SIMPOSIO Il microbiota intestinale e la sua modulazione nelle patologie dell asse intestino cervello. Microbiota e IBS.
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1 SIMPOSIO Il microbiota intestinale e la sua modulazione nelle patologie dell asse intestino cervello Microbiota e IBS Cesare Cremon Policlinico S. Orsola Malpighi Azienda Ospedaliero - Universitaria di Bologna ( )
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3 Microbiota and IBS: what is the link? New diagnosis of IBS after infectious gastroenteritis (Post infectious IBS) Spiller R, Garsed K. Gastroenterology 2009;136: Antibodies anti-flagellin and human β-defensin-2 increased in IBS Cremon C, et al. Expert Rev Mol Diagn 2010;10: Qualitative and quantitative changes in intestinal microbiota composition of IBS Simrén M, Barbara G, et al. Gut 2013;62: Non-absorbable antibiotics and probiotics effective in IBS Pimentel M, et al. N Engl J Med 2011;364:22-32 Moayyedi P, et al. Gut 2010;59:325-32
4 Campylobacter Shigella Salmonella 1.4 episodes/yr Gastrointestinal infection Acute Symptoms Dysbiosis Post-Infectious IBS Recovery Post-Infectious IBS (6-17%) Spiller et al., Gastroenterology 2009;136:
5 Salmonella outbreak in Bologna (October 19, 1994) Tuna sauce contaminated (Salmonella enteritidis D) 36 schools in the Bologna area 19 ottobre subjects infected (acute symptoms) 1684 pupils (93%) children 3-10 yrs 127 teachers or other school employees (7%) adults yrs Positive fecal cultures decreased from 100% to 1.5% at 3 months post-infection Barbara et al., Aliment Pharmacol Ther 2000;14:
6 Early life salmonellosis and IBS in adulthood Salmonella outbreak in Bologna ( ) Prevalence of IBS (%) 44/189 (23.3%) * 75/204 (36.8%) Non-exposed Exposed *P = OR = 1.92 (95% C.I.= ) Cremon C. et al., Gastroenterology 2014;17:69-77
7 Anti-Flagellins in IBS: pathophysiological mechanisms and clinical evidence Commensal microbes A4-Fla2 (%) Fla-X (%) Flagellins NF-Kβ Altered gut permeability IBS (n=112) PI-IBS (n=27) 29 * 26 * Antibodies anti-flagellins Cytokines TLR-5 PMN CD (n=61) UC (n=50) 48 # 52 # 8 10 TLR-5 Activate innate immunity HC (n=43) 7 7 B cells T cells Target of adaptive immunity Dendritic cells Promote adaptative immunity (directly or indirectly) *P<0.01 vs HC P<0.01 vs IBS # P<0.05 vs IBS Adapted from Gewirtz et al., Am J Physiol 2006 Schoepfer et al., Neurogastroenterol Motil 2008;20: Cremon et al., Expert Rev Gastroenterol Hepatol 2008;2:735-40
8 TLR-4 mrna quantification Best cutoff range between IBS and HC: HC IBS UC GUSB GUSB GUSB 1,0 0,9 0,8 0,7 TLR4 TLR4 TLR4 Sensitivity 0,6 0,5 0,4 0,3 0,2 * * * *P=0.005 vs HC **P=0.003 vs IBS 0,1 0,0 0,0 0,1 0,2 0,3 0,4 0,5 0,6 0,7 0,8 0,9 1,0 Specificity Best cutoff range between UC and IBS: ,0 0,9 0,8 0,7 Sensitivity 0,6 0,5 0,4 0,3 0,2 0,1 0,0 0,0 0,1 0,2 0,3 0,4 0,5 0,6 0,7 0,8 0,9 1,0 Specificity Cremon et al., DDW 2013
9 Gut microbiota and factors affecting its distribution Microbiota Microbes that collectively inhabit a given ecosystem (several trillion microbial cells) Simrén M et al., Gut 2013;62:159-76
10 Functional and phylogenetic profiles of human gut microbiome Phylum Class Order Family Genus Species Arumugam M et al., Nature 2011;473:
11 Different composition of fecal microbiota in IBS vs healthy Axis2 (20.3%) 1.5 Multivariate analysis (RDA) HC IBS 62 primary care IBS (Rome II), 46 HC Deep molecular analysis 2-fold Firmicutes/Bacteroidetes ratio Multivariate analysis identifies 2 distinct enterotypes -1.5 C V IBS symptoms correlated with 18 phylogenetic groups (R = ) -1.5 Axis1 (50%) 1.5 Rajilić-Stojanović et al., Gastroenterology 2011;141:
