Pathogens’ Exploitation of the Intestinal Food Web
Authors: Tu Anh Pham N., Trevor D. Lawley
Journal: Cell Host & Microbe (2014)

Competition for nutrients is a key factor controlling pathogen colonization within the gastrointestinal tract. In this issue, Ferreyra et al., 2014Ferreyra J.A. Wu K.J. Hryckowian A.J. Bouley D.M. Weimer B.C. Sonnenburg J.L. Cell Host Microbe. 2014; 16 (this issue): 770-777Abstract Full Text Full Text PDF PubMed Scopus (213) Google Scholar and Curtis et al., 2014Curtis M.M. Hu Z. Klimko C. Narayanan S. Deberardinis R. Sperandio V. Cell Host Microbe. 2014; 16 (this issue): 759-769Abstract Full Text Full Text PDF PubMed Scopus (188) Google Scholar show that diverse enteric pathogens can exploit a metabolic byproduct from the commensal microbiota, succinate, to enhance their own virulence expression and proliferation. Competition for nutrients is a key factor controlling pathogen colonization within the gastrointestinal tract. In this issue, Ferreyra et al., 2014Ferreyra J.A. Wu K.J. Hryckowian A.J. Bouley D.M. Weimer B.C. Sonnenburg J.L. Cell Host Microbe. 2014; 16 (this issue): 770-777Abstract Full Text Full Text PDF PubMed Scopus (213) Google Scholar and Curtis et al., 2014Curtis M.M. Hu Z. Klimko C. Narayanan S. Deberardinis R. Sperandio V. Cell Host Microbe. 2014; 16 (this issue): 759-769Abstract Full Text Full Text PDF PubMed Scopus (188) Google Scholar show that diverse enteric pathogens can exploit a metabolic byproduct from the commensal microbiota, succinate, to enhance their own virulence expression and proliferation. The human large intestine is home to a complex and dynamic consortium of microbes, also known as the microbiota. Akin to a physiologic organ, the microbiota fulfils many important functions to maintain host health, including nutrition acquisition, immune development, and pathogen defense. Among the most well-studied functions of the microbiota is its tremendous metabolic capacity. The microbiota contributes to the production of vitamins (e.g., vitamins K and B12 and folic acid), enhances ionic absorption of calcium and magnesium, and is indispensable for energy salvage from nutrients otherwise nondigestible by human cells (Gill et al., 2006Gill S.R. Pop M. Deboy R.T. Eckburg P.B. Turnbaugh P.J. Samuel B.S. Gordon J.I. Relman D.A. Fraser-Liggett C.M. Nelson K.E. Science. 2006; 312: 1355-1359Crossref PubMed Scopus (3286) Google Scholar). Interestingly, while some metabolic activities of the microbiota such as methanogenesis or oxalate degradation may vary widely between different individuals, the ability to ferment nondigestible carbohydrates and proteins is highly conserved among those functions encoded by the human core microbiome (Qin et al., 2010Qin J. Li R. Raes J. Arumugam M. Burgdorf K.S. Manichanh C. Nielsen T. Pons N. Levenez F. Yamada T. et al.MetaHIT ConsortiumNature. 2010; 464: 59-65Crossref PubMed Scopus (7275) Google Scholar). The principle end products of bacterial metabolism in the large intestine are short-chain fatty acids (SCFAs), which mainly arise from anaerobic fermentation of nondigestible carbohydrates. In the large bowel, these consists of nonstarch polysaccharides (e.g., dietary fiber and plant polysaccharides including cellulose and pectin), resistant starch, simple carbohydrates not yet digested in the small intestine, as well as those derived from sloughed goblet cells and host mucin glycoproteins. As small (1- to 6-carbon) organic fatty acids, SCFAs are readily absorbed and metabolized by the intestinal mucosa and the liver, where they play a substantial role in host nutrition (Macfarlane and Macfarlane, 2003Macfarlane S. Macfarlane G.T. Proc. Nutr. Soc. 2003; 62: 67-72Crossref PubMed Scopus (1120) Google Scholar). SCFAs can also modulate the intestinal immune response, such as by inhibiting excessive proinflammatory cytokines in chronic inflammation (Smith et al., 2013Smith P.M. Howitt M.R. Panikov N. Michaud M. Gallini C.A. Bohlooly-Y M. Glickman J.N. Garrett W.S. Science. 