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http://apc.ucc.ie Microbial metabolite production by gut microbes and implications for host health Catherine Stanton APC Microbiome Institute (APC) & Teagasc Food Research Centre, Moorepark, Fermoy, Co. Cork, Ireland. E-mail: [email protected] Microbiome is defining in terms of human health http://apc.ucc.ie Human ~10 trillion cells Bacterial Community ~23 thousand genes …a hidden organ Microbiota ~100 trillion cells ~3 million genes Intestinal Microbiota http://apc.ucc.ie Complex and dynamic community 1014 microorganisms/g contents 10 times more bacteria than human cells 100-fold more unique genes than our own genome Important functions: METABOLIC MORPHOLOGIC PROTECTIVE Guarner et al., 2011 • Fermentation of food components • Production of SCFAs, vitamins, bioactives • Control of epithelial cell proliferation • Development of the immune system • Barrier effect • Production of antimicrobial substances/pathogen inhibition Microbiota Impacts Host Metabolism http://apc.ucc.ie e.g. SCFA Ryan & Delzenne, 2016. Microbiome has intimate ties in almost every facet of host health http://apc.ucc.ie 5 4 2 1 3 Gut Microbes and Obesity http://apc.ucc.ie Felix Sommer & Fredrik Bäckhed Nature Reviews Microbiology 11, 227-238 (April 2013) Gut Microbes & Diabetes http://apc.ucc.ie Brain-Gut-Microbiota Axis http://apc.ucc.ie http://apc.ucc.ie Human Gut Microbiota -large potential for health http://apc.ucc.ie Bioactive metabolites PERTURBED MICROBIOTA • Necrotizing enterocolitis • Obesity • Diabetes • Metabolic syndrome • Irritable bowel syndrome • Inflammatory bowel disease •Colon cancer • Altered CNS development GI microbiota over lifetime Your microbiota assembles in the first years of life and remains relatively stable until old age Assembly Stability http://apc.ucc.ie Collapse Opportunities for interventions/diagnostics, for food, biotech & pharma APC Hypothesis http://apc.ucc.ie http://apc.ucc.ie We can mine the gut microbiota for products that promote health or treat disease • • • • • Diagnostics Antibiotics Anti-inflammatories Medical foods Functional foods Mining the Gut Microbiota for Bioactives http://apc.ucc.ie Pharmabiotics http://apc.ucc.ie http://apc.ucc.ie The gut microbiota plays a role in determining health - we can mine for pharmabiotics • • • • • • Faecal transplants Microbial consortia Probiotics Prebiotics Metabolites Bacteriophage http://apc.ucc.ie Microbiota Immune System Modulation of Intestinal Microbiota http://apc.ucc.ie “Open window of opportunity” (Fouhy et al., 2012) Importance of the correct establishment of intestinal microbiota Early postnatal period constitutes key moment Modulation to the establish a healthy microbial profile Early life: Setting the la immune balance forinmune life Edad temprana: Base de homeostasis para toda la vida -9 months -9 meses Nacimiento Birth ~ 36 meses ~ 36 months Alergia Allergy Obesidad Obesity Enfermedades Coronary Heart coronarias Diabetes Diseases Enfermedades Diabetes autoinmunes Autoimmunity Salud HEALTHY LIFE Bajo riesgo de enfermedad ↓ Risk disease Kerperiem et al., 2012 Mode of Delivery: Phylum level http://apc.ucc.ie Hill et al (2017) (MICROBIOME) Increase in Diversity over Time http://apc.ucc.ie Hill et al (2017) (MICROBIOME) By Year 2 Microbiota Becomes More Adult-like http://apc.ucc.ie C) A) 100% Unclassified d = 0.05 Other 90% Clostridium_IV Coprococcus 80% 23.9% Alistipes Erysipelotrichaceae incertae sedis 70% Clostridium sensu stricto Gemmiger 60% Clostridium XI 4.7% Prevotella 50% B) Clostridium XVIII Ruminococcus Shannon Diversity 40% Clostridium XlVa Roseburia 30% Anaerostipes 20% Lachnospiracea incertae sedis Blautia 10% Faecalibacterium Bacteroides Year 1 Year 2 *** 0% Year 1 Year 2 *** Bifidobacterium (data unpublished) Pharmabiotics http://apc.ucc.ie Conjugated Isomers Bacteriocins SCFA Gut Bacterial Exopolysaccharides Metabolites Vitamin B Bioactive Peptides Neuroactive Compounds Antihypertensive Antithrombitic Caseinophosphopeptides Immunomodulatory Antioxidant Opioid Cytomodulatory Conjugated Linoleic Acid (CLA) http://apc.ucc.ie Anti-Cancer Improves Heart Health Improves Immune System Regulating Improves Body Composition Bone Formation Fat Recombinant Lb. paracasei producing t10, c12 CLA in vivo GLC http://apc.ucc.ie LA Lactoacillus paracasei t10, c12 CLA Expressing CLA isomerase (P. acnes) Increased t10, c12 CLA content of adipose tissue following dietary intervention 0.03 g/100 g FAME *** 0.02 n=8 0.01 8 weeks 0.00 Vector Control CLA Producing Rosberg-Cody et al (2011) Microbiology Production of Bioactive Lipids - CLA http://apc.ucc.ie 90 80 Bifidobacterium breve 70 60 LA 50 % 49 Conversion to CLA 30 20 10 GLC CLA Bifidobacterium longum Linoleic acid (g/100g FAME) Administered