Microbiome

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?“

• 75-80% of tx cases do not recur; 20-25% of cases recur and have worse outcomes.

  • theory: pts never return to normal microbiota, hence if restore normal microbiota -> cure

• Hx fecal tx (Fecal Microbiota Transplantation, FMT)

  • Pliny the Elder: fermented milk and fecal tx
  • Ge Hong: 4th C
  • another guy whose name I didn't catch: “yellow soup” == poop supernatant
  • surgeons in 50s: successful fecal tx for abx-associated
  • 2013 NEJM: 94% success rate for FMT (16pts), 30% vanco, trial ended early

• Prior to FMT, community is “less diverse” than donors

• FMT results in transfer of community structure to pts

• Structure does NOT predict function - some pts who do not recover do have more diverse micriobiota, and some pts who do recover remain less diverse

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.