2013; 341: 569-573Crossref PubMed Scopus (3052) Google Scholar), and exert a direct trophic effect on the intestinal epithelium. While the beneficial effect of microbiota-associated metabolites, particularly SCFAs, to the host has been a subject of intense research, how these substrates influence bacterial-bacterial interactions is less well understood. The metabolic landscape of the gut can vary greatly depending on the microbiota structure, intestinal transit time, and availability of fermentable substrates. However, butyrate (C4), propionate (C3), and acetate (C2) are typically the most abundant and together make up over 80% of total SCFAs produced during health (Macfarlane and Macfarlane, 2003Macfarlane S. Macfarlane G.T. Proc. Nutr. Soc. 2003; 62: 67-72Crossref PubMed Scopus (1120) Google Scholar). These molecules generally arise from oxidative metabolism of hexose sugars (e.g., glucose and fructose) through the nearly ubiquitous Embden-Meyerhof glycolysis pathway. Other SCFAs such as valerate, formate, and isobutyrate are products of branched-chain amino acid metabolism and exist in much lower levels, while lactate, ethanol, and succinate are metabolic intermediates that are converted to other SCFAs to various degrees depending on the extent of microbial cross-feeding within the intestinal microenvironment. Therefore, these intermediates are rarely present at significant levels in the gut. Interestingly, succinate has been found to accumulate during intestinal inflammation, such as in antibiotic-associated diarrhea and infection with the pathogen Clostridium difficile in human and mice (Lawley et al., 2012Lawley T.D. Clare S. Walker A.W. Stares M.D. Connor T.R. Raisen C. Goulding D. Rad R. Schreiber F. Brandt C. et al.PLoS Pathog. 2012; 8: e1002995Crossref PubMed Scopus (405) Google Scholar), although its role in disease pathogenesis is still unclear. In this issue of Cell Host & Microbe, two studies by Ferreyra et al., 2014Ferreyra J.A. Wu K.J. Hryckowian A.J. Bouley D.M. Weimer B.C. Sonnenburg J.L. Cell Host Microbe. 2014; 16 (this issue): 770-777Abstract Full Text Full Text PDF PubMed Scopus (213) Google Scholar and Curtis et al., 2014Curtis M.M. Hu Z. Klimko C. Narayanan S. Deberardinis R. Sperandio V. Cell Host Microbe. 2014; 16 (this issue): 759-769Abstract Full Text Full Text PDF PubMed Scopus (188) Google Scholar present important mechanistic insights into the role of succinate in commensal-pathogen interactions within the competitive gut ecosystem. Importantly, both studies provide compelling evidence to suggest that intestinal metabolites induced by a commensal bacterium, Bacteroides thetaiotaomicron, can unexpectedly enhance pathogen virulence expression and colonization in the gut, through the production of succinate (Figure 1). B. thetaiotaomicron is a Gram-negative obligate anaerobe, which possesses an arsenal of enzymes to degrade complex polysaccharides. Among other Bacteroides species, B. thetaiotaomicron can readily produce SCFAs as well as convert host mucin into succinate and acetate, which in turn allows the production of butyrate by other secondary fermentative microbes (Fischbach and Sonnenburg, 2011Fischbach M.A. Sonnenburg J.L. Cell Host Microbe. 2011; 10: 336-347Abstract Full Text Full Text PDF PubMed Scopus (306) Google Scholar). Thus, B. thetaiotaomicron exemplifies a commensal symbiont well-adapted to survive within and to support the intestinal metabolic network. Curtis et al., 2014Curtis M.M. Hu Z. Klimko C. Narayanan S. Deberardinis R. Sperandio V. Cell Host Microbe. 