Microbiota and What the Clinical Gastroenterologist Needs to Know

Transcription

1 Microbiota and What the Clinical Gastroenterologist Needs to Know Co-Speakers: Premysl Bercik and Michael Surette, Farncombe Family Digestive Health Research Institute McMaster University Small Group Session: Sunday, February 11, 11h00-11h40 Room: Saskatchewan of Canada. Reproduced with permission. 1

2 Name: Dr. Michael Surette Conflict of Interest Disclosure (over the past 24 months) Commercial or Non- Profit Interest Takeda Pharmaceuticals Weston Foundation Gilead BioK Relationship consultant research support research support sponsored research

3 Name: Dr. Premysl Bercik Conflict of Interest Disclosure (over the past 24 months) Commercial or Non- Profit Interest Nestle Switzerland Allergan Canada LUPIN Pharma Canada IM HealthScience Innovate Biopharma Relationship Consultant, research support advisory board, consultant advisory board advisory board advisory board

4 CanMEDS Roles Covered PB Medical Expert (as Medical Experts, physicians integrate all of the CanMEDS Roles, applying medical knowledge, clinical skills, and professional values in their provision of highquality and safe patient-centered care. Medical Expert is the central physician Role in the CanMEDS Framework and defines the physician s clinical scope of practice.) Communicator (as Communicators, physicians form relationships with patients and their families that facilitate the gathering and sharing of essential information for effective health care.) Collaborator (as Collaborators, physicians work effectively with other health care professionals to provide safe, high-quality, patient-centred care.) PB Leader (as Leaders, physicians engage with others to contribute to a vision of a high-quality health care system and take responsibility for the delivery of excellent patient care through their activities as clinicians, administrators, scholars, or teachers.) Health Advocate (as Health Advocates, physicians contribute their expertise and influence as they work with communities or patient populations to improve health. They work with those they serve to determine and understand needs, speak on behalf of others when required, and support the mobilization of resources to effect change.) PB MS Scholar (as Scholars, physicians demonstrate a lifelong commitment to excellence in practice through continuous learning and by teaching others, evaluating evidence, and contributing to scholarship.) Professional (as Professionals, physicians are committed to the health and well-being of individual patients and society through ethical practice, high personal standards of behaviour, accountability to the profession and society, physician-led regulation, and maintenance of personal health.) of Canada. Reproduced with permission. 4

5 Learning Objectives: At the end of this session participants will be able to: 1. Understand the basic analysis of microbiota profiling analysis and metagenomics, and reported measures (such alpha and beta diversity); 2. Understand the differences in methodological approaches and how they may influence outcome; 3. Review our current understanding of the role of microbiota in GI diseases, focusing on clinical studies in IBD and IBS. of Canada. Reproduced with permission. 5

6 Microbiome PubMed publications with key word Microbiome 11,000 paper by end of ,300 papers published of Canada. Reproduced with permission. 6

7 of Canada. Reproduced with permission. 7

8 of Canada. Reproduced with permission. 8

9 of Canada. Reproduced with permission. 9

10 of Canada. Reproduced with permission. 10

11 of Canada. Reproduced with permission. 11

12 The Human Microbiome The organisms, their genomes and environments on or in us is the human microbiome. Every surface on the human body has a distinct microbiome. Every individual has their own unique microbiome. Nature Rev. Microbiol. 9, (2011) of Canada. Reproduced with permission. 12

13 The Human Microbiome Varies in composition and increase in bacterial density along its length. GI tract is 10m in length Stool is representative of the colon Stomach cfu/ml Duodenum cfu/ml Jejunum/ileum cfu/ml Colon cfu/ml of Canada. Reproduced with permission. 13

14 What does your gut microbiome do for you? produce vitamins that we need (e.g. K, B 12 ). break down our food to extract energy and nutrients (SCFAs). train and maintain our immune systems. first-line defense against pathogens colonization resistance. of Canada. Reproduced with permission. 14

15 The Complexity of the Human Gut Microbiota Comprised of species of bacteria. Human Microbiome 1,000,000+ genes Human Genome 23,000 genes of Canada. Reproduced with permission. 15

16 The Microbiome Across the Life Course We are born essentially sterile Colonized at birth Stabilizes by 1-3 years Co-evolves with immune system uniquely in each individual In the absence of disease, the microbiome is stable throughout most of life Later in life the immune and microbiome disentangle and lose stability of Canada. Reproduced with permission. 16

17 The Microbiome Across the Life Course Perturbations to the microbiome can have long term consequences, particularly early in life. e.g. Antibiotics, Infection, Diet of Canada. Reproduced with permission. 17

18 Changes in the gut microbiome have been correlated with a wide range of chronic diseases. Inflammatory Bowel Disease Allergy & Asthma Irritable Bowel Syndrome Cardiovascular Disease Obesity Diabetes Psychological Disorders e.g. Anxiety and Depression of Canada. Reproduced with permission. 18