B. breve is metabolically active in the gut http://apc.ucc.ie Linoleic acid + B. breve Linoleic acid r= -0.863 c9, t11 CLA (g/100g FAME) Wall et al., AJCN 2009 89: 1393-1401 Impact of administered B. breve on FA composition http://apc.ucc.ie *** LA + B. breve LA + B. breve LA Control * * BALB/c mice SCID mice Wall et al., AJCN 2009, 2012 Pigs Elevated Lc-PUFA in Adipose Tissue and Brain http://apc.ucc.ie EPA (Eicosapentaenoic Acid) DHA (Docosahexaenoic Acid) Unsupplemented * *** B. breve 702258 supplemented n=8 * = p<0.05 *** = p<0.001 Wall et al. Am. J. Clin. Nutr. 2009 Microbiome-mediated therapies for heart health? http://apc.ucc.ie Probiotic • BSH • EPS Prebiotic • Arabinoxylan • Oat β-glucan Archaebiotics • TMADepletion EPS Producing LAB: Probiotic for Heart Health? http://apc.ucc.ie EPS Lb. mucosae 6426: Genome Sequence http://apc.ucc.ie The genome revealed a plethora of homologues linked to carbohydrate metabolism (EPS operon) and mucin Lactobacillus mucosae DPC6426 binding. In addition, several putative bile salt hydrolase genes (BSH) were identified, along with a potential novel phage and CRISPR elements. DPC6426 Reduces Atherosclerosis – In Vivo http://apc.ucc.ie High Fat Control Heat Killed n = 14 n = 14 n = 14 A 24-week intervention with either Live (lDPC) or Heat-Killed (hkDPC) Lb. mucosae DPC6426 fed in conjunction with a high-fat diet significantly attenuated cholesterol (and in particular LDL-C) accumulation when compared to the high-fat control (HFC). In turn, the strain reduced the development of aortic plaque in the atherosclerosis-prone apolipoprotein-E-deficient (apo-E-/-) mouse model. Bile Salt Hydrolase Activity & Specificity http://apc.ucc.ie Porcine Murine (Ryan et al., unpublished) Live Lactobacillus mucosae Alters Microbiome Composition & Functionality http://apc.ucc.ie hkDPC (Ryan et al., unpublished) HFC 16S MiSeq U/w UniFrac liveDPC Faecal 1H-NMR OPLS-DA liveDPC HFC * hkDPC * * * Antiatherogenic Activity of DPC6426 http://apc.ucc.ie Brain-gut-microbiota axis http://apc.ucc.ie • Brain gut axis is a bi-directional signalling between the brain and the GI tract (O’Mahony 2011; Dinan and Cryan, 2016) • Gut microbiota may play a role in neuronal development and plasticity, modulating pain perception and even behaviour (Forsythe et al., 2010; Dina et al., Biol Psychiatry. 2013) • Microbes produce a wide spectrum of neuroactive compounds, including fatt acids, GABA (Lyte, 2011; Barrett et al., 2012) • Studies have shown the ability of probiotics to alleviate distress in humans and an anxiolytic-like activity in rats (Lyte, 2011) Microbes and neurotransmitters http://apc.ucc.ie Genus Neurochemical Lactobacillus, Bifidobacterium GABA Streptococcus, Escherichia, Enterococcus, Lactococcus, Lactobacillus Serotonin Escherichia, Bacillus Escherichia, Bacillus, Lactococcus, Lactobacillus, Streptococcus Lactobacillus, Bacillus Norepinephrine Dopamine Lactobacillus, Lactococcus, Streptococcus, Enterococcus Histamine Acetylcholine From Wall et al., 2014; Bacterial Neuroactive Compounds Produced by Psychobiotics Adv Exp Med & Biol 817, pp 221-241 GABA = Microbial Metabolite http://apc.ucc.ie • γ-aminobutyric acid (GABA) is synthesised through decarboxylation of glutamic acid by glutamic acid decarboxylase (GAD) • GABA: main inhibitory neurotransmitter in the CNSbiological functions of GABA are mediated by activation of GABA receptors in the brain and periphery 91 intestinally-derived bacteria assessed, one Lactobacillus brevis strain (Lb. brevis DPC 6108) could convert up to 90% MSG to GABA in vitro Anti-anxiety effect of GABA producing Lb brevis 6108 http://apc.ucc.ie Unsupplemented GABA powder L. brevis DPC 6108 Inner Zone duration Inner Zone distance moved 0.0511 50 600 500 * 400 cm 30 300 20 200 10 100 0 0 Total distance moved 5000 4000 *P<0.05 cm sec 40 3000 2000 1000 0 (Marques et al., unpublished) http://apc.ucc.ie Sunday 28th June 2015 Gut Microbes, Metabolites and Health http://apc.ucc.ie • Gut Microbiome-central role in host metabolism • Microbial metabolism-range of signalling molecules, which directly and indirectly impact on host lipid metabolism/cholesterol synthesis/brain function • Probiotics have potential, but understanding mechanisms critical • Future studies required to fully comprehend role of gut microbiome in: host-lipid metabolism, CNS development, ageing • Targeted gut microbiome modulation dietary interventions for optimised health throughout life Acknowledgments http://apc.ucc.ie COLLABORATORS Paul Ross Paul O’Toole Ger Fitzgerald Fergus Shanahan Ted Dinan John Cryan Noel Caplice Eamonn Quigley Tony Ryan Gene Dempsey RESEARCHERS Paul Ryan Rebecca Wall Elaine Patterson Ruairi Robertson Lis London Tatiana Marques Mairead Coakley Eva Rosberg Alan Hennessy Eoin Barrett