Therapeutic Manipulation of the Gut Microbiota in Patients with IBD

Transcription

1 Therapeutic Manipulation of the Gut Microbiota in Patients with IBD Karen Madsen, PhD Director of Center of Excellence for Gastrointestinal Inflammation and Immunity Research (CEGIIR)

2 Disclosure of Commercial Support This program has received financial support from CIHR, Alberta Innovates, and Alberta Health Services in the form of research grants and salary support. This program has received in-kind support from Center of Excellence for Gastrointestinal Inflammation and Immunity for infrastructure and operating costs.

3 Objectives Understand the role the gut microbiome has in the pathogenesis of IBD Gain an understanding of how diet influences the microbiome Appreciate how diet could potentially be used to manipulate the microbiome and treat IBD

4 Figure 1 Increasing trend of IBD in industrialized countries Kaplan and Ng. Gastroenterology 2017 Gastroenterology , e2DOI: ( /j.gastro )

5 Figure 2 Environmental factors are altering our gut microbiota Kaplan and Ng. Gastroenterology 2017

6 The gut microbiota exists as an eco-system bacteria, viruses, fungi, archaea.. Tree of life Over 50 known bacterial phyla Generally a balance of 6 main phyla found in gut Bacteroidetes Firmicutes Health Actinobacteria Verrucomicrobia Proteobacteria Fusobacteria Disease How is living in western society altering our gut microbes?

7 The gut microbiome in non-industrialized and western societies

8 Western populations have depleted diversity and are missing many bacterial taxa Sonnenburg et al. Nature 529:

9 What are potential mechanisms?

10 Diet is a main determinant of microbial composition Voreades et al. Front. Microbiol. Sept 22, 2014

11 Diet-induced extinctions in the gut microbiota compound over generations Sonnenburg et al. Nature 529:

12 Dietary compounds serve as substrates for use by gut microbiota for production of numerous small molecules Pioneer colonizers: Enterobacteria & Bifidobacteria (modulate host genes to promote their own growth) Holmes et al. Cell Meta 2012; 16:555

13 A loss of certain microbial species can remove immune modulating metabolites Huttenhower et al Immunity (6):843

14 DIETARY CHANGES IN WESTERN SOCIETY

15 Consumption of sugar and processed foods is increasing

16 WHAT IS THE EFFECT OF A DIET HIGH IN REFINED CARBOHYDRATES ON OUR GUT MICROBIOTA? DOES A DIET HIGH IN SUGAR ALTER SUSCEPTIBILITY TO INFLAMMATORY DISEASE?

17 WT mice placed on a high sugar diet for 28 days had significant alterations in microbial composition Increased High Sugar Chow Robert Fedorak Akkermansia Sutterella Lactococcus Enterobacteriaceae Decreased KEY BUTYRATE and ACETATE PRODUCERS

18 Mice fed high sugar had Increased gut permeability Decreased expression of tight junction proteins Decreased mucin gene expression More inflammatory microbes Reduced levels of butyrate and acetate Did this make them more susceptible to injury?

19 Score Percentage Score Mice on high sugar diet had earlier onset and increased severity of disease when administered DSS Weight loss Stool Consistency WCD WHS Day on DSS Blood in stool WCD WHS WCD WHS Mice on high sugar diets also had increased tissue levels of pro-inflammatory cytokines Day on DSS

20 WHAT ABOUT SHORT TERM EXPOSURE TO HIGH LEVELS OF REFINED CARBOHYDRATE?

21 A 2 day diet of sugar was enough to alter microbial profiles and reduce Firmicutes Day 0 Day 2 Increased Akkermansia Decreased Lachnospiraceae

22 A 2 day diet of sugar was enough to alter microbial SCFA levels

23 Koh et al. From Dietary Fiber to Host Physiology: Short-Chain Fatty Acids as Key Bacterial Metabolites SCFA have both systemic and local effects

24 A 2 day diet of sugar was sufficient to increase disease susceptibility Stool Consistency DSS removed Chow High Sugar Blood in Stool Chow High Sugar

25 Production of butyrate requires cooperation Could we provide acetate and increase both acetate and butyrate and would it help?

