Presentation is loading. Please wait.

Presentation is loading. Please wait.

Introducing the Microbiome Dr Ailsa Hart Director IBD Unit, Consultant Gastroenterologist, St Mark’s Honorary Senior Clinical Lecturer, Imperial College.

Similar presentations


Presentation on theme: "Introducing the Microbiome Dr Ailsa Hart Director IBD Unit, Consultant Gastroenterologist, St Mark’s Honorary Senior Clinical Lecturer, Imperial College."— Presentation transcript:

1 Introducing the Microbiome Dr Ailsa Hart Director IBD Unit, Consultant Gastroenterologist, St Mark’s Honorary Senior Clinical Lecturer, Imperial College

2 What is the gut microbiome? How does the gut microbiome play a role in disease? - role in inflammatory bowel disease How can we modulate the gut microbiota as a therapy - faecal transplant Introduction

3 The gut microbiota gut bacteria and cells in body Most densely populated ecosystem on Earth 4 major phyla (Bacteroidetes, Firmicutes, Actinobacteria, Proteobacteria) Provide traits we have not had to evolve on our own “Virtual” organ Genes in gut flora 100 times our own genome

4 Function of gut microbiota Germ-free animals Exist and survive But abnormalities of:  Immune function (oral tolerance)  Metabolic function (altered enzymes)  Physiological function (altered motility)  Trophic function (altered cell turnover)

5 Host – microbiota interactions Hooper et al. Science 2001 A single commensal bacteria switches on genes involving Mucosal barrier function Nutrient absorption/ dietary energy extraction Enteric nervous system Intestinal maturation Immune system development Function of gut microbiota

6 The Meta HIT project

7 The Human Microbiome Project

8 5 year project 242 healthy men/women - samples from different body sites 10,000 different types of organism found Is there a core set of microbes that all humans share? Diversity of microbes across human beings Diet, host genetics, early microbial exposure Unique communities of microbes at different body sites At specific body sites, many microbes had similar genes/functions The human microbiome project Challenges thinking of one-microbe model of disease More likely “function” of group of microbes changes

9 Gut microbiota “pathology” e.g.inflammatory bowel diseases functional bowel disease gastrointestinal infections non-GI diseases - obesity, metabolic syndrome, atopy/allergy

10 Genetics of IBD 1980’s >160 independent IBD susceptibility loci

11 What has genetics taught us about IBD? -Information about pathways involved in disease process -Over 2/3 of genes are shared between UC &CD -30 CD-specific and 23 UC-specific -Particular overlap between ankylosing spondylitis and psoriasis 1 Jostins et al Nature 491 (7422): ; 2 Lees et al Gut 2011;60: (diagram) > 75,000 cases & controls

12 Experimental models of colitis Germ-Free No Colitis Animal models of colitis

13 Experimental models of colitis Bacterial Colonisation Germ-Free Colitis No Colitis Animal models of colitis

14 In humans…   Faecal stream diversion alleviates Crohn’s   Reanastomosis triggers recurrence   Infusion of luminal contents into excluded normal bowel induces inflammation

15 What part of the gut microbiota drives inflammation? Single organism? Expansion or relative contraction? “Functional” changes?

16 Reduced diversity of faecal microbiota In CD

17 Reduced Firmicutes in Crohn’s disease

18 - Reduction of a major member of Firmicutes, F. prausnitzii, associated with higher risk of postoperative recurrence of ileal CD. Experimental replacement of F. prausnitzii had anti-inflammatory effects

19   Major shifts in oxidative stress pathways   Decreased carbohydrate metabolism   Decreased amino acid synthesis   In ileal Crohn’s, increases in virulence and secretion pathways But changes in “function” of microbiota…. Morgan et al. Genome Biology Sept 2012 Microbial function more consistently altered than microbial composition Mucosa/stool samples from 231 IBD patients & controls 16S gene pyrosequencing/shotgun metagenomics

