Journal Article

Microbiota-liberated host sugars facilitate post-antibiotic expansion of enteric pathogens

Higginbottom, Steven K., Naidu, Natasha, Weimer, Bart C., Monack, Denise M., Sonnenburg, Justin L., Choudhury, Biswa, Ng, Katharine M., Kashyap, Purna C., Gopinath, Smita, Lynch, Jonathan B., Ferreyra, Jessica A.

2013

Overview

Antibiotic treatment disturbs the commensal microbiota and is often followed by infection with enteric pathogens such as Salmonella typhimurium and Clostridium difficile; pathogen expansion is fuelled by antibiotic-driven accumulation of commensal-liberated host mucosal carbohydrates. Gut microbes support pathogen proliferation Intestinal microbiota can provide protection against invading pathogens through competition for resources and production of specific antimicrobial products. But disruption of the microbiota with antibiotics can contribute to the emergence of several enteric pathogens. Justin Sonnenburg and colleagues show here that two antibiotic-associated pathogens, Salmonella enterica serovar Typhimurium and Clostridium difficile , catabolize microbiota-liberated host sugars to fuel their growth in the mouse gut. In particular, the ability to use sialic acid cleaved from host polysaccharides by Bacteroides thetaiotaomicron is important for pathogen expansion. These findings identify a role for the gut microbiota in facilitating enteric pathogen infection and provide new options for developing therapeutics. The human intestine, colonized by a dense community of resident microbes, is a frequent target of bacterial pathogens. Undisturbed, this intestinal microbiota provides protection from bacterial infections. Conversely, disruption of the microbiota with oral antibiotics often precedes the emergence of several enteric pathogens 1 , 2 , 3 , 4 . How pathogens capitalize upon the failure of microbiota-afforded protection is largely unknown. Here we show that two antibiotic-associated pathogens, Salmonella enterica serovar Typhimurium ( S. typhimurium ) and Clostridium difficile , use a common strategy of catabolizing microbiota-liberated mucosal carbohydrates during their expansion within the gut. S. typhimurium accesses fucose and sialic acid within the lumen of the gut in a microbiota-dependent manner, and genetic ablation of the respective catabolic pathways reduces its competitiveness in vivo . Similarly, C. difficile expansion is aided by microbiota-induced elevation of sialic acid levels in vivo . Colonization of gnotobiotic mice with a sialidase-deficient mutant of Bacteroides thetaiotaomicron , a model gut symbiont, reduces free sialic acid levels resulting in C. difficile downregulating its sialic acid catabolic pathway and exhibiting impaired expansion. These effects are reversed by exogenous dietary administration of free sialic acid. Furthermore, antibiotic treatment of conventional mice induces a spike in free sialic acid and mutants of both Salmonella and C. difficile that are unable to catabolize sialic acid exhibit impaired expansion. These data show that antibiotic-induced disruption of the resident microbiota and subsequent alteration in mucosal carbohydrate availability are exploited by these two distantly related enteric pathogens in a similar manner. This insight suggests new therapeutic approaches for preventing diseases caused by antibiotic-associated pathogens.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 631/326/2565/2134 / Acids / Animals / Anti-Bacterial Agents - pharmacology / Antibiotics / Bacterial diseases / Bacterial infections / Bacteroides - physiology / Carbohydrate Metabolism - drug effects / Carbohydrates / Clostridium difficile - physiology / Competition / Complications and side effects / Development and progression / Drug therapy / Dysbiosis / Enterocolitis, Pseudomembranous - microbiology / Expansion / Female / Fucose - metabolism / Gene Expression Profiling / Gene Expression Regulation, Bacterial / Health aspects / Humanities and Social Sciences / Infections / Intestinal Mucosa - metabolism / Intestinal Mucosa - microbiology / letter / Male / Metagenome - drug effects / Metagenome - physiology / Mice / Microbiology / Microbiota (Symbiotic organisms) / multidisciplinary / N-Acetylneuraminic Acid - metabolism / Neuraminidase - genetics / Neuraminidase - metabolism / Pathogenic microorganisms / Pathogens / Physiological aspects / Polysaccharides / Salmonella / Salmonella Infections - microbiology / Salmonella typhimurium - physiology / Science / Specific Pathogen-Free Organisms