GUT MICROBIOME: IMPACT ON CLINICAL PRACTICE AMERICAN COLLEGE OF PHYSICIANS MATTHEW BECHTOLD MD, FACP, FASGE, FACG, AGAF DIVISION OF GASTROENTEROLOGY UNIVERSITY OF MISSOURI – COLUMBIA SEPTEMBER 15, 2017
Welcome message from author
This document is posted to help you gain knowledge. Please leave a comment to let me know what you think about it! Share it to your friends and learn new things together.
Transcript
GUT MICROBIOME: IMPACT ON CLINICAL PRACTICE
AMERICAN COLLEGE OF PHYSICIANS
MATTHEW BECHTOLD MD, FACP, FASGE, FACG, AGAF
DIVISION OF GASTROENTEROLOGY
UNIVERSITY OF MISSOURI – COLUMBIA
SEPTEMBER 15, 2017
BACKGROUND
IDEOLOGY
GERM
THEORY
DISEASE
MODIFIERS
Young VB. BMJ 2017
BACKGROUND
Young VB. BMJ 2017
RESEARCH ARTICLES ON MICROBIOME
Young VB. BMJ 2017
Qin J, et al. Nature 2010
• Microbiome:
– Microbes and environment which they live
• Includes microbiota, immune components, epithelium,
and products of microbiota and host
• Microbiota:
– Micro-organisms present in specific site
– Gut has 1000-1200 bacterial species and at
least 1014 bacteria
– Most in the colon
What is the
microbiome?
Cockburn DW, et al. J Mol Biol 2016
Wong JM, et al. J Clin Gastroenterol 2006
Haiser HJ, et al. Science 2013
Young VB. BMJ 2017
What does the
microbiota do?
CATABOLISM
BIOCONVERSION OF COMPLEX MOLECULES
SYNTHESIS OF COMPOUNDS
AUGMENT HOST PATHWAYS
DRUG METABOLISM (DIGOXIN, 5-ASA)
FERMENT RESISTENT POLYSACCHARIDES (NON-
DIGESTABLE STARCH) TO SHORT CHAIN FATTY
ACIDS
ENERGY SOURCE FOR COLONOCYTES
ANTI-INFLAMMATORY
ANTITUMORBut wait, there’s more…
Ridlon JM, et al. J Lipid Res 2006
Wahlstrom A, et al. Cell Metab 2016
Fiorucci S, et al. Trends Mol Med 2015
CONJUGATED BILE ACIDS
UNCONJUGATED BILE ACIDS
SECONDARY BILE ACIDS
BILE ACIDS
FARNESOID X RECEPTORS
(FXRs)
Nuclear hormone receptors
CHOLESTEROL AND LIPID
METABOLISM
Microbially-mediated conversion
Rooks MG, et al. Nat Rev Immunol 2016
Bonder MJ, et al. Nat Genet 2016
Sivan A, et al. Science 2015
IMMUNE SYSTEM
• Increases development and activity of
immune system
• Increase mucus and nutrient receptors in
mucosal epithelium
• Alter antitumor responses to
immunotherapies affecting cytotoxic T
lymphocyte associated protein 4 or
programmed cell death 1 (PD-1)
Vollaard EJ, et al. Antimicrob Agents Chemother 1994
Lawley TD, et al. Immunology 2013
PROTECTION
• Colonization resistance to pathogenic
organisms:
– Direct competition for nutrients
– Short chain fatty acid production
– Immunologic effects on host
MICROBIOME IN
SPECIFIC DISEASES
Young VB. BMJ 2017
DEFINITIONS
PREBIOTIC• NUTRIENT FAVORING THE
GROWTH AND
PREDOMINANCE OF
BENEFICIAL MICROBES
• MOST ARE
CARBOHYDRATES THAT
HUMANS CANNOT BREAK
DOWN BUT MICROBIOTA
CAN
PROBIOTIC• “LIVE MICRO-ORGANISMS”
THAT INTEND TO HAVE A
HEALTH BENEFIT TO THE
HOST
• ORIGINALLY BASED ON
FERMENTED FOOD
PRODUCTS
• NOW, BASED MORE ON
MICROBIOME OF HEALTHY
PEOPLE
INFECTIOUS
DISEASES
Pillai A, Nelson R. Cochrane Database Syst Rev 2009
Boyle RJ, et al. Am J Clin Nutr 2006
C. DIFFICILEPROBIOTICS
29/38 30/31
META-ANALYSIS
4 RCTs
n=336
TREATMENT OF INITIAL OR RECURRENT CDADADULTS ON VANCOMYCIN/METRONIDAZOLE +
PROBIOTIC vs PLACEBO/NO PROBIOTIC
INSUFFICIENT EVIDENCE TO RECOMMEND PROBIOTIC
THERAPY AS AN ADJUNCT TO ANTIBIOTIC THERAPY
FOR C. DIFFICILE COLITIS
HARMFUL?
