Chemical Biology of Microbiomes

This Review article explores how uncovering phenotypes linked to the human microbiome often progresses from correlative studies to studies in germ-free animals and fecal microbiota transplants and, finally, to identification of strains and molecules.

An analysis of the interactions between 15 drugs and 25 gut bacterial strains shows that bioaccumulation of drugs within bacterial cells is another mechanism through which gut microorganisms can alter drug availability and efficacy.

Inflammatory bowel diseases (IBD) are associated with increased faecal N-acylethanolamines (NAEs), which are primarily host-produced signalling lipids, in patients and a mouse model of colitis. These metabolites can enhance the growth of bacterial species enriched in IBD faecal samples and are associated with the expression of respiratory chain genes necessary for microbial metabolism of NAEs.

The gut microbiota contributes to host physiology through the production of a myriad of metabolites. In this Review, Bäckhed and colleagues discuss the major classes of microbial metabolites, highlight examples of how microbial metabolites affect host health and provide a potential framework for integration of discovery-based metabolite studies with mechanistic work.

This Review highlights the latest progress on the molecular basis of metabolite signals in regulating aging and longevity, as well as state-of-the-art technological advances in studying bioactive metabolites.

Metabolomics data from germ-free and specific-pathogen-free mice reveal effects of the microbiome on host chemistry, identifying conjugations of bile acids that are also enriched in patients with inflammatory bowel disease or cystic fibrosis.

Akkermansia muciniphila produces P9, a small protein that interacts with intercellular adhesion molecule 2 to increase thermogenesis and glucagon-like peptide-1 secretion in mice.

Ceramides are a type of sphingolipid (SL) that have been shown to play a role in several metabolic disorders. Here, the authors investigate the effect of SL-production by gut Bacteroides on host SL homeostasis and show that microbiome-derived SLs enter host circulation and alter ceramide production.

The biosynthetic pathway that produces the secondary bile acids DCA and LCA in human gut microbes has been fully characterized, engineered into another bacterial host, and used to confer DCA production in germ-free mice—an important proof-of-principle for the engineering of gut microbial pathways.

Microorganisms produce and excrete an array of metabolites with different physico-chemical properties and biological activities. In this Review, Garbeva and colleagues highlight recent discoveries concerning microbial volatile compounds and their roles in intra-kingdom and inter-kingdom communication, and discuss the potential biotechnological applications of microbial volatiles, as well as challenges and perspectives in this emerging research field.

The microbiota of centenarians (aged 100 years and older) comprise gut microorganisms that are capable of generating unique secondary bile acids, including isoallolithocholic acid, a bile acid with potent antimicrobial effects against Gram-positive—but not Gram-negative—multidrug-resistant pathogens.

Decades of research have identified the biochemical basis of many plant specialized metabolic pathways. This Review highlights the biological context of these pathways and how recent advances have extended the new frontiers of phytochemistry.

An analysis of gut microbiomes of patients with non-small-cell lung cancer reveals an association between Bifidobacterium bifidum abundance and response to cancer therapy. In murine models of syngeneic tumours, administration of commercial B. bifidum strains synergizes with immune checkpoint blockade to reduce tumour burden, but the therapeutic potential of B. bifidum is affected by strain-level variation.

Small antibacterial molecules termed bacteriocins can influence microbiome composition by providing an advantage to bacteriocin producers over bacteriocin-sensitive strains. In this Review, Peschel and colleagues provide an overview of the types of bacteriocins, their costs and benefits, and how they may provide new avenues for antibacterial drug development.

RNA-sequencing experiments determine that sorbitol, a metabolite produced by the host enzyme aldose reductase, is exploited by Clostridium difficile in its adaptation to inflammatory conditions in the gut.

Escherichia coli are a common component of the human microbiota, producing a diverse collection of small molecules that regulate intra- and interspecies interactions, including those with other microorganisms and with the host.

Arabidopsis thaliana plants lacking the rbohD gene, which encodes the NADPH oxidase RBOHD, have an altered leaf microbiome including an enrichment of opportunistic pathogens, indicating that RBOHD is essential for maintaining leaf microbiota homeostasis.

The gut microbiome regulates behaviour in a number of species. Here the authors show that depletion of the gut microbiome in Drosophila reduced aggressive behaviour, in an octopamine-dependent manner.

In Drosophila, an amino acid deficit triggers the expression of the neuropeptide CNMamide in gut enterocytes, which promotes a compensatory appetite for essential over non-essential amino acids, and this process is modulated by the microbiome.

In this Review, Morais, Schreiber and Mazmanian discuss emerging and exciting evidence of intricate and potentially important connections between the gut microbiota and the brain involving multiple biological systems, and possible contributions by the gut microbiota to complex behaviours.

A microbiome-focused metabolomics pipeline and interactive metabolomics profile explorer are a powerful tool for the characterization of gut-resident microorganisms and the interactions between microorganisms and their host.

Glial metabolic reprogramming by gut-derived cytokines in Drosophila results in lasting changes in the sensory system of an ageing organism

Clostridial nonribosomal peptide synthase (NRPS)-like enzymes use exogenous substrates common in diet to produce fatty acid amides that can interact with human G-protein-coupled receptors.

The gut microbiota in mice can modulate social behaviour by influencing activity in stress-related brain areas.

A covalent pan-inhibitor of bacterial bile salt hydrolases developed by adding a chenodeoxycholic acid moiety to the warhead is not bactericidal and is therefore useful for studying the effects of bile acids on host physiology.

A synthetic yeast-based therapeutic that secretes an ATP-degrading enzyme in response to pro-inflammatory extracellular ATP in the gut reduces intestinal inflammation, fibrosis and dysbiosis in mouse models of colitis and enteritis.

Microbiomes designed with predictable functions could enable broad applications in health, agriculture and bioprocessing. Here the authors use a model-guided approach to design diverse synthetic human gut communities for production of the health-relevant metabolite butyrate.

Gut microbiome composition is remodeled using small peptides.

Gene circuits that exploit the mutual interaction between nutrient diffusion, bacterial growth and gene regulation enable the control of microbial colony structure in complex environments.

Fecal microbiota transplantation and probiotics have been tested/used as potential therapeutics against inflammatory bowel diseases (IBD). Here the authors use a bottom-up rational consortium design approach that combines well-characterized strains isolated from healthy human stool samples to produce two consortia of metabolically interdependent strains for the treatment of IBD.

An orally administered gel that is retained in the colon modulates the gut microbiome of mice with murine tumours, inducing systemic memory-T-cell responses and amplifying the antitumour activity of a checkpoint inhibitor.