Probing and manipulating the gut microbiome with chemistry and chemical tools

Abstract

The human gut microbiome represents an extended "second genome" harbouring about 10¹⁵ microbes containing >100 times the number of genes as the host. States of health and disease are largely mediated by host-microbial metabolic interplay, and the microbiome composition also underlies the differential responses to chemotherapeutic agents between people. Chemical information will be the key to tackle this complexity and discover specific gut microbiome metabolism for creating more personalised interventions. Additionally, rising antibiotic resistance and growing awareness of gut microbiome effects are creating a need for non-microbicidal therapeutic interventions. We classify chemical interventions for the gut microbiome into categories like molecular decoys, bacterial conjugation inhibitors, colonisation resistance-stimulating molecules, "prebiotics" to promote the growth of beneficial microbes, and inhibitors of specific gut microbial enzymes. Moreover, small molecule probes, including click chemistry probes, artificial substrates for assaying gut bacterial enzymes and receptor agonists/antagonists, which engage host receptors interacting with the microbiome, are some other promising developments in the expanding chemical toolkit for probing and modulating the gut microbiome. This review explicitly excludes "biologics" such as probiotics, bacteriophages, and CRISPR to concentrate on chemistry and chemical tools like chemoproteomics in the gut-microbiome context.

Keywords: chemical probes; chemistry; conjugation inhibitors; gut microbiome; prebiotics.

Graphical abstract

Figure 1.

(A) Functional classification of molecules to preserve/restore the gut microbiome. (B) Chemical diversity of molecules with microbiome preserving/restoring functions; 1 = General structure of inulins (endogenous prebiotic), 2 = resiquimod or R848 (synthetic stimulant of colonisation resistance); 3 = tanzawaic acid B or TZA-B (natural product colonisation inhibitor); and 4 = a mannoside (mannose-containing decoy for urinary pathogens which preserves the gut microbiota).

Figure 2.

Examples of chemical probes used to interrogate the GM – D-amino acid-based fluorescent probes = TADA (5) and Cy5ADA (6); a multifunctional probe showing different parts shaded in distinct colours = amine directed probe based on sulpho-N-hydroxysuccinimide (7); photoactive unnatural amino acid probes = DiZPK (8) and ACPK (9); a cysteine-targeted probe = Biotin-Gly-CMK (10); bioluminescent bile acid-luciferin conjugates for bile salt hydrolase (BSH) activity = series of compounds with H or OH at the positions R1 and R2 (11).

Figure 3.

Specific enzyme inhibition can be a strategy to selectively manipulate the gut microbiome, and some inhibitors of gut bacterial enzymes are shown. 12 = betaine aldehyde, inhibits choline TMA-lyase (CutC); 13 = fluoromethyl ketone suicide inhibitor of bile salt hydrolase (BSH); 14, 15 = piperazine-containing β-glucuronidase inhibitors; 16 = acarbose, inhibits starch and pullulan utilisation; and 17 = M4284 mannoside, inhibits FimH in uropathogenic E. coli.

Figure 4.

Molecular mechanism of G protein-coupled receptors on the cell surface. The ligand binds to the receptor protein, causing the G-protein subunits to disassemble and exchange bound GDP with GTP. The G-protein α-subunit is bound to the receptor, whereas the other subunits signal to other proteins involved in intracellular responses. GTP hydrolysis drives the dissociation of the α-subunit from the receptor and a return to the GDP-bound multi-subunit G-protein complex.