A metagenomic β-glucuronidase uncovers a core adaptive function of the human intestinal microbiome

Abstract

In the human gastrointestinal tract, bacterial β-D-glucuronidases (BG; E.C. 3.2.1.31) are involved both in xenobiotic metabolism and in some of the beneficial effects of dietary compounds. Despite their biological significance, investigations are hampered by the fact that only a few BGs have so far been studied. A functional metagenomic approach was therefore performed on intestinal metagenomic libraries using chromogenic glucuronides as probes. Using this strategy, 19 positive metagenomic clones were identified but only one exhibited strong β-D-glucuronidase activity when subcloned into an expression vector. The cloned gene encoded a β-D-glucuronidase (called H11G11-BG) that had distant amino acid sequence homologies and an additional C terminus domain compared with known β-D-glucuronidases. Fifteen homologs were identified in public bacterial genome databases (38-57% identity with H11G11-BG) in the Firmicutes phylum. The genomes identified derived from strains from Ruminococcaceae, Lachnospiraceae, and Clostridiaceae. The genetic context diversity, with closely related symporters and gene duplication, argued for functional diversity and contribution to adaptive mechanisms. In contrast to the previously known β-D-glucuronidases, this previously undescribed type was present in the published microbiome of each healthy adult/child investigated (n = 11) and was specific to the human gut ecosystem. In conclusion, our functional metagenomic approach revealed a class of BGs that may be part of a functional core specifically evolved to adapt to the human gut environment with major health implications. We propose consensus motifs for this unique Firmicutes β-D-glucuronidase subfamily and for the glycosyl hydrolase family 2.functional core | intestinal microbiota | functional metagenomics | glycosyl hydrolase | Firmicutes

Impact of the gut microbiota, prebiotics, and probiotics on human health and disease

“…[14] A novel β-glucuronidase enzymatic activity was also identified in Firmicutes using a functional metagenomic approach. [15] Similarly, xenobiotic-responsive genes involved in pathways related to antibiotic resistance, drug metabolism, and stress response were recently identified. [16] Intestinal microbes can also generate catecholamines that have an effect on gut physiology.…”

Sulfatases and a Radical S-Adenosyl-l-methionine (AdoMet) Enzyme Are Key for Mucosal Foraging and Fitness of the Prominent Human Gut Symbiont, Bacteroides thetaiotaomicron

“…Metagenomic studies of fecal microbial communities have indicated that in a healthy adult, this microbiota is composed of several hundred species-level phylogenetic types (phylotypes), although there is considerable interpersonal variation in species composition, even among monozygotic twins (2,3). Nonetheless, shotgun sequencing of fecal community DNA has shown that these different species assemblages contain shared functional features, including the ability to process otherwise indigestible components of our varied diets such as plant polysaccharides (1)(2)(3)(4).…”

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“…Bioanalysis of the sequences allows to identify new enzymes and to model their 3D structures. Once their physiological role determined, these can become a new validated source of druggable targets and will be managed through classical drug discovery processes [91][92][93][94][95].…”