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Targeting the human gut microbiome with small-molecule inhibitors

Nature Reviews Chemistry volume 7, pages 319–339 (2023)Cite this article

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A Publisher Correction to this article was published on 13 June 2023

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Abstract

The human gut microbiome is a complex microbial community that is strongly linked to both host health and disease. However, the detailed molecular mechanisms underlying the effects of these microorganisms on host biology remain largely uncharacterized. The development of non-lethal, small-molecule inhibitors that target specific gut microbial activities enables a powerful but underutilized approach to studying the gut microbiome and a promising therapeutic strategy. In this Review, we will discuss the challenges of studying this microbial community, the historic use of small-molecule inhibitors in microbial ecology, and recent applications of this strategy. We also discuss the evidence suggesting that host-targeted drugs can affect the growth and metabolism of gut microbes. Finally, we address the issues of developing and implementing microbiome-targeted small-molecule inhibitors and define important future directions for this research.

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Fig. 1: Approaches for studying the gut microbiome.
Fig. 2: Small-molecule inhibitors as tools to study the gut microbiome.
Fig. 3: Historical use of small-molecule inhibitors in microbial ecology.
Fig. 4: Inhibition of gut bacterial β-glucuronidases.
Fig. 5: Inhibition of anaerobic choline metabolism in gut bacteria.
Fig. 6: Inhibition of gut bacterial BSHs.
Fig. 7: Inhibition of amino acid decarboxylation by gut bacteria.

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Acknowledgements

The authors thank V. Nieto for helpful feedback and his critical review of this manuscript. Figures 1 and 2 were created with BioRender.com.

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Authors and Affiliations

  1. Harvard University, Department of Chemistry and Chemical Biology, Cambridge, MA, USA

    Amelia Y. M. Woo, Miguel A. Aguilar Ramos, Rohan Narayan, Khyle C. Richards-Corke, Michelle L. Wang, Walter J. Sandoval-Espinola & Emily P. Balskus

  2. Universidad Nacional de Asunción, Facultad de Ciencias Exactas y Naturales, Departamento de Biotecnología, Laboratorio de Biotecnología Microbiana, San Lorenzo, Paraguay

    Walter J. Sandoval-Espinola

  3. Howard Hughes Medical Institute, Harvard University, Cambridge, MA, USA

    Emily P. Balskus

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  1. Amelia Y. M. Woo
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Contributions

E.P.B. and W.J.S.-E. conceived this Review. W.J.S.-E. wrote a first draft. E.P.B., A.Y.M.W., M.A.A.R., R.N., K.C.R.-C. and M.L.W. wrote and revised subsequent drafts. A.Y.M.W., M.A.A.R., R.N., K.C.R.-C. and M.L.W. contributed equally.

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Correspondence to Emily P. Balskus.

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Competing interests

E.P.B. is an inventor on patents describing small-molecule inhibitors of anaerobic gut microbial choline metabolism and l-dopa decarboxylation.

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Glossary

Activity-based protein profiling

Proteomics method of identifying functional and expressed proteins (often enzymes) in a native system that uses small-molecule probes, which undergo reaction with specific amino acid residues to form stable covalent linkages, allowing for subsequent protein labeling and/or pulldown.

Conventional (animal)

Having a native, typically diverse microbiome.

Culture-independent

Method that does not require growing an organism in a laboratory setting.

Faecal microbiome transplant

(FMT). The administration of faecal matter from a healthy donor into the intestinal tract of a recipient in order to directly change the recipient’s gut microbial composition and confer a health benefit.

Germ-free

An environment in which no microorganisms are present.

Gnotobiotic

An environment in which all microorganisms present are known; usually germ-free before being inoculated with a defined group of microorganisms.

Host

Organism in which the microbiome resides.

Metabolomics

Analysis of small molecules in biological samples used to identify and quantify either global or targeted metabolites, typically through mass spectrometry-based and nuclear-magnetic-resonance-based methods.

Metagenomics

Analysis of total genetic material (DNA) isolated from complex (microbial) samples obtained directly from environments (for example, gut or skin microbiomes), typically used to study the diversity, abundance and potential functions of community members without requiring cultivation.

Metatranscriptomics

Gene expression profiling of complex (microbial) samples obtained directly from environments (gut or skin microbiomes), typically used to identify and quantify actively transcribed genes in microbial habitats.

Microbiome

The collective community of microorganisms (bacteria, viruses, fungi, protozoa, archaea) living in a habitat.

Prebiotics

Substrates (typically carbohydrates) that are selectively utilized by gut microorganisms conferring health benefits.

Probiotic

Live microorganism which, when administered in adequate amounts, confers a health benefit for the host.

Proteomics

Analysis of proteomes of biological samples used to identify and quantify either global or targeted proteins, typically through mass-spectrometry-based and gel-based methods.

Xenobiotic

A substance that is not endogenous to the environment or system.

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Woo, A.Y.M., Aguilar Ramos, M.A., Narayan, R. et al. Targeting the human gut microbiome with small-molecule inhibitors. Nat Rev Chem 7, 319–339 (2023). https://doi.org/10.1038/s41570-023-00471-4

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