Investigation of transcriptional differences between healthy infected vs morbid infected vs uninfected identified many non-immune pathways unregulated in healthy infected (matching, again, disease tolerance mechanisms rather than antagonistic inflammatory responses)
One major upregulated pathway was iron metabolism - and iron supplementation of diet was sufficient to be completely protective up to 1000x LD100 (>10^10 cfu) of Citrobacter, even with comparable pathogen burden in stool
Dietary iron protected from intestinal epithelial damage, prevented systemic dissemination of Citrobacter, and lowered expression of virulence genes in Citrobacter through an indirect mechanism (not acting on Citrobacter directly) and independently of microbiota
Iron increased glucose levels in the intestine through induction of insulin resistance, resulting in suppression of virulence genes through modulation of pathogen metabolism (glucose alone suppressed Citrobacter virulence genes)
Most excitingly, dietary iron results in evolution of Citrobacter towards non-pathogenic commensal phenotype - stably persisting in the gut, but non-lethal even after removal of iron and, eventually, non-lethal even in untreated mice at >LD100 CFU counts!
In summary: heterogeneity in host response to identical pathogen challenge (the LD50 effect) allowed identification of tolerance mechanisms that are capable of driving a long-term shift in bacterial phenotype towards commensalism. Many questions coming out after reading this…
Dietary iron protected from extra-intestinal dissemination of Citrobacter, but the healthy infected mice at LD50 had comparable Citrobacter loads in all tissues. So what additional tolerance mechanisms are active at LD50 that allow tolerance of systemic Citrobacter?
When do tolerance mechanisms “kick in”? At LD0, do mice show long-term carriage of Citrobacter, or do they clear it completely? Can pre-treatment with LD0 (10^5 cfu) induce tolerance mechanisms that provide greater protection against subsequent LD100 infection?
(This experiment would require right timescale to prevent immune-confounding effects, e.g. memory responses / vaccination or increase in innate responses, e.g. AMP production, that will inhibit initial colonization - does LD0 induce any pathology / persistent inflammation?)
How “cooperative” is this response? Evolved “commensal” citrobacter have no fitness defect (in vitro) - but what is the fitness effect on the host of long-term Citrobacter maintenance? Fig1E shows healthy infected look like LD0 infected, but what about comparison to uninfected?
Overall many interesting lines of thought that arise from these very exciting findings - look forward to seeing the future work! Amazing job by @theayreslab, and now I'm even more excited for her seminar @YaleIBIO next June! #Microbiota #DiseaseTolerance #Evolution
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