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.
Highlights
Crohn's disease (CD) is a multifactorial incurable inflammatory bowel disease (IBD) of the human digestive tract whose etiology is unknown
The exploration for both GUS and Firmicute-BG β-D-glucuronidase loci was performed using as queries: E. coli K12 GUS locus, H11G11 BG and C7D2 BG loci of two metagenomic clones from respectively a healthy subject and a CD patient [17]
No specific sequence signature was observed for GusA and BG and for the two transporters GusB and H11G11 (S1 and S2 Figs) but the C7D2 transporter revealed a good segregation between CDR and CDU subjects (S3 Fig)
Summary
Crohn's disease (CD) is a multifactorial incurable inflammatory bowel disease (IBD) of the human digestive tract whose etiology is unknown. It affects 26–200 per 100 000 persons in Europe [1]. It is thought that both genetic predisposition and environmental factors contribute to immune system problems. A positive family history is thought to be a predictive factor for 20% of IBD patients [2]. The number of independent human genetic loci reportedly contributing to CD exceeds 100, one third of which have been related to the innate immune system and autophagy pathways [3,4]. Increased frequency of CD in the industrialized countries is mainly explained by environmental risk
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