Vincent B Young MD PhD, Ann Arbor

Microbiome: community of microbes and environment they inhabit

Microbiota: the microbes themselves

Focus on C. Diff

2-3% of healthy outpts have identifiable, toxin-producing C. Diff

“Antibiotic Associated Colitis” 1977 papers that first described C. Diff related to abx, using hamsters as a model organism.

“An Epidemic, Toxin Gene-Variant Strain of Clostridium difficile” 2005 NEJM

C diff dx: PCR/LAMP, glutamate dehydrogenase testing (GDH) two vs three step, EIA for toxins.

Controversy: Nucleic acid amplification tests (NAAT) cannot distinguish colonization vs infx (NAAT does detect toxin gene).

20-30% of pts will test + for NAAT during hospitalization (?colonization, spore passing through).

Controversy: should we use the most sensitive test (NAAT) to find even colonization, to control spread? Or use toxin tests up front, to catch the cases severe enough to produce detectable toxin? (i.e. use a purposefully less sensitive test that is possibly more specific for more severe dz)

Classifying severe/complicated CDI - Severe: WBC >15k, Cr >1.5x normal, absolute serum Cr >1.5 if no baseline available - Fulminant: hypotn, shock, ileus, toxi megacolon - Recurrent: 2-8wks from last positive specimen OR clinical response

Studying microbiome - Anatomy - structure: “who is there?“ - Physiology: - actual function: “what is it doing?“ - potential function: “what can it do?“

Microbiome -> metabolome, and metabolome significantly contributes to generation of spores vs inhibition of infx

Mice != humans, mouse microbiome != human microbiome. Human feces known to be effective in tx CDI in humans is not effective in tx recurrent CDI in mice. Mouse FMT restores bile acid metabolism in mice, thought to be the main mxn.

Jenna Wiens, PhD: ML for microbiome. 2018 Infx ctl and hosp epi, “A Generalizable, Data-Driven Approach to Predict Daily Risk of…”

A generalizable approach vs a generalizable model. YES. (You can feed hospital-specific data to the same code, with some variation in preprocessing, and have a new model using a generalizable approach).

Wiens now doing prospective work - YES again.

Next steps - moving from association to causation - precision medicine that includes host genome and microbiota genomes, etc.