Gut Microbes: Systemic Disease. Mark Pimentel, MD. Cedars-Sinai Medical Center. Mark Pimentel, MD, FACG

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1 Gut Microbes: Role in Health, IBS, GI and Systemic Disease Mark Pimentel, MD Director, GI Motility Program Cedars-Sinai Medical Center 1

2 Lacks cellulase cannot breakdown cellulose Depends completely on microbial flora to digest cellulose 50 billion bacteria per 1mm of rumen Anerobic enviroment Byproduct: Methane Kill ALL GI microbes Kill SOME GI microbes 2

3 Number of Cells 100x more Bacterial cells Bacterial Cells Human Cells Types of Cells Clostridium Lactobacillus Methanobrevibacter E.coli 500 different species Enterococcus 3

4 Types of Cells Clostridium Lactobacillus Methanobrevibacter E.coli 500 different species Enterococcus Micro-environments Air pocket Intestinal Wall Mucus Layer Oxygen/CO 2 / Nitrogen/H 2 Liquid Phase Anaerobic Solid Phase-Stool 4

5 SIBO- What is it? Duodenum Small Bowel ~ 0 cfu/ml Colon cfu/ml Cecum Jejunum Ileum 10 1 cfu/ml 10 2 cfu/ml 10 3 cfu/ml Breath Testing is abnormal in IBS Forest plot of all age-sex matched studies Type of % % Author Breath Test OR (95% CI) CI) Weight Weight Grover sucrose 2.29 (0.89, 5.87) 5.87) Lupascu Pimentel glucose lactulose (3.52, 33.71) 33.71) (5.29, 80.69) 80.69) Parodi glucose 4.30 (1.24, 14.98) 14.98) Scarpellini Collin lactulose lactulose l (7.35, 80.15) 80.15) (6.55, 49.71) 49.71) Overall (I-squared = 67.9%, p = 0.008) 9.64 (4.26, 21.82) 21.82) NOTE: Weights are from random effects analysis Shah, et al Dig Dis Sci,

6 Is Breath Testing Accurate? Orocecal Transit= 5% in cecum Tc + Lactulose ppm Issues -95% in small bowel -Time to peak fermentation -Is 0.5g of lactulose enough Yu, et al. Gut 2011 Is Breath Testing Accurate? 37ºC Hydrogen (ppm) Stool 0.5g Lactulose + PBS Winter, et al. ACG,

7 Is Breath Testing Accurate? 99Tc + Lactulose Orocecal Transit= 5% in cecum 60 minutes ppm Winter, et al. ACG 2012 Small Bowel Culture in IBS ercent of Subjects P P<0.05 P< % 24% 12% 4% >10,000 coliforms >5,000 coliforms Control IBS N=165 IBS, 26 controls Posserud, et al, Gut, 2007;56:

8 Mechanism: SIBO = IBS (Culture) ercent of Subjects % 60% P= Non- D-IBS D-IBS P 10 0 N=77 non-d-ibs, N=35 D-IBS Pyleris, et al. DDS, 2012 Mechanism: SIBO = IBS (qpcr) DUODENAL ASPIRATES 6 P<0.05 acteria quantity Log10 B P<0.05 Healthy Not-IBS IBS 0 E. coli Klebsiella N=77 non-d-ibs, N=35 D-IBS Pyleris, et al. UEGW,

9 Risk of PI-IBS Increases 7-fold After Infectious Gastroenteritis* Protective Effect Study (year/bacteria) Ji (2005/Shigella) Mearin (2005/Salmonella) Wang (2004/Unspecified) Okhuysen (2004/Unspecified) Cumberland (2003/Unspecified) llnyckyj (2003/Unspecified) Parry (2003/Bacterial NOS) Rodriguez (1999/Bacterial NOS) Pooled estimate t Increased Risk OR OR (95% Cl) 2.8 ( ) 8.7 ( ) 10.7 ( ) 10.1 ( ) 6.6 ( ) 2.7 ( ) 9.9 ( ) 11.3 ( ) 73( ( ) 1) 9.8% IBS in cases vs 1.2% IBS in controls *Systematic review of 8 studies involving 588,061 subjects; follow-up ranged from 3 to 12 months. Halvorsen HA et al. Am J Gastroenterol. 2006;101: Characteristics of Acute Illness Identify Patients at Risk for PI-IBS 10 P=.000 OR for IBS After Acute Gastroenteritis* P=.029 P=.006 P=.013 P=.001 P= Age Female Diarrhea >7 d Bloody Stools Abdominal Cramps Weight Loss >10 lbs *Identified from multiple logistic regression analysis from 2069 participating in the Walkerton Health Study. Marshall JK et al. Gastroenterology. 2006;131:

10 Salmonella and PI-IBS Percent with Relative Risk IBS at 1 year (CI) Irritable Bowel 12% 5.2 ( ) Non-ulcer dyspepsia 15% 7.8 ( ) Nausea was a risk factor for NUD Mearin, et al. Gastro, 2006 NORMAL ACUTE GASTROENTERITIS 90% 10% COMPLETE ~GENETIC SUSCEPTIBILIITY RECOVERY ~ABNORMAL HOST RESPONSE ~TOXIN INTENSITY FUNCTIONAL POST-INFECTIOUS GI DISEASES? IBS 10

11 Post-infectious IBS = IBS Shah, et al J Neurogastroenterol Motil, 2012 Mechanism: Rat Model (SIBO = IBS) n=33 n=33 C. jejuni Stool = Campy- No Acute Gastroenteritis Stool = Campy+ Acute Gastroenteritis 3 Months After Recovery Stool Consistency Evaluation Stool = Campy- Recovery Bacterial Quantitation by RT-PCR of Duodenum, Jejunum, Ileum Pimentel, et al. Dig Dis Sci,

12 Mechanism: Rat Model (SIBO = IBS) Percent of rats with SI IBO % 21% 17% 6.7% Duodenum Jejunum ileum Total 3 months after Campylobacter jejuni infection Pimentel, et al., Dig Dis Sci, 2008 ICC and CDT toxin C. jejuni E. Coli Salmonella Shigella Cytolethal Distending Toxin (CDT) All cause IBS A B Cell G2 Phase Unknown Entry Arrest 12

13 IBS Mechanism/CdtB causes IBS Campy CDT- P-value Rifaximin P-value Stool % wet weight 60.1± ± ± Consistency 1.51± ±0.27 < ±0.30 < Standard Deviation 8.4± ±2.4 < ±2.3 < Proportion with normal bowel form all 3 days 17.8% 50.0% <0.01 OR= % < OR=6.7 Note: No significant differences were seen between CDT- and Rifaximin treated arms of the study. Morales, et al. J Neurogastroenterl Motil, 2012 Pimentel, et al. Dig Dis Sci, 2011 IBS Mechanism/Nerve Damage CONTROLS 20x Jee, et al. World J Gastroenterol,

14 IBS Mechanism/Nerve Damage Campy with SIBO 20x Jee, et al. World J Gastroenterol, 2010 IBS Mechanism/Nerve Damage Campy no CdtB 20x Jee, et al. World J Gastroenterol,

15 IBS Mechanism/Autoimmune to Nerves RAT MODEL Pre-immune serum (CONTROL) wab (ANTI- CDTB) Rat Ganglia Rat ICC ckit + wab wab Anti-CdtB is Anti-Glial Anti-CdtB is anti-icc 15

16 IBS Mechanism/Nerve Damage GANGLIA OF HUMAN ILEAL SECTIONS wab S-100 S wab Anti-CdtB is also Anti-glial in humans IBS Mechanism/Sequence/Main Food Poisoning Bacterial Toxin Autoimmunity Gut Nerve Damage Bacterial Overgrowth IBS 16