2014; 16 (this issue): 759-769Abstract Full Text Full Text PDF PubMed Scopus (188) Google Scholar observed that in the presence of B. thetaiotaomicron, the human pathogen enterohemorrhagic E. coli dramatically upregulates the expression of numerous virulence factors, including those encoded by the locus of enterocyte effacement (LEE) pathogenicity island. Interestingly, this transcriptional regulation is driven by a sugar-sensing mechanism, controlled by the catabolite repressor/activator protein Cra (Njoroge et al., 2012Njoroge J.W. Nguyen Y. Curtis M.M. Moreira C.G. Sperandio V. MBio. 2012; 3 (e00280–e12)Crossref PubMed Scopus (96) Google Scholar). Under nutrient-rich conditions where glycolytic catabolites (e.g., glucose and fructose) are plentiful, Cra is inhibited from binding to and activating the transcription of ler, the master regulatory gene of the LEE. In glucose-poor environments, however, E. coli can switch to utilizing gluconeogenic substrates such as lactate, succinate, and glycerate. Meanwhile in these gluconeogenic conditions, Cra can bind to the ler promoter and enhance expression of the LEE genes. This is thought to be an important virulence mechanism for E. coli to establish colonization at the intestinal mucosa and attach to the host epithelial surface, where glucose is far less abundant than in the gut lumen. Thus, the finding by Curtis et al., 2014Curtis M.M. Hu Z. Klimko C. Narayanan S. Deberardinis R. Sperandio V. Cell Host Microbe. 2014; 16 (this issue): 759-769Abstract Full Text Full Text PDF PubMed Scopus (188) Google Scholar indicates that sensing of metabolites produced by the commensal B. thetaiotaomicron can direct virulence and colonization potential of a pathogen. Using the Citrobacter rodentium infection model in mice, which mimics human E. coli infection, the authors further identified succinate as a key metabolite during pathogenesis in vivo. In the presence of B. thetaiotaomicron, succinate level rises significantly during C. rodentium infection. This in turn enhances the expression of C. rodentium virulence genes such as ler and eae, responsible for the formation of attaching-effacing lesions on epithelial cells that are central to C. rodentium pathogenicity. Accordingly, mice infected with C. rodentium experienced a greater morbidity and more severe intestinal pathology when their microbiota had first been colonized by B. thetaiotaomicron. Moreover, this effect was not associated with a higher density of C. rodentium in the gut, but rather an increase in its virulence and a greater loss of various protective mucosal mechanisms such as the production of mucin and antimicrobial peptides. Ferreyra et al., 2014Ferreyra J.A. Wu K.J. Hryckowian A.J. Bouley D.M. Weimer B.C. Sonnenburg J.L. Cell Host Microbe. 2014; 16 (this issue): 770-777Abstract Full Text Full Text PDF PubMed Scopus (213) Google Scholar studied the major metabolic pathways employed by another intestinal pathogen, Clostridium difficile, in the presence of B. thetaiotaomicron. C. difficile infection is an important cause of antibiotic-associated diarrhea worldwide and typically occurs when the indigenous microbiota is severe disturbed by antibiotic exposure (Lawley et al., 2012Lawley T.D. Clare S. Walker A.W. Stares M.D. Connor T.R. Raisen C. Goulding D. Rad R. Schreiber F. Brandt C. et al.PLoS Pathog. 2012; 8: e1002995Crossref PubMed Scopus (405) Google Scholar). In this study, the authors used a simplified gnotobiotic mouse model, in which mice were either monocolonized with each bacterial species or both C. difficile and B. thetaiotaomicron. In addition, mice were fed with a normal (polysaccharide-rich) diet or a polysaccharide-deficient diet in order to shift the metabolic landscape of the gut. Similarly to the observations made in E. coli, Ferreyra et al., 2014Ferreyra J.A. Wu K.J. Hryckowian A.J. Bouley D.M. Weimer B.C. Sonnenburg J.L. Cell Host Microbe. 2014; 16 (this issue): 770-777Abstract Full Text Full Text PDF PubMed Scopus (213) Google Scholar noted that C. difficile was able to respond rapidly to the availability of carbohydrates in the gut and the presence of B. thetaiotaomicron by changing its own metabolic programs. Consistent with a previous report by Ng et al., 2013Ng K.M. Ferreyra J.A. Higginbottom S.K. Lynch J.B. Kashyap P.C. Gopinath S. Naidu N. Choudhury B. Weimer B.C. Monack D.M. Sonnenburg J.L. Nature. 