the role of the gut microbiome on functional bowel...
TRANSCRIPT
William D. Chey, MD, FACG
The Role of the Gut Microbiome on Functional Bowel Symptoms
William D. Chey, MD, FACGTT Nostrant Professor of Medicine
University of Michigan Health SystemAnn Arbor, Michigan
Factors Influencing the Gut Microbiome
Parkes et al. Am J Gastroenterol 2008
2016 ACG Governors/ASGE Best Practices Course Copyright 2016 American College of Gastroenterology
Page 1 of 15
William D. Chey, MD, FACG
Talley & Fodor. Gastroenterol 2011;141:1555
Dysbiosis and IBS
• Dysbiosis
• Genetic Susceptibility
• Environmental Insults
Altered Permeability
Increased Antigen
Presentation
Mast Cell Activation
ExtraGI
Symptoms
Systemic Cytokines
& Chemokines IBS
Altered Enteric
Neuronal & Smooth Muscle
Function
Functional/Medical Foods?
Antibiotics?Probiotics?Prebiotics?Synbiotics?
Diet? FMT?
The Gut Microbiota: A Potential IBS Treatment Target
2016 ACG Governors/ASGE Best Practices Course Copyright 2016 American College of Gastroenterology
Page 2 of 15
William D. Chey, MD, FACG
Functional/Medical Foods?
Antibiotics?Probiotics?Prebiotics?Synbiotics?
Diet? FMT?
The Gut Microbiota: A Potential IBS Treatment Target
Food: Metabolic & Functional Consequences
2016 ACG Governors/ASGE Best Practices Course Copyright 2016 American College of Gastroenterology
Page 3 of 15
William D. Chey, MD, FACG
Low-FODMAP Diet vs. Australian Diet in IBS
30 IBS patients and 8 HVs: 1 week baseline followed by 21 days of low-FODMAP diet or typical Australian diet before crossing over to other diet. Significant benefits for overall IBS symptoms, bloating, pain, and wind (p<0.001). Benefits for King’s Stool Chart only for IBS-D (p<0.04)
Halmos, et al. Gastroenterology 2014; 146:67
VAS(0-100 mm)
20
60
-7 21
40
p<0.001
7
20
60
-7 21
40
7
Day Day
BaselineTypical Aust.Low FODMAP
1414
IBS Healthy Contols
Halmost et al. Gut 2015;64:93-100
FODMAP Effects on the Microbiome
• Low FODMAP diet: higher fecal pH – 7.37 [7.23-7.51] vs. 7.16 [7.02-7.3]; P=.001
• LFD and Australian diets: similar SCFA levels
• LFD: increased microbial diversity and reduced total bacterial abundance – 9.63 [9.53-9.73] vs. 9.83 [9.72-9.93] log10 copies/g; P<.001
• Australian diet – increased butyrate-producing Clostridium cluster XIVa (P<.001) and mucus-
associated Akkermansia muciniphila (P<.001), but decreased Ruminococcus torques.
• “The functional significance and health implications of such changes might lead to caution about reducing FODMAP intake in the longer term”
• “The low FODMAP diet should not be recommended for asymptomatic populations.”
2016 ACG Governors/ASGE Best Practices Course Copyright 2016 American College of Gastroenterology
Page 4 of 15
William D. Chey, MD, FACG
Chumpitazi et al. Aliment Pharmacol Ther 2015; 42: 418–427
FODMAP Microbiome Biomarkers and Response to the Low-FODMAP Diet
• Thirty-three children with IBS completed the study.
• Less abdominal pain occurred during the low FODMAP diet vs. typical U.S. childhood diet
• Responders were enriched at baseline in taxa with known greater saccharolytic metabolic capacity
– e.g., Bacteroides, Ruminococcaceae, Faecalibacterium prausnitzii
• Responders also enriched at baseline for 3 Kyoto Encyclopedia of Genes and Genomes orthologues
– two relate to carbohydrate metabolism
The Gut Microbiota: A Potential IBS Treatment Target
Functional/Medical Foods?
Antibiotics?Probiotics?Prebiotics?Synbiotics?
Diet? FMT?
