TGR5 activation induces intestinal growth and improves intestinal mucositis in mice. Hannelouise Kissow

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1 TGR5 activation induces intestinal growth and improves intestinal mucositis in mice Hannelouise Kissow Department of Biomedical Sciences Faculty of Health and Medical Sciences

2 Faculty Disclosure x No, nothing to disclose Yes, please specify: Company Name Honoraria/ Expenses Consulting/ Advisory Board Funded Research Royalties/ Patent Stock Options Ownership/ Equity Position Employee Other (please specify)

3 7/1/18 3 Background cells GLP-1 and GLP-2 are secreted from L Hormones are co-distributed Secreted after oral food intake Exogenous GLP-2 ameliorates GI mucositis

4 7/1/18 4 Background GLP-1 and GLP-2 are essential for intestinal healing Compensatory hyperproliferation and healing

5 7/1/18 5 Background GLP-1 and GLP-2 are essential for intestinal healing Compensatory hyperproliferation and healing

6 7/1/18 6 Background GLP-1 and GLP-2 are essential for intestinal healing % c h a n g e in B W WT Saline WT 5-FU Tg 5-FU Tg 5-FU GLP-2 Tg 5-FU GLP-1 Tg 5-FU Co-treatment - 2 Rasmus Hytting-Andreasen et al. Endogenous glucagon-like peptide- 1 and 2 are essential for regeneration after acute intestinal injury in mice PLoS One 218; 13(6): e19846

7 7/1/18 7 Background TGR5 is expressed on the L-cells TGR5 Compensatory hyperproliferation and healing Bile acid receptor G protein coupled Widely distributed Activation à GLP-1 secretion Increase gallbladder filling

8 7/1/18 8 Background Secondary BA s are the most potent TGR5 activators LCA > CDCA DCA > CA Production of camp in CHO-TGR5 transfected cells Maruyama T et al. Identification of membrane-type receptor for bile acids (M-BAR). Biochem Biophys Res Commun. 22 Nov 15;298(5):714 9

9 7/1/18 9 Background Microbiota controls the dehydroxylation

10 7/1/18 1 Background Does microbiota control intestinal healing? CDCA CA LCA DCA TGR5 Compensatory hyperproliferation and healing

11 7/1/18 11 Method Ex 1 Sacrificed after 1 days of treatment TGR5 agonist Vehicle Main endpoints Intestinal weight Morphology Tissue hormone concentration 3 mg/kg oral gavage x 2 Ex 2 TGR5 agonist Sacrificed 72 h after 5-FU (4 mg/kg i.p) 5-FU Vehicle 5-FU TGR5 agonist Vehicle Main endpoints Body weight Small intestinal weight Morphology Mucositis severity

12 7/1/18 12 Results TGR5 activation induced small intestinal growth S m a ll In te s tin e W e ig h t C o lo n W e ig h t 5 **** 1.5 % o f B W % o f B W R O V e h ic le. R O V e h ic le 8 * * 1 V illu s h e ig h t (µ m ) * R O V e h ic le C ry p t d e p th (µ m ) D u o d e n u m J e ju n u m Ile u m D u o d e n u m J e ju n u m Ile u m Mean ± SEM n=8 *=p <.5, **=p <.1, **** =p <.1

13 7/1/18 13 Results TGR5 activation induced GLP-1 and GLP-2 secretion A c tiv e G L P -1 in S m a ll In te s tin e A c tiv e G L P -1 in C o lo n * * 1 3 p m o l/g 5 p m o l/g 2 1 R O V e h ic le R O V e h ic le A c tiv e G L P -2 in S m a ll In te s tin e A c tiv e G L P -2 in C o lo n * * 4 p m o l/g 3 2 p m o l/g R O V e h ic le R O V e h ic le Mean ± SEM n=8 **=p <.1

14 7/1/18 14 Results TGR5 activation ameliorates GI mucositis C h a n g e in B W V illu s h e ig h t F U + R O F U + v e h ic le 5 6 * _ R O V e h ic le % µ m D u o d e n u m J e ju n u m Ile u m 1 5 M u c o s it is s e v e r ity s c o r e * * 5 -F U + R O F U + V e h ic le 1 s c o re 5 Mean ± SEM n(5-fu)=8, n(control)=4 *=p <.5 D u o d e n u m J e ju n u m Ile u m

15 7/1/18 15 Conclusion Activation of the BA receptor TGR5 led to small intestinal growth and GLP-1 and GLP-2 secretion in the colon Activation of the BA receptor TGR5 was able to ameliorate 5-FU induced GI mucositis Perspective s

16 Acknowledgements Jenna Hunt Bolette Hartmann Jens Juul Holst Cristoph Ullmer, Roche Innovation Center, Basel, Switzerland Financial support A. P. Møller Foundation Krista and Viggo Petersen Foundation