestinal tract are frequently associated with dysbiosis 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 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 caused by Salmonella enterica serovar Typhimurium increases the availability of electron acceptors that fuel a respiratory growth of the pathogen in the intestinal lumen. Here we show that one of the carbon sources driving this respiratory expansion in the mouse model is 1,2-propanediol, a microbial fermentation product. 1,2-propanediol utilization required intestinal inflammation induced by virulence factors of the pathogen. S. Typhimurium used both aerobic and anaerobic respiration to consume 1,2-propanediol and expand in the murine large intestine. 1,2-propanediol-utilization did not confer a benefit in germ-free mice, but the pdu genes conferred a fitness advantage upon S. Typhimurium in mice mono-associated with Bacteroides fragilis or Bacteroides thetaiotaomicron. Collectively, our data suggest that intestinal inflammation enables S. Typhimurium to sidestep nutritional competition by respiring a microbiota-derived fermentation product.

Conventional wisdom holds that microbes support their growth in vertebrate hosts by exploiting a large variety of nutrients. We show here that use of a specific nutrient (ethanolamine) confers a marked growth advantage on Salmonella enterica serovar Typhimurium (S. Typhimurium) in the lumen of the inflamed intestine. In the anaerobic environment of the gut, ethanolamine supports little or no growth by fermentation. However, S. Typhimurium is able to use this carbon source by inducing the gut to produce a respiratory electron acceptor (tetrathionate), which supports anaerobic growth on ethanolamine. The gut normally converts ambient hydrogen sulfide to thiosulfate, which it then oxidizes further to tetrathionate during inflammation. Evidence is provided that S. Typhimurium's growth advantage in an inflamed gut is because of its ability to respire ethanolamine, which is released from host tissue, but is not utilizable by competing bacteria. By inducing intestinal inflammation, S. Typhimurium sidesteps nutritional competition and gains the ability to use an abundant simple substrate, ethanolamine, which is provided by the host.

Our intestine is host to a large microbial community (microbiota) that educates the immune system and confers niche protection. Profiling of the gut‐associated microbial community reveals a dominance of obligate anaerobic bacteria in healthy individuals. However, intestinal inflammation is associated with a disturbance of the microbiota—known as dysbiosis—that often includes an increased prevalence of facultative anaerobic bacteria. This group contains potentially harmful bacterial species, the bloom of which can further exacerbate inflammation. Here, we review the mechanisms that generate changes in the microbial community structure during inflammation. One emerging concept is that electron acceptors generated as by‐products of the host inflammatory response feed facultative anaerobic bacteria selectively, thereby increasing their prevalence within the community. This new paradigm has broad implications for understanding dysbiosis during gut inflammation and identifies potential targets for intervention strategies. Intestinal inflammation is associated with alterations of the microbiota and outgrowth of potentially harmful bacterial species. How these changes in microbial community structure occur is discussed here, highlighting the role of electron acceptors in feeding facultative anaerobic bacteria.

Salmonella effector proteins trigger host innate immunity through the activation of small Rho GTPases, which, in turn, is sensed by the NOD1/2 signalling pathway. Identification of harmful microbial invaders The mammalian innate immune system distinguishes self from invading microbes through the detection of conserved pathogen-associated molecular patterns (PAMPs) by Toll-like receptors. But that is not enough: all microbes, regardless of pathogenic potential, produce PAMPs and the innate immune system has mechanisms to determine which microbes pose the greatest threats. One such system is described here. The Salmonella virulence factor SopE, and peptidoglycans from other pathogens, are shown to trigger host immunity by activating small Rho GTPases that are in turn sensed by the NOD1/2 signalling pathway. Thus by monitoring the activation state of small Rho GTPases, a cell can recognize toxin-producing intruders. Our innate immune system distinguishes microbes from self by detecting conserved pathogen-associated molecular patterns 1 . However, these are produced by all microbes, regardless of their pathogenic potential. To distinguish virulent microbes from those with lower disease-causing potential the innate immune system detects conserved pathogen-induced processes 2 , such as the presence of microbial products in the host cytosol, by mechanisms that are not fully resolved. Here we show that NOD1 senses cytosolic microbial products by monitoring the activation state of small Rho GTPases. Activation of RAC1 and CDC42 by bacterial delivery or ectopic expression of SopE, a virulence factor of the enteric pathogen Salmonella , triggered the NOD1 signalling pathway, with consequent RIP2 (also known as RIPK2)-mediated induction of NF-κB-dependent inflammatory responses. Similarly, activation of the NOD1 signalling pathway by peptidoglycan required RAC1 activity. Furthermore, constitutively active forms of RAC1, CDC42 and RHOA activated the NOD1 signalling pathway. Our data identify the activation of small Rho GTPases as a pathogen-induced process sensed through the NOD1 signalling pathway.