2016 ACG Governors/ASGE Best Practices Course Copyright 2016 American College of Gastroenterology
Page 5 of 15
William D. Chey, MD, FACG
Interfere with growth or survival of
bacteria in gut lumen
Improve mucosal barrier function
and mucosal immune system
Affect systemic immune system
Possible Mechanisms of Probiotic Activity
Adapted from Rijkers GT, et al. J Nutr. 2010;140:671S-676S
Utility of Probiotics for IBS: A Statistical Review and Meta-analysis
• Forty-three RCTs included• RR of IBS symptoms persisting with probiotics vs placebo
was 0.79 (95% CI 0.70-0.89)– Probiotics had beneficial effects on global IBS, abdominal pain,
bloating, and flatulence scores– Effects of individual species or combinations marginal to non-
existent– NNT = 7 (95% CI 4-12.5)– NNH - 35
Ford AC, et al. Am J Gastroenterol 2014; 109:S2
2016 ACG Governors/ASGE Best Practices Course Copyright 2016 American College of Gastroenterology
Page 6 of 15
William D. Chey, MD, FACG
Proportion Reporting Adequate Reliefof IBS Symptoms
*p=.027
*p=.004
N=88/60 N=91/49
B. lactis CNCMI-2494 (1.25×1010 cfu), S. thermophilus & L. bulgaricus (1.2×109 cfu)Roberts et al. BMC Gastroenterology 2013, 13:45
Pro
po
rtio
n o
f R
esp
on
der
s(S
GA
)
L. paracasei F19, L acidophilus La5 & Bif Bb12 in doses of 3x109 to 7x109 ; 4 capsules qd
Begtrup et al. Scand J Gastro 2013, 48:1127
*P = .027N=88/60 N=91/49
20
0
40
60
80
100 Treatment Follow-up
Months
Placebo (64)
Probiotic (67)
3 6 3 6
No significant differences at 6 months
Ad
equ
ate
Rel
ief
of
IBS
Proportion Reporting Adequate Reliefof IBS Symptoms
2016 ACG Governors/ASGE Best Practices Course Copyright 2016 American College of Gastroenterology
Page 7 of 15
William D. Chey, MD, FACG
The Gut Microbiota: A Potential IBS Treatment Target
Functional/Medical Foods?
Antibiotics?Probiotics?Prebiotics?Synbiotics?
Diet? FMT?
MeasureOutcomes
Response rates (%)Weight ARR NNT
Rifaximin Placebo
Sharara 27.0 9 1.4% 18% 5.6
Pimental 32.5 9 1.6% 23.5% 4.3
Lembo 52.3 44.2 25.2% 8.1% 12.3
Target 1 40.8 31.2 34.9% 9.6 10.4
Target 2 40.6 32.2 36.8% 8.4 11.9
Overall 43.3 34.2 100% 9.1 11.0
Heterogeneity: �2=5.26, df=4 I2=24% p=0.26Menees et al. AJG 2012;107:28
Rifaximin for Global Improvement in IBS: A Meta-analysis
2016 ACG Governors/ASGE Best Practices Course Copyright 2016 American College of Gastroenterology
Page 8 of 15
William D. Chey, MD, FACG
Rifaximin (n=1103) Placebo (n=829)
Any TEAE 52.5% 52.6%
Serious TEAE 1.5% 2.2%
TEAE resulting in discontinuation
2.0% 1.7%
Any GI TEAE 12.2% 12.2%
Nausea 3.1% 2.3%
Abdominal pain 2.4% 2.5%
Diarrhea 1.4% 1.3%
Vomiting 1.1% 0.6%
Any Infection TEAE 8.5% 9.5%
C. difficile colitis 0% 0%Schoenfeld, et al. APT 2014;39:1161
Pooled Safety Analysis of Rifaximin for Non-C IBS
• Data analyzed from 2 phase 3 and 1 phase 2b trials of rifaximin
TARGET 3: Study Design
Screening Open-Label Rifaximin 550 TID x 2 weeks
2w RFX 4w f/u
Non-Responders withdrawn and proceed to EOS
ObservationPhase
Up to 18w
2nd RepeatTreatment
4w f/u
4w f/u
Repeat Treatment
ObservationPhase
6w
6w
1st RepeatTreatment
2w RFX 4w f/u
4w f/u2w PBO
Ran
dom
ize
1:1
2w PBO
End
Follow up
4 W7-13 d PBO
2w RFX
Chey et al. DDW 2015
Study Day 1
Primary Evaluation Period
Open-label Treatment Phase Double-blind Treatment Phases
Responders followed; only
patientswith relapserandomized
2016 ACG Governors/ASGE Best Practices Course Copyright 2016 American College of Gastroenterology
Page 9 of 15
William D. Chey, MD, FACG
TARGET 3n = 2579
Experienced Relapse n = 692 (64%)*
No Relapsen = 382 (36%)
Rifaximin n = 328
Placebon = 308
Ope
n-La
bel
Doub
le-b
lind
Placebon = 283
Rifaximinn = 295
TARGET 3 - Subject Disposition
19
* 56 (5%) not randomized due to enrollment closure
Obs
erva
tion
n = 2331
1st Repeat Treatment
2nd Repeat Treatment
FDA Respondern = 1074 (46%)
FDA Non-Responder n = 1257 (54%)
Discontinued Earlyn = 248
Lembo A et al. American College of Gastroenterology Annual Meeting. Program no. 45.
