Chains of evidence from correlations to causal molecules in microbiome-linked diseases - PubMed (original) (raw)
Review
Chains of evidence from correlations to causal molecules in microbiome-linked diseases
Snehal N Chaudhari et al. Nat Chem Biol. 2021 Oct.
Abstract
Human-associated microorganisms play a vital role in human health, and microbial imbalance has been linked to a wide range of disease states. In this Review, we explore recent efforts to progress from correlative studies that identify microorganisms associated with human disease to experiments that establish causal relationships between microbial products and host phenotypes. We propose that successful efforts to uncover phenotypes often follow a chain of evidence that proceeds from (1) association studies; to (2) observations in germ-free animals and antibiotic-treated animals and humans; to (3) fecal microbiota transplants (FMTs); to (4) identification of strains; and then (5) molecules that elicit a phenotype. Using this experimental 'funnel' as our guide, we explore how the microbiota contributes to metabolic disorders and hypertension, infections, and neurological conditions. We discuss the potential to use FMTs and microbiota-inspired therapies to treat human disease as well as the limitations of these approaches.
© 2021. Springer Nature America, Inc.
Conflict of interest statement
Competing Interests
S. D. is an ad hoc consultant for Takeda Pharmaceuticals and Axial Therapeutics. The other authors declare that no competing interests exist.
Figures
Figure 1.. Evidence progression from correlation to causation in human microbiome research.
We propose that evidence linking the microbiota with a particular human disease can be evaluated as five-tiered funnel. Here we use the example of commensal bacteria combatting Clostridium difficile infection (CDI) as an illustrative example. First, correlations in human data indicate that the microbiome community is altered in diseased versus healthy subjects. Antibiotic-induced dysbiosis places patients at increased risk for developing CDI. Second, antibiotic-treated humans or germ-free (GF) mice display altered disease phenotypes compared to untreated or conventional controls. Treatment of conventional mice with an antibiotic such as clindamycin followed by C. difficile challenge results in CDI. Third, fecal microbiota transplant (FMT) transfers a phenotype from a donor to a recipient. FMT from healthy subjects into patients with recurrent CDI resolves infection in up to 90% of cases. Fourth and fifth, specific microorganisms and the molecules they produce, respectively, generate a phenotype in vivo. The commensal bacterium Clostridium scindens and its close genetic neighbors possess the bile acid-inducible (bai) operon, which encodes enzymes that 7α-dehydroxylate primary bile acids (e.g., cholic acid) to produce secondary bile acids (e.g., deoxycholic acid), which inhibit C. difficile growth.
Figure 2.. FMTs transfer metabolic disorder phenotypes and affect metabolic state.
a, FMT from obese humans or mice transfers disease-associated phenotypes into recipient mice. Specifically, GF recipients exhibit decreased glucose uptake, insulin sensitivity and gut barrier integrity, and increased liver steatosis, blood pressure, and weight gain. b, FMT from lean mice or human donors ameliorates some metabolic phenotypes in murine or human recipients. Both human and murine recipients exhibit increased glucose uptake, insulin sensitivity, and gut barrier integrity. FMTs have not been reproducibly shown to induce weight loss in either group.
Figure 3.. Development of microbial metabolite analogs as therapies for disease.
a, Gut bacterial bile salt hydrolases convert the host-produced conjugated bile acids tauro- and glycochenodeoxycholic acid (TCDCA and GCDCA) and tauro- and glycocholic acid (TCA and GCA) into chenodeoxycholic acid (CDCA) and cholic acid (CA), respectively. CDCA is an FXR agonist that improves metabolic syndrome phenotypes in vivo. INT-747 is a synthetic derivative of CDCA that is 2–5 times more potent and is currently in phase II clinical trials. INT-747 treatment improves diabetes, weight gain and liver fibrosis in rodent models and human patients. INT-777 is a derivative of CA, a weak TGR5 agonist, with over 10-fold higher potency. INT-777 improves metabolic disease phenotypes in rodents, including diabetes, obesity, atherosclerosis, and inflammation. b, SCFAs are generated by gut bacterial degradation of dietary carbohydrates, fiber, and intestinal mucin. Of the SCFAs produced by the microbiota, butyrate shows potential as a therapeutic for treatment of metabolic diseases. Treatment with mono-, di-, or tri-butyrin improves hyperglycemia, inflammation, obesity, and liver steatosis in rodents.
Figure 4.. FMTs transfer neurological phenotypes and affect neurological state.
a, FMT from human donors with neurological disorders transfers disease-associated phenotypes into recipient mice. Specifically, FMT from PD patients into GF α-synuclein overexpressing mice resulted in impaired motor function and increased constipation; FMT from MS patients into a GF mice with EAE resulted in worsened disease phenotypes such as paralysis and neuron demyelination; and FMT from patients with ASD into GF mice resulted in behavioral abnormalities in the offspring of these animals. b, FMT from healthy human donors improves neurological abnormalities in murine or human recipients. Post-natal mice displayed increased protection against seizures when treated with an FMT from ketogenic-fed conventional mice and increased fear extinction learning when treated with an FMT from conventional mice. In a limited number of case studies, FMTs from healthy donors also reduced seizures, increased neurological, motor, and GI tract function, and ameliorated behavioral and GI symptoms in patients with epilepsy, MS, and ASD, respectively.
References
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