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Chains of evidence from correlations to causal molecules in microbiome-linked diseases

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.

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Fig. 1: Evidence progression from correlation to causation in human microbiome research.
Fig. 2: FMTs transfer metabolic disorder phenotypes and affect metabolic state.
Fig. 3: Development of microbial metabolite analogs as therapies for disease.
Fig. 4: FMTs transfer neurological phenotypes and affect neurological state.

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Acknowledgements

This work was supported by National Institutes of Health grants R35 GM128618 and R01 DK126855 (A.S.D.). S.N.C. acknowledges an American Heart Association Postdoctoral Fellowship. M.D.M. acknowledges an NSF Graduate Research Fellowship (DGE1745303). Figures created with BioRender.com.

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Correspondence to Snehal N. Chaudhari or A. Sloan Devlin.

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A.S.D. is an ad hoc consultant for Takeda Pharmaceuticals and Axial Therapeutics. The other authors have declared no competing interests.

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Chaudhari, S.N., McCurry, M.D. & Devlin, A.S. Chains of evidence from correlations to causal molecules in microbiome-linked diseases. Nat Chem Biol 17, 1046–1056 (2021). https://doi.org/10.1038/s41589-021-00861-z

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