Fitness advantage of <i>Bacteroides thetaiotaomicron</i> capsular polysaccharide in the mouse gut depends on the resident microbiota.

Abstract

Many microbiota-based therapeutics rely on our ability to introduce a microbe of choice into an already-colonized intestine. In this study, we used genetically barcoded <i>Bacteroides thetaiotaomicron</i> (<i>B. theta</i>) strains to quantify population bottlenecks experienced by a <i>B. theta</i> population during colonization of the mouse gut. As expected, this reveals an inverse relationship between microbiota complexity and the probability that an individual wildtype <i>B. theta</i> clone will colonize the gut. The polysaccharide capsule of <i>B. theta</i> is important for resistance against attacks from other bacteria, phage, and the host immune system, and correspondingly acapsular <i>B. theta</i> loses in competitive colonization against the wildtype strain. Surprisingly, the acapsular strain did not show a colonization defect in mice with a low-complexity microbiota, as we found that acapsular strains have an indistinguishable colonization probability to the wildtype strain on single-strain colonization. This discrepancy could be resolved by tracking in vivo growth dynamics of both strains: acapsular <i>B.theta</i> shows a longer lag phase in the gut lumen as well as a slightly slower net growth rate. Therefore, as long as there is no niche competitor for the acapsular strain, this has only a small influence on colonization probability. However, the presence of a strong niche competitor (i.e., wildtype <i>B. theta</i>, SPF microbiota) rapidly excludes the acapsular strain during competitive colonization. Correspondingly, the acapsular strain shows a similarly low colonization probability in the context of a co-colonization with the wildtype strain or a complete microbiota. In summary, neutral tagging and detailed analysis of bacterial growth kinetics can therefore quantify the mechanisms of colonization resistance in differently-colonized animals.