Colonic microbiota can promote rapid local improvement of murine colitis by thioguanine independently of T lymphocytes and host metabolism

Oancea, I., Movva, R., Das, I., Aguirre de Carcer, D., Schreiber, V., Yang, Y., Purdon, A., Harrington, B., Proctor, M., Wang, R., Sheng, Y., Lobb, M., Lourie, R., Cuiv, P.O., Duley, J.A., Begun, J. and Florin, T.H.J. (2016) Colonic microbiota can promote rapid local improvement of murine colitis by thioguanine independently of T lymphocytes and host metabolism. Gut, 66 1: 59-69. doi:10.1136/gutjnl-2015-310874

Author Oancea, I.
Movva, R.
Das, I.
Aguirre de Carcer, D.
Schreiber, V.
Yang, Y.
Purdon, A.
Harrington, B.
Proctor, M.
Wang, R.
Sheng, Y.
Lobb, M.
Lourie, R.
Cuiv, P.O.
Duley, J.A.
Begun, J.
Florin, T.H.J.
Title Colonic microbiota can promote rapid local improvement of murine colitis by thioguanine independently of T lymphocytes and host metabolism
Journal name Gut   Check publisher's open access policy
ISSN 1468-3288
Publication date 2016-07-13
Year available 2016
Sub-type Article (original research)
DOI 10.1136/gutjnl-2015-310874
Open Access Status DOI
Volume 66
Issue 1
Start page 59
End page 69
Total pages 12
Place of publication London, United Kingdom
Publisher BMJ Publishing Group
Language eng
Subject 2715 Gastroenterology
Abstract Thiopurines are analogues of endogenous purines. They are pro-drugs which require the purine salvage pathway to convert them to the active drug nucleotides (TGN). These drugs are used to maintain clinical remission in patients with inflammatory bowel diseases. In our recent Gut paper, we showed that thioguanine worked quickly to improve colitis in the absence in the host animal of the key guanine salvage enzyme, hypoxanthine-guanine-phosphoribosyltransferase (HPRT). Current evidence favours the proposition that active drug delivery to the host lacking HPRT requires translocation of TGN-loaded bacteria across the inflamed mucosal barrier, and most likely delivery by phagocytosis. Alternatively, the efficacy of thioguanine in treating colitis could be mediated by modulation of the community of the microbiota in the intestine, or there are novel host pathways for conversion of the thioguanine pro-drug to TGN.
Formatted abstract
Objective Mercaptopurine (MP) and pro-drug azathioprine are ‘first-line’ oral therapies for maintaining remission in IBD. It is believed that their pharmacodynamic action is due to a slow cumulative decrease in activated lymphocytes homing to inflamed gut. We examined the role of host metabolism, lymphocytes and microbiome for the amelioration of colitis by the related thioguanine (TG).

Design C57Bl/6 mice with or without specific genes altered to elucidate mechanisms responsible for TG's actions were treated daily with oral or intrarectal TG, MP or water. Disease activity was scored daily. At sacrifice, colonic histology, cytokine message, caecal luminal and mucosal microbiomes were analysed.

Results Oral and intrarectal TG but not MP rapidly ameliorated spontaneous chronic colitis in Winnie mice (point mutation in Muc2 secretory mucin). TG ameliorated dextran sodium sulfate-induced chronic colitis in wild-type (WT) mice and in mice lacking T and B lymphocytes. Remarkably, colitis improved without immunosuppressive effects in the absence of host hypoxanthine (guanine) phosphoribosyltransferase (Hprt)-mediated conversion of TG to active drug, the thioguanine nucleotides (TGN). Colonic bacteria converted TG and less so MP to TGN, consistent with intestinal bacterial conversion of TG to so reduce inflammation in the mice lacking host Hprt. TG rapidly induced autophagic flux in epithelial, macrophage and WT but not Hprt−/− fibroblast cell lines and augmented epithelial intracellular bacterial killing.

Conclusions Treatment by TG is not necessarily dependent on the adaptive immune system. TG is a more efficacious treatment than MP in Winnie spontaneous colitis. Rapid local bacterial conversion of TG correlated with decreased intestinal inflammation and immune activation.
Keyword Harnessing microbial strategies for treatment of human disease
Role of commensal flora in GI diseases
Role of gut microbiome in GI disease
purine salvage
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status UQ

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