2013; 502: 96-99Crossref PubMed Scopus (647) Google Scholar, cocolonization with B. thetaiotaomicron under polysaccharide-poor condition led to enhanced metabolism of sialic acid by C. difficile. Sialic acids are monosaccharides naturally occurring at the end of host mucin molecules and epithelial cell surfaces that can be released enzymatically by Bacteroides spp. Thus, C. difficile has evolved a strategy to utilize a nutrient derived from host-commensal interactions to enhance its own colonization. Furthermore, when polysaccharides are abundant and in the presence of competition by B. thetaiotaomicron, C. difficile switches on alternative metabolic pathways allowing the utilization of sorbitol and fructose and the conversion of Bacteroides-produced succinate to butyrate. Importantly, induction of the succinate-to-butyrate pathway also promotes proliferation and host colonization by C. difficile. This is demonstrated by the observation that given an abundance of succinate in the gut, a C. difficile mutant lacking the succinate transporter could not colonize to similarly high density as wild-type C. difficile. Interestingly, in addition to C. difficile-induced diarrhea, Ferreyra et al., 2014Ferreyra J.A. Wu K.J. Hryckowian A.J. Bouley D.M. Weimer B.C. Sonnenburg J.L. Cell Host Microbe. 2014; 16 (this issue): 770-777Abstract Full Text Full Text PDF PubMed Scopus (213) Google Scholar found that succinate also accumulates during antibiotic treatment and during polyethylene-glycol-induced osmotic diarrhea. Thus, succinate utilization may represent a common beneficial strategy for pathogens to expand in a competitive gut ecosystem during different perturbations to the microbiota. Intestinal pathogens are well known to exploit the host inflammatory response or host-derived metabolic byproducts to outcompete other microbes and establish colonization. Here, Ferreyra et al., 2014Ferreyra J.A. Wu K.J. Hryckowian A.J. Bouley D.M. Weimer B.C. Sonnenburg J.L. Cell Host Microbe. 2014; 16 (this issue): 770-777Abstract Full Text Full Text PDF PubMed Scopus (213) Google Scholar and Curtis et al., 2014Curtis M.M. Hu Z. Klimko C. Narayanan S. Deberardinis R. Sperandio V. Cell Host Microbe. 2014; 16 (this issue): 759-769Abstract Full Text Full Text PDF PubMed Scopus (188) Google Scholar both found that a commensal-derived metabolite, succinate, can also directly benefit diverse pathogens belonging to the Firmicutes (C. difficile) and the Proteobacteria (EHEC and C. rodentium) phyla (Figure 1). Thus, although the commensal microbiota often plays a fundamental role in colonization resistance against invading pathogens, enteric pathogens also have evolved different strategies to exploit metabolic intermediates available in the inflamed gut for their own advantage (Keeney and Finlay, 2011Keeney K.M. Finlay B.B. Curr. Opin. Microbiol. 2011; 14: 92-98Crossref PubMed Scopus (68) Google Scholar). Together, this work represents valuable insight into the function of microbiota-derived metabolites, which can guide the development of approaches to attenuate pathogen virulence or colonization by modulating the intestinal metabolic pathways. Gut Microbiota-Produced Succinate Promotes C. difficile Infection after Antibiotic Treatment or Motility DisturbanceFerreyra et al.Cell Host & MicrobeDecember 10, 2014In BriefNutrient resource partitioning by gut microbes is typically efficient. Ferreyra et al. demonstrate that upon antibiotic treatment or motility disturbance, succinate, an interspecies metabolic intermediate, transiently spikes to high levels. C. difficile induces a succinate-to-butyrate conversion pathway to take advantage of the succinate spike and expand during these gut perturbations. Full-Text PDF Open ArchiveThe Gut Commensal Bacteroides thetaiotaomicron Exacerbates Enteric Infection through Modification of the Metabolic LandscapeCurtis et al.Cell Host & MicrobeDecember 10, 2014In BriefHost-microbiota interactions influence infection and disease. Curtis et al. demonstrate that the commensal Bacteroides thetaiotaomicron (Bt) enhances virulence gene expression of enterohemorrhagic E. coli and exacerbates Citrobacter rodentium infection. Bt modifies the metabolite environment, increasing metabolites involved in gluconeogenesis, which are sensed through the transcription factor Cra to activate virulence. Full-Text PDF Open Archive