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 (1088 2017)
Microbiota and IBS: what is the link? New diagnosis of IBS after infectious gastroenteritis (Post infectious IBS) Spiller R, Garsed K. Gastroenterology 2009;136:1979-88 Antibodies anti-flagellin and human β-defensin-2 increased in IBS Cremon C, et al. Expert Rev Mol Diagn 2010;10:389-93 Qualitative and quantitative changes in intestinal microbiota composition of IBS Simrén M, Barbara G, et al. Gut 2013;62:159-76 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
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;136:1979-88
Salmonella outbreak in Bologna (October 19, 1994) Tuna sauce contaminated (Salmonella enteritidis D) 36 schools in the Bologna area 19 ottobre 1994 1811 subjects infected (acute symptoms) 1684 pupils (93%) children 3-10 yrs 127 teachers or other school employees (7%) adults 19-59 yrs Positive fecal cultures decreased from 100% to 1.5% at 3 months post-infection Barbara et al., Aliment Pharmacol Ther 2000;14:1127-31
Early life salmonellosis and IBS in adulthood Salmonella outbreak in Bologna (1994-2010) Prevalence of IBS (%) 44/189 (23.3%) * 75/204 (36.8%) Non-exposed Exposed *P = 0.004 OR = 1.92 (95% C.I.= 1.23-2.98) Cremon C. et al., Gastroenterology 2014;17:69-77
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 * 52 44 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;20:1110-8 Cremon et al., Expert Rev Gastroenterol Hepatol 2008;2:735-40
TLR-4 mrna quantification Best cutoff range between IBS and HC: 1.063-1.149 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: 1.536-1.653 1,0 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
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
Functional and phylogenetic profiles of human gut microbiome Phylum Class Order Family Genus Species Arumugam M et al., Nature 2011;473:174 180
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 = 0.29-0.43) -1.5 Axis1 (50%) 1.5 Rajilić-Stojanović et al., Gastroenterology 2011;141:1792-801
Irritable bowel syndrome subtype defined by species-specific alterations in faecal microbiota Sequenced 30.000 16S 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 2012,61:997-1006
Gut microbiota composition and host-microbe cross-talk Jalanka-Tuovinen J et al., Gut 2014;63:1737-45
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
Intestinal microbiota and IBS severity Tap J et al., Gastroenterology 2017;152:111 123
Strategies for modifying gut microbiota Fecal microbial transfer Simrén M et al., Gut 2013;62:159-76
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
Bifidobacterium lactis DN-173 010 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
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 150 100 50 0 * *P=0.001 B. infantis L. salivarius Placebo Weeks O Mahony et al., Gastroenterology 2005;128:541-51
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;144:1394-401
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-173 010 80 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: 864 86
Rifaximin for patients with IBS without constipation % Responders 50 40 30 20 10 0 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
IBS-D Rifaximin Re-Treatment Study (TARGET 3) Lembo A et al., Gastroenterology 2016;151:1113-21
IBS patient s experiences, suffering & life thru artwok
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