17 Primary Outcome (4 weeks after Tx) Efficacy Outcome Study Primary SGA-IBS Weekly Odds Ratio (95% CI) p-value (1.10,2.12) (1.05,2.01) (1.18,1.88) Key Secondary IBS Bloating Weekly (1.16,2.27) (1.08,2.06) (1.23,1.96) Other Secondary SGA-IBS Daily IBS Bloating Daily IBS Ab Pain Daily (1.26,2.47) (1.13,2.24) (1.28,2.04) < (1.01,1.97) (1.26,2.44) (1.21,1.92) (1.05,2.02) (1.05,2.03) (1.13,1.78) FDA Proposed Ab Pain & Stool Daily (FDA) Ab Pain Daily (FDA) Stool Consist. Daily (FDA) (1.02,1.92) (1.12,2.13) (1.17,1.84) (1.08,2.03) (1.06,2.00) (1.17,1.83) (1.25,2.59) (1.12,2.21) (1.31,2.14) < Pimentel, et al NEJM, Odds Ratio and 95% CI Favors Placebo Favors Rifaximin Durability of Response (3 months) Efficacy Odds Study (95% CI) p-value Outcome Ratio 1.35 (1.00, 1.82) Primary SGA-IBS 1.52 (1.13, 2.03) Weekly 1.44 (1.17, 1.77) Key Secondary IBS Bloating Weekly (0.95, 1.73) (1.16, ) (1.15, 1.75) Other Secondary SGA-IBS Daily IBS Bloating Daily IBS Ab Pain Daily (1.18, 2.18) (1.09, 1.99) (1.20, 1.83) (1.10, 2.04) (1.24, 2.25) (1.24, 1.89) (1.00, 1.83) (1.01, 1.81) (1.06, 1.61) < FDA Proposed Ab Pain & Stool Daily (FDA) Ab Pain Daily (FDA) Stool Consist. Daily (FDA) (1.01, 1.83) (1.08, 1.92) (1.14, 1.72) (0.98, 1.75) (1.03, 1.83) (1.09, 1.64) (1.24, 2.33) (1.09, 2.00) (1.27, 1.97) < Odds Ratio and 95% CI Pimentel, et al NEJM, 2011 Favors Placebo Favors Rifaximin 17

18 Antibiotic Resistance Conventional Antibiotics Recurrence SIBO 40% Eradicated 25% Eradicated Rifaximin Recurrence 70% Eradicated 100% Eradicated Yang, et al. Dig Dis Sci, Harm with Drugs in IBS DRUG NNT NNH Benefit to Harm Desipramine Alosetron Rifaximini i NNT=Number needed to treat. NNH=Number needed to harm. NNH=number of subjects treated for one subject to withdraw due to an adverse event that was greater than the equivalent in placebo. Shah, et al. Am J Med,

19 Harm with Drugs in IBS Drug Desipramine Alosetron Rifaximin Excess of Placebo Only Dry mouth, flushing, constipation, insomnia, decreased appetite, palpitations Constipation, Abdominal pain/discomfort Bad Taste in mouth Shah, et al. Am J Med, in press. Compared to other Drugs +12.5% +13% +10% -16% -17% Net value -3.5% -4% +10% Shah, et al. DDW,

20 Retreatment with Rifaximin Percent of subjects who respo onded /40 17/18 54/65 6/7 3/4 1st RTX 2nd RTX 3rd RTX 4th RTX 5th RTX Pimentel, et al. Dig Dis Sci, Retreatment with Rifaximin before an number of months relapse Media N=63 Range= mo N=46 Range=1-45 months N=21 Range=2-37 mo N=6 Range=1-18 mo N=4 Range=2-24 mo 1st RTX 2nd RTX 3rd RTX 4th RTX 5th RTX Note: RTX is the retreatment number. In this figure, the time (in months) refers to the number of months of wellness before the treatment number in each column. For example, for 1 RTX, it would be the number of months the patient was well after the first rifaximin administration and prior to the 1 RTX. Note: Rare patients were missing accurate dates and thus were not included here. Note: The median is a more accurate depiction of the duration of benefit since the ranges were wide. Pimentel, et al. Dig Dis Sci,

21 Complexities of Gas Production Methane Hydrogen 70 Hydrogen Producers H 2 M illio n P a r t s P e r M Methane 10 Producers 0 4H 2 1CH Time (Minutes) 70 on Parts Per Milli Time (Minutes) H 2 H 2 S Producers 5H 2 1H 2 S P a rts P e r M illio n Time (Minutes) Methane- Important in C-IBS Meta-analysis of studies Author Year OR (95% (95% CI) CI) % % Weight Weight Peled 1987 Fiedorek 1990 Pimentel 2003 Pimentel 2003 Majewski 2007 Bratten 2008 Parodi 2009 Hwang 2009 Attaluri 2009 Overall (I-squared = 64.6%, p = 0.004) 0.83 (0.20, (0.20, 3.56) 3.56) 4.32 (1.60, (1.60, 11.68) 11.68) 5.58 (2.22, (2.22, 14.03) 14.03) (2.48, (2.48, ) ) 1.81 (0.70, (0.70, 4.67) 4.67) 2.22 (1.14, (1.14, 4.33) 4.33) 1.89 (0.79, (0.79, 4.51) 4.51) (8.73, (8.73, ) ) 3.70 (2.06, (2.06, 6.66) 6.66) 3.51 (2.00, (2.00, 6.16) 6.16) NOTE: Weights are from random effects analysis Kunkel, et al. Dig Dis Sci,

