Gut microbiota within-host evolution enforces colonization resistance against enteric infection

Salvado Silva, M.; Woelfel, S.; Eberl, C.; Medeiros Selegato, D.; Durai Raj, A.; Münch, P. C.; Jung, B. K.; Omer, H.; Hellwig, M.; Osbelt, L.; Nguyen, B. D.; Bolsega, S.; Wudy, S.; Garzetti, D.; Ring, D.; Matchado, M. S.; Gaissmaier, M.; von Strempel, A.; Hussain, S.; Fuchs, L.; Basic, M.; Ludwig, C.; Lassak, J.; Slack, E.; Strowig, T.; McHardy, A. C.; Hardt, W.-D.; Zimmermann, M.; Haller, D.; Stecher, B.

doi:10.64898/2026.03.27.714693

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bioRxiv · 10.64898/2026.03.27.714693

Gut microbiota within-host evolution enforces colonization resistance against enteric infection

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Abstract

Limited resource availability in the gut promotes competitive interactions between bacteria, which drive adaptive within-host evolution (1-3). While adaptive evolution of bacterial communities has been increasingly studied in the recent years (4-7), its functional implications for host physiology remain unknown. Here, we show that within-host evolution of the human commensal Enterococcus faecalis boosts colonization resistance to enteric Salmonella enterica serovar Typhimurium (S. Typhimurium) infection. During gut colonization, E. faecalis evolves the ability to metabolize fructoselysine, an abundant Amadori rearrangement product generated by thermal food processing. The depletion of this diet-derived nutrient prevents S. Typhimurium colonization by restricting an essential resource. This protective mechanism was conserved across independent mouse colonies and arises via diverse evolutionary trajectories, including nucleotide polymorphisms, gene amplifications, and a horizontal gene transfer event. Additionally, analysis of E. faecalis isolates from human infants revealed that adaptation to fructoselysine availability occurs in a diet-dependent manner. Isolates from infants fed with fructoselysine-rich formula were able to utilize fructoselysine, whereas those from infants fed with fructoselysine-poor breast milk were not. Conclusively, our results identify an inherent microbiome-driven self-healing mechanism, wherein bacterial evolution restores colonization resistance against enteric pathogens through evolved nutrient depletion. Understanding these evolutionary dynamics will inform microbiome-targeted approaches to prevent and treat infectious diseases by harnessing adaptive bacterial metabolism.

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Salvado Silva, M., Woelfel, S., Eberl, C., Medeiros Selegato, D., Durai Raj, A., Münch, P. C., Jung, B. K., Omer, H., Hellwig, M., Osbelt, L., Nguyen, B. D., Bolsega, S., Wudy, S., Garzetti, D., Ring, D., Matchado, M. S., Gaissmaier, M., von Strempel, A., Hussain, S., Fuchs, L., Basic, M., Ludwig, C., Lassak, J., Slack, E., Strowig, T., McHardy, A. C., Hardt, W.-D., Zimmermann, M., Haller, D., Stecher, B.. 2026-03-28. Gut microbiota within-host evolution enforces colonization resistance against enteric infection. https://doi.org/10.64898/2026.03.27.714693

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