20 Challenges Clinical phenotype confounders age, gender, smoking ethnicity, diet, surgery medications “healthy” controls Sampling faeces v mucosa axial and longitudinal variation replication multiple samples from same region longitudinal sampling Technical 16S sequence metagenomics metatranscriptomics metabonomics … economics Communication clinicians microbial ecologists bioinformatics statisticians

21 Can the gut microbiota be modified? If so, how?

22 Faecal transplantation - history   1600s – “transfaunation” – gastric contents transplanted into animals unable to ruminate   Bedouin of northern Africa – “coprphagia” – ingestion of camel dung as treatment for dysentery   WWII – same practice in soldiers – led to Bacillus subtilis as probiotic   Faecal transplant (FT ) - treatment in humans for pseudomembranous colitis in1958 Landy et al. Aliment Pharmacol Ther 2011; 34:

23 Publications on faecal transplantation

24 Faecal transplantation in C. difficile   Over 376 cases of faecal transplant (FT) for C. diff infection   17/22 studies of FT are in refractory/fulminant C. diff   Enemas; via duodenal tubes; via colonoscopes   Overall success rates of >90% Landy et al. Aliment Pharmacol Ther 2011; 34:

25 Faecal transplantation in C. difficile   First randomised controlled trial   Aimed to recruit 120 patients – stopped early   13/16 (81%) in FT group – resolution of diarrhoea   4/13 (31%) in vancomycin group   3/13 (23%) in vancomycin + bowel lavage   After FT, ↑diversity (similar to healthy donors) Van Nood et al. NEJM January 2013

26 Faecal transplantation in IBD Damman et al. Am J Gastro. 2012; 107: ; Anderson et al. APT Sept patients with IBD (27 UC; 12 CD; 2 indeterminate) Majority (19/25) had reduction in symptoms/ 15/24 remission Resolution of C. diff infection in 15/15

27 Faecal transplantation in pouchitis Hypothesis – increasing diversity and altering selection of resistant bacteria with faecal transplantation may be effective in refractory pouchitis Pilot study of faecal transplantation in patients with chronic pouchitis Microbiological; immunological; histological & clinical assessment pre and post transplant

28 Landy et al. ECCO 2013 Faecal transplantation in pouchitis PDAI CGQoL score pouch frequency No major adverse events; 3 patients reported adverse effects nausea (n=3); bloating (n=2)

29

30

31 Unresolved issues…   Can microbiota be altered in IBD with FT?   If so, does genetic pressure / indigenous bacteria affect ability to change?   Donor - mixture of phylogenetically diverse bacteria – which?   Frequency and route of administration?   Use of concomitant treatment?   Fresh versus frozen (banks)?   Safety?

32 Altering microbiota - beyond IBD …..  Other gastrointestinal disorders Functional bowel disorders Functional bowel disorders  Gastrointestinal infections e.g. Clostridium difficile, rotavirus  Non-intestinal disorders  Atopic diseases  Type I diabetes/ metabolic syndrome  Obesity ……

33 Obesity

34  Calorie extraction from food varies depending on gut flora depending on gut flora  “Obese flora” more effective at extracting energy from food extracting energy from food Could manipulation of gut microbiota influence obesity?

35 Malnutrition  Calorie extraction from food varies depending on gut flora depending on gut flora  “Obese flora” more effective at extracting energy from food extracting energy from food Could manipulation of gut microbiota influence malnutrition?

36 Summary   Gut microbiota – virtual organ; microbiome; metobonome   Role of microbiota in IBD   Modulation of gut flora as a therapeutic intervention   Mechanistic approach   Far reaching potential in GI (and non-GI) disease


Download ppt "Introducing the Microbiome Dr Ailsa Hart Director IBD Unit, Consultant Gastroenterologist, St Mark’s Honorary Senior Clinical Lecturer, Imperial College."

Similar presentations


Ads by Google