22 Methane as a diagnostic test C-IBS Not C-IBS Methane No Methane Sensitivity=0.92, Specificity=0.81, Positive Predictive Value=0.79, Negative Predictive Value=0.93 Pimentel, et al Dig Dis Sci Methanobrevibacter smithii- the cause of constipation Hydrogen Producing IBS Stool Methane Producing IBS Stool Kim, et al. DDW,

23 Methanobrevibacter smithii or methane as a test- dictates treatment Percen nt eradicating CH4 CH4 Eradication Clinical Response 100 P= P= Neomycin Rifaximin Neo+Rifax Percent with Clinical Response Neomycin Rifaximin Neo+Rifax Low, et al. Gastroenterol and Hepatol 2010 IBS/SIBO WORKSHEET 3.0 Molecular Mimicry Acute Gastroenteritis Immune response Anti-CDT Ab Other Ab React to neural elements/myenteritis Reduced DMP-ICC Immunity to Infection STRESS PROKINETIC SMALL BOWEL COLON CRF DYSMOTILITY METHANE SIBO/ IBS HYDROGEN SLOW TRANSIT C-IBS ANTIBIOTIC D- AND M-IBS 23

24 Lessons from the Germ Free Mouse Reduced organ weight Reduced cardiac output Reduced O2 consumption Increased food intake Reduced mediastinal and sympathetic lymph nodes Reduced mucosal associated lymphoid tissue Reduced serum immunoglobulins Tannaock, Am J Clin Nutrition 2001 Defense of Host by detecting and sampling Nutrients for Host Information for Host immune development IMMUNE REGULATION GUT FLORA DEFENSE AGAINST PATHOGENS NUTRITION/ METABOLISM 24

25 Specific Host Microbe Interaction Modulate Immune Response Modulate other Bacteria Impact Appetite Regulation Digest the Indigestible Vitamin Production and Metabolism Produce Peptide Mediators Gut Microbes Generate Heat and change BMR Gas Production and Effects Inflammatory Response Germ Free Animals Germ Free -Low body weight -Increased oral intake + = Add Fecal Flora Gain 60% more body weight with reduced oral intake Backhed F Proc Natl Acad Sci U S A Nov 2 101(44)

26 Fecal Transplant Germ Free -Low body weight -Increased oral intake + = Add Fecal Flora (Bacteroidetes>Firmicutes) Gain weight with reduced oral intake Germ Free -Low body weight -Increased oral intake + = Add Fecal Flora from Obese mice (Firmicutes>Bacteroidetes) Far greater weight gain Turnbaugh Nature 444, (21 December 2006) Energy lost in stool Bomb calorimetry of the fecal gross energy content (kcal g -1 )of lean (+/+) and obese (ob/ob) conventionally raised ( *P<0.05, ***P<0.001) In addition ob/ob cecal microbiota = increased Methanogenic archaea Turnbaugh Nature 444, (21 December 2006) 26

27 Methanogen Model No Methanobrevibacter smithii Indigestible Substrate H 2 Intoxicates self Methanobrevibacter smithii Indigestible Substrate H 2 H 2 H 2 H 2 CH 4 Energy Digestible Substrates ENERGY DIGESTIBLE SUBSTRATE = Syntroph = Methanogen Body Mass Index and PCOS Mathur R et al Digestive Disease Sciences. 55(4):1085,

28 Percent Body Fat and PCOS Mathur R, et al Digestive Disease Sciences. 55(4):1085, 2010 Methane in Obese Patients Mathur et al, Gastro and Hep,

29 Methane in Non-obese Patients BMI Multivariate analysis controlling for age, sex, diabetes, anti depressant and other confounding (P<0.001) Normal Breath test N=792 Positive Hydrogen Breath Test Only Methane Methane and Hydrogen Positive Mathur R, et al. JCEM in press 2013 Methane and Glucose Metabolism Glucose AUC (mg/dl) 800 n= No methane P=0.03 Methane 29

30 M smithii and Body Weight in New Animal Model Mathur R, et al. Obesity 2013 Conclusions The basis for IBS may be acute gastroenteritis and SIBO Antimicrobial therapies benefit IBS subjects Autoimmunity may play a role in IBS and gut microbe changes Bacteria are important in obesity Methanogens have a significant future role in constipation and metabolic syndrome 30