12 Irritable bowel syndrome subtype defined by species-specific alterations in faecal microbiota Sequenced S rrna gene V4 region amplicons per subjects High Firmicutes:Bacteroidetes ratio IBS (red) Normal Firmicutes:Bacteroidetes ratio IBS (blu) HAD depression score in normal-like IBS group Jerrery IB et al., Gut 2012,61:
13 Gut microbiota composition and host-microbe cross-talk Jalanka-Tuovinen J et al., Gut 2014;63:
14 Pre-dominant bacteria contributing to dysbiosis in IBS Firmicutes (Bacilli) Proteobacteria Actinobacteria Shigella/Escherichia Ruminococcus gravus Casén C et al., Aliment Pharmacol Ther 2015;42:71-83
15 Intestinal microbiota and IBS severity Tap J et al., Gastroenterology 2017;152:
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17 Strategies for modifying gut microbiota Fecal microbial transfer Simrén M et al., Gut 2013;62:159-76
18 Major claims of probiotics in IBS Modulate gastrointestinal motility Reduce visceral hypersensitivity Reduce low grade mucosal immune activation Improve epithelial permeability Enhance gut-brain communication Restore intestinal dysbiosis (?) Several of these claims based on convincing experimental evidence from preclinical studies Ohland CL. Et al. Am J Physiol Gastrointest Liver Physiol 2010 ;298:G807-19
19 Bifidobacterium lactis DN improves symptoms and gastrointestinal transit in patients with IBS-C 34 Rome III IBS patients with IBS-C Randomized, controlled, double-blind, parallel group trial 4 weeks of treatment Test product Control product Agrawal A et al., Aliment Pharmacol Ther 2009;29:104-14
20 Bifidobacterium infantis improves IBS symptoms and reduces minimal inflammation 77 Rome II IBS patients (64% women) all bowel habits Pre-Treatment Post-Treatment 200 Composite Likert Score * * * * * * * Treatment Period *P=0.05 IL-10:IL-12 ratio * *P=0.001 B. infantis L. salivarius Placebo Weeks O Mahony et al., Gastroenterology 2005;128:541-51
21 Fermented milk product with probiotic modulates brain activity in healthy women Four-week intake of FMPP (Bifidobacterium animalis subsp Lactis, Streptococcus thermophiles, Lactobacillus bulgaricus, and Lactococcus lactis subsp Lactis) can modulate the responsiveness of an extensive brain network in healthy women Tillisch K et al., Gastroenterology 2013;144:
22 Systematic review: probiotics in the management of gastrointestinal symptoms in clinical practice an evidence-based international guide Symptom Probiotics Agreement % Grade of evidence Overall IBS Bifidobacterium bifidum MIMBb75, B. Longum subsp. infantis 35624, Escherichia coli DSM17252, investigative combinations, marketed combinations 100 High IBS-C B. animalis subsp. lactis DN Low IBS-D B. longum subsp. infantis 35624, marketed combinations 100 Moderate Statement Specific probiotics help relieve overall symptom burden in some patients with IBS However No claims approved by European Food & Health Safety Authority (EFSA) Hungin APS et al,. Aliment Pharmacol Ther 2013; 38:
23 Rifaximin for patients with IBS without constipation % Responders Primary End-point Placebo Rifaximin * *P<0.001 Two identically designed, phase 3, multicentre, double blind, placebo-controlled studies (TARGET 1 and TARGET 2) in 1260 patients with IBS Pimentel et al., N Engl J Med 2011;364:22-32
24 IBS-D Rifaximin Re-Treatment Study (TARGET 3) Lembo A et al., Gastroenterology 2016;151:
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26 IBS patient s experiences, suffering & life thru artwok
27 Leonardo da Vinci, La Gioconda, , Musèe du Louvre, Paris
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