Molecules from the Microbiome

Abstract

The human microbiome encodes a second genome that dwarfs the genetic capacity of the host. Microbiota-derived small molecules can directly target human cells and their receptors or indirectly modulate host responses through functional interactions with other microbes in their ecological niche. Their biochemical complexity has profound implications for nutrition, immune system development, disease progression, and drug metabolism, as well as the variation in these processes that exists between individuals. While the species composition of the human microbiome has been deeply explored, detailed mechanistic studies linking specific microbial molecules to host phenotypes are still nascent. In this review, we discuss challenges in decoding these interaction networks, which require interdisciplinary approaches that combine chemical biology, microbiology, immunology, genetics, analytical chemistry, bioinformatics, and synthetic biology. We highlight important classes of microbiota-derived small molecules and notable examples. An understanding of these molecular mechanisms is central to realizing the potential of precision microbiome editing in health, disease, and therapeutic responses. Expected final online publication date for the Annual Review of Biochemistry, Volume 90 is June 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

Nutrition for precision health: The time is now

“…Such heterogeneities have been largely due to the highly individual or population-specific nature of the gut microbiome profiles, the temporal variability, the gut microbiomeimmune system interactions that establish the fragile equilibrium in the gut ecosystem, and the interactions with environmental factors, among others (69,70). In addition, although the species composition of the human microbiome has been deeply explored, detailed mechanistic studies linking the specific microbial species to host phenotypes are still nascent (71). An obvious need exists to investigate diet-gut microbiome-host interactions in sufficiently powered studies with validations, especially in well-designed prospective studies and RCTs.…”

Role of microbial secreted proteins in gut microbiota-host interactions

“…One of the most relevant mechanisms of this influence effect is releasing a variety of molecules into their niches (Shine and Crawford, 2021). From fermentation products to antimicrobial peptides, these molecules are involved in various processes influencing the host and other community members.…”

“…The study of the role of the SCFA on the relation between human microbiota and human cells is a relatively well-covered topic covered in other reviews (Tan et al, 2014;Zheng et al, 2022). Moreover, other reviews cover the effect and role of the pleiad of secreted metabolites on the interaction between human microbiota and the host and the interaction between microbial communities themselves (e.g., (Shine and Crawford, 2021)). Among the repertoire of secreted compounds produced by the microbiota, an increasingly relevant group of study targets corresponds to the poorly studied secretable proteins known as the secretome (Tjalsma et al, 2000).…”

Escherichia coli-Derived γ-Lactams and Structurally Related Metabolites Are Produced at the Intersection of Colibactin and Fatty Acid Biosynthesis

“…Biosynthetic gene clusters (BGCs) encoded within the human microbiome can produce diverse bioactive natural products that have profound impacts on individual physiology. , Colibactin is a genotoxic secondary metabolite produced by select members of the gut microbiota, including Escherichia coli and other Enterobacteriaceae. , Colibactin is synthesized by a 54 kb BGC termed clb [or pks (Figure S1A)], and the presence of this locus causes colorectal tumor formation in animal models under inflammatory conditions . Within the mature, linear colibactin metabolite, two electrophilic cyclopropane warheads alkylate adenine residues, , causing DNA interstrand cross-links (ICLs). , This structure mechanistically accounts for a mutational signature found in colibactin-exposed cell lines and colorectal cancer patient samples. , However, the colibactin biosynthetic pathway is diversity-oriented and produces a large set of intermediate metabolites, including a range of precolibactins (see also Figure S1B), some of which can be detected in high abundance.…”

“…3 Biosynthetic gene clusters (BGCs) encoded within the human microbiome can produce diverse bioactive natural products that have profound impacts on individual physiology. 4,5 Colibactin is a genotoxic secondary metabolite produced by select members of the gut microbiota, including Escherichia coli and other Enterobacteriaceae. 6,7 Colibactin is synthesized by a 54 kb BGC termed clb [or pks 6 (Figure S1A)], and the presence of this locus causes colorectal tumor formation in animal models under inflammatory conditions.…”