BACTEREMIA
FUNGEMIA
Hempel S, et al. JAMA 2012
29/38 30/31
META-ANALYSIS
63 RCTs
n=11,811
INCIDENCE OF
ANTIBIOTIC-
ASSOCIATED
DIARRHEAADULTS & CHILDREN ON
ANTIBIOTIC(S) +
PROBIOTIC vs
PLACEBO/NO PROBIOTIC
PREVENTION AND
TREATMENT
TOGETHER
C. DIFFICILEPROBIOTICS
Johnston BC, et al. Ann Intern Med 2012
29/38 30/31
C. DIFFICILEPROBIOTICS
META-ANALYSIS
20 RCTs
n=3,818
INCIDENCE OF CDADADULTS & CHILDREN ON ANTIBIOTIC(S) + PROBIOTIC
vs
PLACEBO/NO PROBIOTIC
Ridlon JM, et al. J Lipid Res 2006
Theriot CM, et al. mSphere 2016
Wilson KH. J Clin Microbiol 1983
Rao K, et al. Infect Dis Clin North Am 2015
Grehan MJ, et al. J Clin Gastroenterol 2010
• BENEFITS:
– Direct competition with C. difficile for nutrients
– Microbiota may converts conjugated bile salts
secreted from liver to unconjugated primary
bile acids or secondary bile acids
• Some of these inhibit the growth of the vegetative
form of C. difficile
– Remains stable for up to 24 weeks
C. DIFFICILEFECAL MICROBIOTA TRANSPLANT
ORALUP TO 30 FROZEN FMT CAPSULES OF HEALTHY UNRELATED DONORS WITH
MEAN FECAL MATTER PER CAPSULE 1.6g (1.0-2.05g)
ENEMARETENTION ENEMA OF 150g FRESH STOOL/300cc STERILE WATER
COLONOSCOPYBOWEL PREP
200-300g DONOR STOOL (≤ 6 HOURS) IN 200-300cc STERILE SALINE
NASOENTERIC TUBE25-30g DONOR STOOL IN 50cc STERILE SALINE (2 TO 3 MINUTES PER 50cc)
Youngster I, et al. JAMA 2014
Kassam Z, et al. Arch Intern Med 2012
Mattila E, et al. Gastroenterology 2012
van Nood E, et al. NEJM 2013
C. DIFFICILEFMT
Mattila E, et al. Gastroenterology 2012
SAMPLE INFECTIOUS AGENTS TO BE TESTED LABORATORY TESTS
Stool C difficile Culture and toxin A/B test
Enteric bacterial pathogens Selective media culture
Ova and parasites Light microscopy
Serum HBV HBV surface antigen
HCV Anti-HCV antibodies by EIA
HIV 1 and HIV 2 Anti-HIV antibodies by EIA