26 Oral acetate attenuated high-sugar induced increased disease susceptibility Stool Consistency DSS removed Chow High Sugar HS + Acetate Hemoccult Chow High Sugar HS + Acetate Oral acetate also reduced pro-inflammatory cytokine secretion

27 Cecum at day 2 Chow Oral acetate did not change microbial profiles HS HS + acetate Stool at day 0 and 2 Baseline Suggests that it is microbial-produced metabolites that are the primary driving force in disease susceptibility Day 2 HS HS + Acetate

28 High sucrose Depletes SCFA Induces a colitogenic microbiota Reduces barrier function Diet can dramatically increase disease susceptibility, partially through changes in microbial metabolism Represents a key modifiable factor Increased bacterial translocation Enhanced immune response *Lack of proper repair

29 Figure 2 Diet can shift the microbiome and immune profiles along a wide spectrum and alter susceptibility to disease

30 CAN DIET BE USED TO TREAT ACTIVE DISEASE OR MAINTAIN REMISSION IN PATIENTS WITH IBD?

31 The Specific Carbohydrate Diet

32 Multicenter open label trial testing efficacy of specific carbohydrate diet for 12 wk Excludes all grains, sugars, processed foods, and dairy (except honey, yogurt, some hard cheeses N=12 (10-17 yrs of age) Suskind et al J Clin Gastroenterol Dec 2016

33 PROOF OF PRINCIPLE THAT DIET CAN BE MANIPULATED TO REDUCE INFLAMMATION

34 Diet and Risk of IBD INCREASED RISK? DECREASED RISK? Total Fat PUFA Omega-6 Meat Refined sugar Fiber (CD) Fruits (CD) Vegetables (UC) Hou et al. AJG 2011:106

35 Crohn s disease patients have decreased diversity and dysbiosis Proteobacteria Enterobacteriaceae (facultative aerobes) Adherent invasive E. coli Fusobacterium Caudovirales Serratia marcescens Candida tropicalis D Peterson et al. Cell Host and Microbe 3: Firmicutes Clostridial cluster IV F. prausnitzii Bacteroidetes Roseburia (butyrate producing microbes) Becker et al. ILAR Journal 2015 Hoarau et al Mbio Sept 2016

36 CAUSE OR EFFECT?

37 Products of Inflammation Feed the Expansion of Colitogenic Pathobionts Anaerobic Respiration CHO Clostridia Bacteriodia Enterobacteriaceae Modified from Winter et. al. EMBO, 2013

38 But colitis can also be transferred through the gut microbiota in mouse models These animal studies demonstrate proof of principle that certain strains of bacteria can transfer colitis phenotype Dysbiosis Inflammation Schaubeck et al. Gut 65:

39 If gut microbial dysbiosis is a contributing cause to the pathogenesis of IBD, then Using therapies aimed at the gut microbiota should help in the induction or the maintenance of remission How (and when) to manipulate a gut dysbiosis?

40 Fiber Fruits, vegetables Prebiotics Probiotics/Antibiotics Defined consortium Fecal transplants FEED THE TRANSPLANT!

41 Moving from a battleground to wildlife/park management in treatment of IBD Sartor and Wu Gastroenterology 152:

42 Trainee CAG Membership Trainee members are graduate or undergraduate students, residents, post-doctoral or clinical fellows holding a training position related to gastroenterology CAG Trainee Member benefits: No annual fee Low early registration fee of $25 for the Canadian Digestive Disease Week TM (CDDW TM ) meeting Access to Trainee Programs (Scholars, GRIT, Research Topics, and Basic Webinar Lectures) Eligibility to apply for research funding Access to accredited CME programs including the CAG e-portal To become a CAG Trainee Member, application can be downloaded at:

43 CAG Regular Member benefits: Regular CAG Membership CAG regular members may be gastroenterologists, surgeons, pathologists, radiologists, biomedical scientists, nurses and other health professionals in all allied fields committed to the advancement of gastrointestinal health and the study of gastrointestinal disease Early registration fee of only $75 for the Canadian Digestive Disease Week TM (CDDW TM ) meeting Canadian Association of Gastroenterology correspondence and e-newsletters Eligibility to apply for research funding Access to accredited CME programs including the CAG e-portal Opportunity to serve on committees of the CAG Voting privileges Membership Fee: $400 for one year or $1,050 for three years To become a CAG Regular Member, applications can be downloaded at:

44 Research Opportunities! and competitions program program program program meeting program program For more information regarding research opportunities at

45

46 Acknowledgements Madsen Lab Dr. Troy Perry Dr. Mike Laffin Dr. Heekuk Park Naomi Hotte Robert Fedorak Ammar Keshteli Aman Gill Aiden Zalasky Braden Millan Matt Emberg Collaborators University of Alberta Dr. Karen Kroeker Dr. Richard Fedorak Dr. Leo Dieleman Dr. Bryan Dicken Dr. Dina Kao Dr. Andy Mason University of Calgary Dr. Gil Kaplan George Mason University Dr. Patrick Gillivet Dr. Masoumeh Sikaroodi