Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, California 94305, USA.
Nature. 2013 Oct 3;502(7469):96-9. doi: 10.1038/nature12503. Epub 2013 Sep 1.
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. 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.
人类肠道中定植着密集的常驻微生物群落，是细菌病原体的常见靶标。在未受干扰的情况下，肠道微生物群提供了免受细菌感染的保护。相反，口服抗生素破坏微生物群通常会先于几种肠道病原体的出现。病原体如何利用微生物群提供的保护失效是一个很大的未知数。在这里，我们表明，两种与抗生素相关的病原体，鼠伤寒沙门氏菌（Salmonella enterica serovar Typhimurium，S. typhimurium）和艰难梭菌（Clostridium difficile），在肠道内扩张时利用了一种共同的策略，即分解微生物群释放的粘膜碳水化合物。S. typhimurium以微生物群依赖的方式在肠道腔中摄取岩藻糖和唾液酸，并且代谢途径的遗传缺失会降低其在体内的竞争力。同样，艰难梭菌的扩张也得益于微生物群诱导的体内唾液酸水平升高。用缺乏唾液酸酶的拟杆菌属（Bacteroides thetaiotaomicron）突变体定植无菌小鼠，降低了游离唾液酸水平，导致艰难梭菌下调其唾液酸代谢途径，并表现出扩张受损。通过外源性饮食添加游离唾液酸可以逆转这些影响。此外，抗生素治疗常规小鼠会导致游离唾液酸激增，而无法代谢唾液酸的沙门氏菌和艰难梭菌突变体的扩张也受损。这些数据表明，抗生素诱导的常驻微生物群破坏和随后粘膜碳水化合物可用性的改变，被这两种远缘肠道病原体以类似的方式利用。这一见解为预防与抗生素相关的病原体引起的疾病提供了新的治疗方法。
