Yan He1, Hengyuan Yu1, Yixuan Ge1, Xueting Li1, Mingshan Jiang2, Yuanli Liu1, Xue Li1, Yan Wang1, Mengru Guo1, Xiaofa Qin3, Xiuhong Wang4. 1. Department of Biochemistry and Molecular Biology, Heilongjiang Provincial Science and Technology Innovation Team in Higher Education Institutes for Infection and Immunity, Harbin Medical University, Harbin, China. 2. Department of General Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, China. 3. GI Biopharma Inc., Westfield, NJ, 07090, USA. Electronic address: xiaofa_qin@yahoo.com. 4. Department of Biochemistry and Molecular Biology, Heilongjiang Provincial Science and Technology Innovation Team in Higher Education Institutes for Infection and Immunity, Harbin Medical University, Harbin, China. Electronic address: wangxh700417@aliyun.com.
Abstract
OBJECTIVE: Inflammatory bowel diseases (IBD) including ulcerative colitis and Crohn's disease are devastating diseases of the gut. At present, all the treatments are mainly targeting symptoms like inflammation. The disease remains regarded as incurable, largely due to lacking of knowledge on its etiology. Our previous studies suggested that impaired inactivation of digestive proteases by deconjugated bilirubin in experimental colitis, thus bacterial β-glucuronidase for catalyzing the reaction, may have played critical role in the pathogenesis of IBD. METHODS: We first analyzed β-glucuronidase activity in gut tissue and feces of mice by a colitis model. Then the effect of β-glucuronidase on experimental colitis was investigated in detail by administration of β-glucuronidase (from E. coli) and fecal material transplantation to mice with 3% DSS in drinking water for 7 days. RESULTS: Mice with colitis showed unchanged activity of β-glucuronidase in colon tissue but decreased activity in feces. Treatment with bacterial β-glucuronidase at 100 U or above alleviated DSS-induced colitis as demonstrated by the less body weight loss, less disease activity score, increased expression of tight junction proteins and decreased gut permeability, decreases in MPO, TNF-α, IL-1β, TLR-4 and MyD88, and increase in IL-10 and IκBα in gut, restored fecal β-glucuronidase and gut microbiota along with decreases in fecal digestive proteases. Transplantation of fecal material from control to colitis mice showed similar effects as treatment with β-glucuronidase. CONCLUSIONS: Bacterial β-glucuronidase showed strong inhibition on colitis along with the reduction in fecal digestive proteases, which may be a crucial diagnostic and therapeutic target for IBD.
OBJECTIVE:Inflammatory bowel diseases (IBD) including ulcerative colitis and Crohn's disease are devastating diseases of the gut. At present, all the treatments are mainly targeting symptoms like inflammation. The disease remains regarded as incurable, largely due to lacking of knowledge on its etiology. Our previous studies suggested that impaired inactivation of digestive proteases by deconjugated bilirubin in experimental colitis, thus bacterial β-glucuronidase for catalyzing the reaction, may have played critical role in the pathogenesis of IBD. METHODS: We first analyzed β-glucuronidase activity in gut tissue and feces of mice by a colitis model. Then the effect of β-glucuronidase on experimental colitis was investigated in detail by administration of β-glucuronidase (from E. coli) and fecal material transplantation to mice with 3% DSS in drinking water for 7 days. RESULTS:Mice with colitis showed unchanged activity of β-glucuronidase in colon tissue but decreased activity in feces. Treatment with bacterial β-glucuronidase at 100 U or above alleviated DSS-induced colitis as demonstrated by the less body weight loss, less disease activity score, increased expression of tight junction proteins and decreased gut permeability, decreases in MPO, TNF-α, IL-1β, TLR-4 and MyD88, and increase in IL-10 and IκBα in gut, restored fecal β-glucuronidase and gut microbiota along with decreases in fecal digestive proteases. Transplantation of fecal material from control to colitismice showed similar effects as treatment with β-glucuronidase. CONCLUSIONS: Bacterial β-glucuronidase showed strong inhibition on colitis along with the reduction in fecal digestive proteases, which may be a crucial diagnostic and therapeutic target for IBD.
Authors: Cassandra E Gheorghe; Nathaniel L Ritz; Jason A Martin; Hannah R Wardill; John F Cryan; Gerard Clarke Journal: Gut Microbes Date: 2021 Jan-Dec