Like Will to Like: Abundances of Closely Related Species Can Predict Susceptibility to Intestinal Colonization by Pathogenic and Commensal Bacteria

Abstract

The intestinal ecosystem is formed by a complex, yet highly characteristic microbial community. The parameters defining whether this community permits invasion of a new bacterial species are unclear. In particular, inhibition of enteropathogen infection by the gut microbiota ( = colonization resistance) is poorly understood. To analyze the mechanisms of microbiota-mediated protection from Salmonella enterica induced enterocolitis, we used a mouse infection model and large scale high-throughput pyrosequencing. In contrast to conventional mice (CON), mice with a gut microbiota of low complexity (LCM) were highly susceptible to S. enterica induced colonization and enterocolitis. Colonization resistance was partially restored in LCM-animals by co-housing with conventional mice for 21 days (LCM ^con21). 16S rRNA sequence analysis comparing LCM, LCM ^con21 and CON gut microbiota revealed that gut microbiota complexity increased upon conventionalization and correlated with increased resistance to S. enterica infection. Comparative microbiota analysis of mice with varying degrees of colonization resistance allowed us to identify intestinal ecosystem characteristics associated with susceptibility to S. enterica infection. Moreover, this system enabled us to gain further insights into the general principles of gut ecosystem invasion by non-pathogenic, commensal bacteria. Mice harboring high commensal E. coli densities were more susceptible to S. enterica induced gut inflammation. Similarly, mice with high titers of Lactobacilli were more efficiently colonized by a commensal Lactobacillus reuteri ^RR strain after oral inoculation. Upon examination of 16S rRNA sequence data from 9 CON mice we found that closely related phylotypes generally display significantly correlated abundances (co-occurrence), more so than distantly related phylotypes. Thus, in essence, the presence of closely related species can increase the chance of invasion of newly incoming species into the gut ecosystem. We provide evidence that this principle might be of general validity for invasion of bacteria in preformed gut ecosystems. This might be of relevance for human enteropathogen infections as well as therapeutic use of probiotic commensal bacteria.

Author Summary

The commensal microbiota, populating the intestinal tract to high levels, is fundamental to human health. It exerts beneficial effects on the immune system and contributes to protection against gastrointestinal infections ( = colonization resistance) by largely unknown mechanisms. Here, we reveal characteristics of the commensal microbiota indicative for a high or low degree of colonization resistance. Using a mouse model for Salmonella enterica induced gut inflammation and microbiota analysis by 454 amplicon sequencing, we show that mice having different types of microbiota exhibit differential susceptibility to pathogen infection. In addition, our data lead to the description of a new concept in gut ecosystem biology: the intrusion-success of an extrinsic bacterial species into an established gut ecosystem is related to the abundance of closely related bacteria, already present in this gut ecosystem. We show that this principle applies not only to enteropathogen infection but also to inoculation with beneficial gut bacteria. Humans can display largely different degrees of susceptibility to enteric infections. Similarly, the effectiveness of probiotic therapy varies greatly from person to person. Our data might explain these differences and could be used for increasing the efficacy of probiotic therapy and for identifying patients at risk of developing enteric infections.