Treponema pallidum Plasma reagin test
DONOR SCREENING
C. DIFFICILEFMT
van Nood E, et al. N Engl J Med 2013
RCT FROM AMSTERDAM
n=42
RESOLUTION OF RECURRENT CDAD AFTER 10 WEEKSVANCOMYCIN (500 mg PO QID x 4 DAYS) + BOWEL LAVAGE + FMT VIA NASODUODENAL TUBE
vs
VANCOMYCIN (500 mg PO QID x 14 DAYS)
vs
VANCOMYCIN (500 mg PO QID x 14 DAYS) + BOWEL LAVAGE
0
20
40
60
80
100
FMT+VANCOMYCIN+LAVAGE VANCOMYCIN VANCOMYCIN+LAVAGE
81
31
23
%
C. DIFFICILEFMT
p<0.001
13/16
4/133/13
Kassam Z, et al. Am J Gastroenterol 2013
META-ANALYSIS
11 OBSERVATIONAL STUDIES
n=273
TREATMENT OF RECURRENT OR REFRACTORY CDADANTIBIOTICS + FMT
FMT ROUTECOLONOSCOPY
ENEMA
NASOGASTRIC TUBE
NASOJEJUNAL TUBE
GASTROSTOMY
CLINICAL RESOLUTION
245/273 (89.7%)
C. DIFFICILEFMT
Postigo R, Kim JH. Infection 2012
REVIEW WITH POOLED ANALYSIS
12 STUDIES
n=182
TREATMENT OF SEVERE CDADFMT VIA COLONOSCOPY
vs
FMT VIA NASOGASTRIC TUBE
0
10
20
30
40
50
60
70
80
90
100
CLINICAL CURE RECURRENCE
93.2
5.4
85.3
5.9
%
FMT – COLONOSCOPY
FMT - NGT
29/34138/148
p=0.162
p=1.00
C. DIFFICILEFMT
Taur Y, et al. Clin Infect Dis 2012
Dickson RP, et al. New Microbiol 2016
Shogan BD, et al. Microbiome 2014
• Allogeneic Stem Cell Transplantation:
– Microbiota status is associated with risk of
developing bacteremia
• Sepsis and ARDS:
– Enrichment of GI microbes seem to influence
pulmonary inflammatory response
• Surgical Intestinal Anastomoses:
– Composition of GI microbes influence healing
OTHER INFECTIOUS
DISEASES
INFLAMMATORY
BOWEL DISEASE
Lopetuso LR, et al. Dig Dis 2017
INFLAMMATORY BOWEL
DISEASE
EACH DISEASE
HAD ITS OWN
DISTINCT
MICROBIOTA
Morgan XC, et al. Genome Biol 2012
Sartor RB. Gastroenterology 2008
Swidsinski A, et al. J Clin Microbiol 2005
• Intestinal microbiota distinctly different
from non-IBD patients
• 2 issues:
INFLAMMATORY BOWEL
DISEASE
CAUSATION?