Chemotaxis enhances the fitness of Salmonella enterica serotype Typhimurium (S. Typhimurium) during colitis. However, the chemotaxis receptors conferring this fitness advantage and their cognate signals generated during inflammation remain unknown. Here we identify respiratory electron acceptors that are generated in the intestinal lumen as by-products of the host inflammatory response as in vivo signals for methyl-accepting chemotaxis proteins (MCPs). Three MCPs, including Trg, Tsr and Aer, enhanced the fitness of S. Typhimurium in a mouse colitis model. Aer mediated chemotaxis towards electron acceptors (energy taxis) in vitro and required tetrathionate respiration to confer a fitness advantage in vivo. Tsr mediated energy taxis towards nitrate but not towards tetrathionate in vitro and required nitrate respiration to confer a fitness advantage in vivo. These data suggest that the energy taxis receptors Tsr and Aer respond to distinct in vivo signals to confer a fitness advantage upon S. Typhimurium during inflammation by enabling this facultative anaerobic pathogen to seek out favorable spatial niches containing host-derived electron acceptors that boost its luminal growth.

Acute gastrointestinal infection with intracellular pathogens like Salmonella Typhimurium triggers the release of the proinflammatory cytokine interleukin 1β (IL-1β). However, the role of IL-1β in intestinal defense against Salmonella remains unclear. Here, we show that IL-1β production is detrimental during Salmonella infection. Mice lacking IL-1β ( IL-1β -/- ) failed to recruit neutrophils to the gut during infection, which reduced tissue damage and prevented depletion of short-chain fatty acid (SCFA)-producing commensals. Changes in epithelial cell metabolism that typically support pathogen expansion, such as switching energy production from fatty acid oxidation to fermentation, were absent in infected IL-1β -/- mice which inhibited Salmonella expansion. Additionally, we found that IL-1β induces expression of complement anaphylatoxins and suppresses the complement-inactivator carboxypeptidase N (CPN1). Disrupting this process via IL-1β loss prevented mortality in Salmonella -infected IL-1β -/- mice. Finally, we found that IL-1β expression correlates with expression of the complement receptor in patients suffering from sepsis, but not uninfected patients and healthy individuals. Thus, Salmonella exploits IL-1β signaling to outcompete commensal microbes and establish gut colonization. Moreover, our findings identify the intersection of IL-1β signaling and the complement system as key host factors involved in controlling mortality during invasive Salmonellosis.

Salmonella enterica serovar Typhimurium induces intestinal inflammation to create a niche that fosters the outgrowth of the pathogen over the gut microbiota. Under inflammatory conditions, Salmonella 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 Salmonella . Both enzymes fulfilled redundant roles in enhancing fitness in a mouse model of Salmonella -induced colitis, and coupled to tetrathionate, nitrate, and oxygen respiration. The formic acid utilized by Salmonella 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 Salmonella adapts its energy metabolism to the local microenvironment in the gut. 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 Salmonella populations adapt its metabolism to different environments in the gut is incomplete. In the current study, we discovered that Salmonella 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 Salmonella 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.