The Microbiome, Cancer and Cachexia

Transcription

1 Oslo, January 18, 2018 The Microbiome, Cancer and Cachexia Prof. Laure Bindels, PhD

2 Dzutsev et al, Annu Rev Immunol 2017

3 Outline o Introduction to the gut microbiota o Gut microbiota-host crosstalk in chemotherapy o Diet-microbes-host interaction in cancer cachexia

4 The gut microbiota microbes human cells for a 'reference man' (70 kilograms, years old and 1.7 meters tall) Numbers from Sender et al, preprint on biorxiv, Neish, Gastroenterology

5 The gut microbiota : a hot topic

6 The gut microbiota : a hot topic Courtesy of Prof Nathalie Delzenne

7 Microbiota evolution over time Dominguez-Bello et al., Gastroenterology 2011

8 The gut-microbiota crosstalk Delzenne et al., Nat Rev Endocrinol 2011

9 Prebiotics i.e. inulin-type fructans Probiotics i.e. lactobacilli Bacteriocins Antibiotics FMT Gut microbiota Experimental tools to study our microbial partners Adapted from Bindels & Delzenne, Int J Biochem Cell Biol 2013

10

11 Liver Lipid metabolism Immunity Systemic immunity Gastrointestinal tract Energy extraction Metabolites Mucosal immunity Biotransformations Brain Development Behavior Appetite regulation Adipose tissue Adipocyte differentiation Lipogenesis Expansion Cell energy Muscle

12 Liver Non alcoholic steatohepatitis Type 2 diabetes Allergy Type 1 diabetes Gastrointestinal tract Inflammatory bowel diseases Colon cancer Brain EAE Autism Alcohol dependence Cardiovascular disease Adipose tissue Obesity Cancer cachexia Muscle

13 The gut microbiota-host crosstalk Neish, Gastroenterology 2009

14 Holmes et al, Cell Metab 2012 Microbial metabolites

15 Bindels et al, Trends Pharmacol Sci 2013 Microbial metabolites

16 Microbial metabolites Delzenne & Bindels, Nat Rev Gastroenterol 2017

17 Outline o Introduction to the gut microbiota o Gut microbiota-host crosstalk in chemotherapy o Diet-microbes-host interaction in cancer cachexia

18 Microbiota in chemotherapy Alexander et al, Nat Rev Gastroenterol 2017

19 Roy & Trinchieri, Nat Rev Gastroenterol 2017

20

21 Outline o Introduction to the gut microbiota o Gut microbiota-host crosstalk in chemotherapy o Diet-microbes-host interaction in cancer cachexia

22 Cancer cachexia Up to 80% of cancer patients, depending of the tumor site Reduces quality and length of life May be a cause of cancer therapy discontinuation No valid treatment Fearon et al., Cell Metab 2012; Fearon et al., Nat Rev Oncol 2013; Argiles et al, Nat Rev Cancer

23 Diagnostic of cachexia Muscle strength Body composition Anorexia Glasgow prognostic score (CRP & albuminemia) Fearon et al., Lancet Oncol 2011

24 Multimodal approach Physical activity Nutritional support Pharmacological approach Evans et al., Clinical Nutrition 2008 Fearon et al., Nat Rev Oncol 2013 Argiles et al, Nat Rev Cancer 2014 Bindels & Thissen, Clin Nutr Exp 2016

25 Multimodal approach Bindels & Thissen, Clin Nutr Exp

26 A microbial signature in cancer cachexia Community-wide approach to characterize the gut microbiota in two mouse models of cancer cachexia C26 BaF BaF3 cells with Bcr-Abl Bindels et al, The ISME J

27 A microbial signature in cancer cachexia BaF C26 16S rrna genes from the caecal microbiota analysed by Illumina MiSeq. Logarythmic LDA score. Enterobacteriaceae Parabacteroides goldsteinii Lactobacilli Bindels et al, The ISME J

28 Selected synbiotic approach D0 D1 D13 Bcr-Abl-expressing BaF3 cells L. reuteri ITF Bindels et al, The ISME J

29 Score Fraction survival mrna levels (relative expression) Organ weight (% body weight) Benefits of the synbiotic approach BaF 1.0 Bcr-Abl # * *# ND CT BaF BaF-LrI * *$ CT BaF BaF-LrI CT BaF BaF-LrI tibialis gastrocnemius Morbidity score # # Survival 1.2 BaF 1.0 BaF-LrI 0.8 p = median survival + 2 days 0 BaF BaF-LrI Bindels et al, The ISME J Days after BaF injection 29

30 µm mrnalevels (relativeexpression) Number of intact BaF3/w ell control propionate 2mM Bcr-Abl BaF * * Acetate Propionate Butyrate 0.0 ND CTBaF3 BaF3-ITF Propionate Acetate Propionate Butyrate Acetate Propionate Butyrate ITF 0 BaF3 CT af3-itf Bindels et al, Br J Cancer 2012; Bindels*, Neyrinck* et al, Plos ONE

31 A role for the gut barrier? Bindels & Thissen, Clin Nutr Exp

32 mrna levels (relative expression) mrna levels (relative expression) mrna levels (relative expression) A role for the gut barrier? BaF * Gut permeability # # # * * CT BaF BaF-LrI Gut permeability 0.0 occludin ZO-1 Muc2 proglucagon 1.5 Paneth cell differentiation and antimicrobials Antimicrobial peptides Immune system # * * * *# * # TCF4 Lysozyme -defensins Reg3 Pla2g # *# Decreased in leukemic mice Increased by synbiotics * # * # * $ * # Bindels et al, The ISME J 2016 CD3 Tbet IL-17A Foxp3 lymphocytes IL-10 Ebi3 32

33 A role for the gut barrier 33

34 A role for the gut barrier 34

35 A role for the gut barrier

36 LBP at the crossroad of cancer cachexia and gut dysbiosis 36

37 Conclusion & perspectives? Dr M. Sboarina RS ITF? Gut barrier propionate? AXOS POS S. Pötgens Bindels, Neyrinck et al, Plos ONE 2015

38 Primary Objective Composition and activity of the gut microbiota in acute myeloid leukemic patients Urine, feces and blood samples Nutritional assessments Cachexia symptoms Belgian Registration Number: B Dr H. Schoemans Prof J. Maertens Dr V. Havelange Prof JB. Demoulin Dr I. Moors Prof T. Kerre 38

39 Dr M. Sboarina Dr A. Neyrinck Prof P. Cani Prof N. Delzenne S. Pötgens Laure Bindels UCL (BE) Prof G. Muccioli Prof J.P. Thissen Prof O. Feron Prof P. Sonveaux Dr P. Porporato Prof J.B. Demoulin Dr V. Havelange Dr Fl. Bindels ULG (BE) Dr B. Taminiau Prof G. Daube Katholieke Universiteit Leuven (BE) Dr H. Schoemans Prof J. Maertens Institute Pasteur, Lille (FR) Prof B. Pot Dr C. Grangette Prof B. Staels Prof S. Lestavel S. Ducastel University of Alberta (CA) Prof J. Walter Dr I. Martinez INRA AgroParisTech (FR) Prof P. Langella Dr C. Cherbuy Dr L. Bermudez-Humaran University of Reading (UK) Prof S. P. Claus Dr C. I. Leroy

40 40