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:
Introducing the Microbiome Dr Ailsa Hart Director IBD Unit, Consultant Gastroenterologist, St Mark’s Honorary Senior Clinical Lecturer, Imperial College
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
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
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)
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
The Meta HIT project
The Human Microbiome Project
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
Genetics of IBD 1980’s >160 independent IBD susceptibility loci
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
Experimental models of colitis Germ-Free No Colitis Animal models of colitis
Experimental models of colitis Bacterial Colonisation Germ-Free Colitis No Colitis Animal models of colitis
In humans… Faecal stream diversion alleviates Crohn’s Reanastomosis triggers recurrence Infusion of luminal contents into excluded normal bowel induces inflammation
What part of the gut microbiota drives inflammation? Single organism? Expansion or relative contraction? “Functional” changes?
Reduced diversity of faecal microbiota In CD
Reduced Firmicutes in Crohn’s disease
- 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
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
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
Can the gut microbiota be modified? If so, how?
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:
Publications on faecal transplantation
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:
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
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
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
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)
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?
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 ……
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?
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?
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