Unique β-Glucuronidase Locus in Gut Microbiomes of Crohn’s Disease Patients and Unaffected First-Degree Relatives

Abstract

Crohn’s disease, an incurable chronic inflammatory bowel disease, has been attributed to both genetic predisposition and environmental factors. A dysbiosis of the gut microbiota, observed in numerous patients but also in at least one hundred unaffected first-degree relatives, was proposed to have a causal role. Gut microbiota β-D-glucuronidases (EC 3.2.1.33) hydrolyse β-D-glucuronate from glucuronidated compounds. They include a GUS group, that is homologous to the Escherichia coli GusA, and a BG group, that is homologous to metagenomically identified H11G11 BG and has unidentified natural substrates. H11G11 BG is part of the functional core of the human gut microbiota whereas GusA, known to regenerate various toxic products, is variably found in human subjects. We investigated potential risk markers for Crohn’s disease using DNA-sequence-based exploration of the β-D-glucuronidase loci (GUS or Firmicute H11G11-BG and the respective co-encoded glucuronide transporters). Crohn’s disease-related microbiomes revealed a higher frequency of a C7D2 glucuronide transporter (12/13) compared to unrelated healthy subjects (8/32). This transporter was in synteny with the potential harmful GUS β-D-glucuronidase as only observed in a Eubacterium eligens plasmid. A conserved NH2-terminal sequence in the transporter (FGDFGND motif) was found in 83% of the disease-related subjects and only in 12% of controls. We propose a microbiota-pathology hypothesis in which the presence of this unique β-glucuronidase locus may contribute to an increase risk for Crohn’s disease.

Guts and Gall: Bile Acids in Regulation of Intestinal Epithelial Function in Health and Disease

“…Hallmark features of the disease also include enhanced epithelial permeability and alterations to the resident microbiota (15,298,374), although whether these are a cause or consequence of the disease is still not certain. Studies showing that asymptomatic relatives of IBD patients also have enhanced epithelial permeability and dis-tinct microbial fingerprints suggest that such alterations may be necessary, but not sufficient, for disease progression (136,142,156,225). Furthermore, changes in the profile of luminal bile acids have also been closely associated with IBD progression.…”

In vitro assessment of the glucose-lowering effects of berberrubine-9-O-β-D-glucuronide, an active metabolite of berberrubine

“…There are thousands of species present in the gut, and the numerous hydrolases encoded by these species are very important for metabolic homeostasis. β-Glucuronidase is a hydrolase that targets the glucuronidated compounds, releasing glucuronic acid [33] . As our previous study indicated, large amounts of BRB and BRBG could be detected in bile after BRB oral administration, but BRBG could be barely detected in feces (unpublished data).…”

Gut Microbial β-Glucuronidase Inhibition via Catalytic Cycle Interception

“…Intestinal microbes utilize glucuronides as a carbon source; free GlcA can be metabolized via the Entner–Doudoroff pathway to generate pyruvate that enters the citric acid cycle . While bacterial GUS enzymes have been linked to the GI toxicity of chemotherapeutics and NSAIDs (Figure a), , they may also be involved in carcinogenesis, inflammatory bowel diseases, and gall stone formation. − Thus, inhibiting microbial GUS enzymes may improve the tolerance and efficacy of current drugs, while also enabling the treatment or prevention of human disease.…”