TARGET 3: Response to Rifaximin Retreatment
p=.04p=.02
2016 ACG Governors/ASGE Best Practices Course Copyright 2016 American College of Gastroenterology
Page 10 of 15
William D. Chey, MD, FACG
Chey, et al. DDW 2015
Improvement in IBS-D Symptoms During First and Second Double-Blind Repeat Treatment Phases
1st Repeat Treatment 2nd Repeat Treatment
EndpointRFX
(n=328)PBO
(n=308)p-value
RFX (n=295)
PBO (n=283)
p-value
Abdominal Pain 53.0% 43.8% 0.0212 52.5% 44.9% 0.0549
Stool Consistency
45.1% 37.0% 0.0241 45.1% 38.5% 0.0799
Urgency 48.5% 39.6% 0.0251 46.8% 38.5% 0.0355
Bloating 50.3% 42.2% 0.0345 47.1% 35.0% 0.0017
Antibiotics for IBS: Points to Consider
• Reasons for symptom improvement remain unclear– SIBO vs. alteration of colonic microbiome/fermentation?
• Relative benefits of empiric vs. breath test guided therapy
• Benefits of other antibiotic therapies unclear
• Benefits appear transient– How can we predict who will respond?
– How can we increase the durability of response?
• Potential consequences of repeated, widespread antibiotic use?
Chey. AGA Perspectives 2009;4:5-8
2016 ACG Governors/ASGE Best Practices Course Copyright 2016 American College of Gastroenterology
Page 11 of 15
William D. Chey, MD, FACG
The Gut Microbiota: A Potential IBS Treatment Target
Functional/Medical Foods?
Antibiotics?Probiotics?Prebiotics?Synbiotics?
Diet? FMT?
Crowe KM, J Acad Nutr Diet 2013;113:1096http://www.fao.org/docrep/004/y2775e/y2775e08.htm
Functional Foods
• “A foodstuff that provides a health benefit beyond basic nutrition, demonstrating specific health or medical benefits, including the prevention and treatment of disease” (Food & Agricultural Organization, United Nations)
• Can be categorized as:
– Conventional foods that contain bioactive components
– Foods enriched or fortified with bioactive food compounds
– Synthesized food ingredients such as indigestible oligosaccharides that provide a health benefit, or serve as precursors to compounds that provide a health benefit
2016 ACG Governors/ASGE Best Practices Course Copyright 2016 American College of Gastroenterology
Page 12 of 15
William D. Chey, MD, FACG
Weinstock, Open Journal of Gastroenterology, 2014, 4, 329
Medical Foods
• “a food…formulated to be consumed or administered enterally under the supervision of a physician and which is intended for the specific dietary management of a disease or condition for which distinctive nutritional requirements, based on recognized scientific principles, are established by medical evaluation.” (US FDA)
• Serum-derived bovine immunoglobulin isolate
• >50% immunoglobulin
• Survives exposure to gastric acid
• Binds bacterial components in the small intestine
• Possible effects on permeability, immune function, and gut microbiome
Open label treatment with SBI 5 grams BID
SBI = serum bovine IgLBT = lactulose breath testWeinstock, Open Journal of Gastroenterology, 2014, 4, 329
Serum Bovine Ig/Protein Isolate for IBS-D & IBS-M
Pro
po
rtio
n w
ith
Go
od
Res
po
nse
2016 ACG Governors/ASGE Best Practices Course Copyright 2016 American College of Gastroenterology
Page 13 of 15
William D. Chey, MD, FACG
The Gut Microbiota: A Potential IBS Treatment Target
Functional/Medical Foods?
Antibiotics?Probiotics?Prebiotics?Synbiotics?
Diet? FMT?
Pinn & Brandt. ACG Annual Meeting 2013
Fecal Microbial Transplant for IBS
• 13 IBS patients with refractory disease – 54% women, average age 45 years (range: 23-75 years)
– Average time from FMT to data collection 11 months (6-18 months)
– Improved symptoms = 70%
– Abdominal pain = 72%
– Bowel habit = 69%
– Bloating = 50% and flatus = 45%
– Improved quality of life = 46%
2016 ACG Governors/ASGE Best Practices Course Copyright 2016 American College of Gastroenterology
Page 14 of 15
William D. Chey, MD, FACG
IBS Treatments Aimed at the Gut Microbiota: Summary
• Agents that influence the gut microbiota offer a potential target in patients with IBS
• Specific probiotics may improve IBS symptoms in a subset of patients
• Prebiotics remain to be adequately tested in clinical trials
• Antibiotics offer short term benefits to a subset of IBS sufferers
• Medical Foods and FMT require evaluation in RCTs
• Important questions remain regarding which patients are most likely to benefit from these strategies and whether they are safe if used over extended periods of time
Michigan Nutrition Center for Digestive Diseases
2016 ACG Governors/ASGE Best Practices Course Copyright 2016 American College of Gastroenterology
Page 15 of 15