Mechanisms of Resistance
Colonisation resistance protects against invading pathogens through multiple overlapping mechanisms. Commensals consume nutrients (amino acids, iron) that pathogens need, creating competitive exclusion. They occupy attachment sites on intestinal epithelium, preventing pathogen adhesion. They produce antimicrobial peptides (bacteriocins) and inhibitory metabolites. Together, these form a formidable barrier to invasion.
SCFA-Mediated pH Lowering
Bacteria fermenting dietary fiber produce short-chain fatty acids (butyrate, propionate, acetate), lowering colonic pH to 5-6. This acidic environment inhibits pathogens like Clostridium difficile, which prefers pH >6. SCFAs also have direct antimicrobial effects, undissociated short-chain fatty acids crossing bacterial membranes and disrupting metabolism. Antibiotic use reduces SCFA-producing bacteria, raising pH and permitting C. difficile spore germination and vegetative growth.
Bile Acid Transformation
Primary bile acids (cholate, chenodeoxycholate) are converted by bacterial bile salt hydrolase (BSH) to secondary bile acids (deoxycholate, lithocholate). Secondary bile acids suppress C. difficile spore germination. Dysbiosis reduces BSH-expressing bacteria, decreasing secondary bile acids, and increasing C. difficile risk post-antibiotic. This mechanism was discovered through microbial metabolomics and explains antibiotic-associated diarrhea pathogenesis.
Immune Priming and Barrier Function
Commensal metabolites (butyrate, polysaccharide A from Bacteroides fragilis) activate dendritic cells, expanding regulatory T cells (Tregs) and promoting IL-10 secretion. This immune education prevents excessive inflammation yet maintains readiness against pathogens. Loss of these bacteria (via antibiotics or dysbiosis) impairs immune licensing, increasing susceptibility to both infection and inflammatory disease.
Pathogen Exploiting Disruption
Salmonella uses inflammation itself to thrive: AIEC (adherent-invasive E. coli) induces inflammation that creates an oxygen-rich, nutrient-rich niche unavailable to obligate anaerobic commensals. The pathogen benefits from the inflammatory response it triggered. Restoring colonisation resistance requires reestablishing the dysbiotic microbiota, a challenge even for fecal microbiota transplantation.