19 Birth Immature Host (Immune) Immature Microbiome Early Life Adulthood Late Life of Canada. Reproduced with permission. 19

20 Birth Chronic Disease Immature Host (Immune) Immature Microbiome Dysbiosis: an imbalance of the microbiome with respect to the host (immune system). Not define by the composition of the microbiome but by its interaction with the host. of Canada. Reproduced with permission. 20

21 Predicting and manipulating cardiac drug inactivation by the human gut bacterium Eggerthella lenta. Haiser HJ et al, Science Digoxin is a medication used to treat various heart conditions Known that there are responders and non-responders Some patients excrete the inactive digoxin metabolite dihydrodigoxin Co-administration of broad spectrum antibiotics increases serum digoxin Eggerthella lenta in vivo cgr1 cgr2 dependent Non-responders had cgr1 cgr2 Dihydrodigoxin Only 1 of 3 isolates of E. lenta had cgr1 cgr2 and were capable of inactivating digoxin ie. Strain not Species dependent This reaction is inhibited by arginine and dietary protein in monocolonized mice. of Canada. Reproduced with permission. 21

22 Does relative abundance matter? Some processes, like bulk metabolism (eg SCFA production) are carried out by prominent members of the gut community and are usually redundant functions (in many different bacteria). Some processes, like drug metabolism can be carried out by low abundant members of the gut community and are usually specialized functions. Eggerthella Mean abundance <0.001 MetaQuery of Canada. Reproduced with permission. 22

23 Good vs bad bacteria are often context dependent, their functionality is influenced by environment (e.g diet) Low abundant organisms are not necessarily unimportant Often specific functions are strain not species specific of Canada. Reproduced with permission. 23

24 Three approaches to the microbiome 1) Microbial Profiling who is there? 2) Metagenomics what genes are there? 3) Metatransciptomics what genes are expressed of Canada. Reproduced with permission. 24

25 Alpha Diversity The species diversity within a population and is independent of taxonomy (i.e. Two populations can have the same alpha diversity but not share species in common) Richness = the number of species present Evenness = includes the proportion of a species within a population Observed_species (OTUs) ; Chao1; Shannon Diversity; Simpson Diversity; Phylogenetic Diversity of Canada. Reproduced with permission. 25

26 Beta Diversity Is a measure or comparison between different populations and is therefore sensitive to species composition Weighted vs unweighted takes into account the relative abundance of each species (weighted) or simply the presence or absence of a species (unweighted) Phylogenetic beta diversity also include taxonomic distance when calculating distance between two populations (e.g. unifrac) Bray-Curtis Dissimilarity, Weighted Unifrac and Unweighted Unifrac of Canada. Reproduced with permission. 26

27 Study Design Bacterial Community Sample Collection Sample Processing DNA (RNA) Extraction Amplification and Sequencing? Bioinformatics Inferred Community/ Genomics of Canada. Reproduced with permission. 27

28 Each of these steps can influence the outcome Differences between similar studies may arise because of differences in protocols (i.e. technical not biological) Even the samples data run through two different bioinformatics pipelines can give different results of Canada. Reproduced with permission. 28

29 Statistical Challenges with Microbiome Data Variability in methodology study to study. Relationship of data is in relative not absolute abundances. Large compositional variation between individuals results in sparse (zero inflated >70%) datasets. Large datasets >> multiple test correction. of Canada. Reproduced with permission. 29

30 Microbiota composition in obesity studies Walters & Knight. FEBS Lett 2014 of Canada. Reproduced with permission. 30

31 Microbiota composition in obesity studies Walters & Knight. FEBS Lett 2014 of Canada. Reproduced with permission. 31

32 Microbiota composition in UC vs Healthy Unweighted Unifrac Walters & Knight. FEBS Lett 2014 of Canada. Reproduced with permission. 32

33 Microbiota composition in Crohn s vs Healthy Unweighted Unifrac Walters & Knight. FEBS Lett 2014 of Canada. Reproduced with permission. 33

34 Temporal variation in the microbiota Halfvarson et al, Nat Microbiology 2017 of Canada. Reproduced with permission. 34

35 Inconsistent microbiota signature in UC Courtesy of F. Tse, G. Leontiadis and P. Moayyedi, unpublished of Canada. Reproduced with permission. 35

36 Microbiota transplantation in germ-free mice (examples) Mice with UC microbiota have increased sensitivity to experimental colitis (Natividad et al, Inflamm Bowel Dis 2015) Microbiota from IBS-D patients induces immune activation and gut dysfunction (De Palma et al, Science Transl Med 2017) Microbiota from patients with UC display temporal changes in proteolytic activity (Bermudez et al, poster #...). of Canada. Reproduced with permission. 36

37 Pan-Canadian study: 2000 patients with Crohn s disease 2000 patients with Ulcerative colitis 2000 patients with IBS 2000 healthy controls Followed for 5 years of Canada. Reproduced with permission. 37

38 Evaluation and Certificate of Attendance Please download the CDDW app to complete the session evaluation and to receive your certificate of attendance.