HOST GENETIC
SUSCEPTIBILITY
IBD ALTERED MICROBIOTA
OR
ALTERED MICROBIOTA IBD
Cui B, et al. J Transl Med 2015
29/38 30/31
PILOT STUDY FROM CHINA
n=14
STEROID-DEPENDENT ULCERATIVE COLITIS1 OR MORE FMT (STEP-UP FMT)
IBD
FMT
0
20
40
60
80
100
CLINICAL RESPONSE SUSTAINED RESPONSE AT LEAST 3
MONTHS
57
288/14
4/14
%
Paramsothy S, et al. Lancet 2017
29/38 30/31
RCT FROM AUSTRALIA
n=81
STEROID-FREE REMISSION WITH ENDOSCOPIC
REMISSION IN CHRONIC ULCERATIVE COLITISINTENSIVE FMT
(COLONOSCOPY FMT ENEMAS 5/WEEK x 8 WEEKS)
vs PLACEBO
0
10
20
30
40
50
INTENSIVE FMT PLACEBO
27
8
%
3/40
11/41
IBD
FMT
p=0.021
Costello SP, et al. Aliment Pharmacol Ther 2017
29/38 30/31
META-ANALYSIS
4 RCTs
n=277
REMISSION IN ACTIVE ULCERATIVE COLITISFMT vs PLACEBO
STILL DEBATING
FREQUENCY & PREPARATION
IBD
FMT
Neish AS, et al. Science 2000
IBD
PROBIOTICS
29/38 30/31
WHY?HYPOTHESIZED INTERACTION
Derwa Y, et al. Aliment Pharmacol Ther 2017
IBD
PROBIOTICS
29/38 30/31
META-ANALYSIS
9 RCTs
n=651
INDUCING REMISSION IN ACTIVE UCPROBIOTICS VS 5-ASA OR PLACEBO
Schultz M, et al. BMC Gastroenterol 2004
IBD
PROBIOTICS
29/38 30/31
RCT FROM GERMANY
n=11
PREVENTING CLINICAL RELAPSE IN CROHN’S
DISEASEPROBIOTIC VS PLACEBO x 6 MONTHS
0
1
2
3
4
5
Lactobacillus Placebo
2 2SUSTAINED
REMISSION
(n)
IBD
PROBIOTICS
29/38 30/31
META-ANALYSIS
4 RCTs
n=333
PREVENTING CLINICAL
OR ENDOSCOPIC
RELAPSE AFTER
SURGERY IN CROHN’S
DISEASEPROBIOTICS VS PLACEBO
Derwa Y, et al. Aliment Pharmacol Ther 2017
OBESITY
Grujic D, et al. J Biol Chem 1997
OBESITY
MICROBIOME INFLUENCES THE CALORIES THAT ARE ABSORBED
MICROBIOTA ENZYMES CAN TURN THOSE DIETARY
POLYSACCHARIDES INTO DIGESTIBLE SOURCES OF ENERGY
HUMANS CONVERT STARCHES INTO SIMPLE SUGARS THAT ARE
ABSORBED EASILY
HUMANS CANNOT DIGEST MANY DIETARY POLYSACCHARIDES
MICROBIOTA ↔ OBESITY
OBESE PEOPLE LOSE WEIGHT
Bacteroidetes increases relative to Firmicutes
OBESE PEOPLE RESUME PREVIOUS DIET
Proportion of Firmicutes increases
Greiner TU, et al. Mol Metab 2016
OBESITY
MICROBIOTA-PRODUCED
SHORT CHAIN FATTY ACIDS
&
BILE ACIDS
GLUCAGON-LIKE PEPTIDE 1
&
PEPTIDE YY
Ley RE, et al. Nature 2006
Rajala MW, et al. Endocrinology 2014
Sze MA et al. Mbio 2016
• Association between obesity and intestinal
microbiota in human and mouse models
• Precise mechanism unknown
• Meta-analysis shows direct association may
be weaker than originally thought
OBESITY
EMERGING
TREATMENTS
EMERGING TREATMENTS
ANTIBIOTICS
NUTRITIONAL
THERAPY
PROBIOTICS PREBIOTICS/SYNBIOTICS
BACTERIOPHAGES
MULTISPECIES
COMMUNITIES
Young VB. BMJ 2017
• Target specific group(s) of microbiota to
allow for more desirable species
ANTIBIOTICS
ARTIFICIAL SELECTION
SMALL INTESTINAL
BACTERIAL OVERGROWTH
HEPATIC
ENCEPHALOPATHY
IRRITABLE BOWEL
SYNDROME
POUCHITIS
Young VB. BMJ 2017
VERY EMPIRIC
Shah SC, et al. Aliment Pharmacol Ther 2014
ANTIBIOTICS
SIBO
29/38
META-ANALYSIS
4 STUDIES
BREATH TEST NORMALIZATION IN SIBOANTIBIOTIC vs PLACEBO
ANTIBIOTICS VS PLACEBO RIFAXIMIN VS PLACEBO
Ghoshal UC, et al. Eur J Gastroenterol Hepatol 2016
ANTIBIOTICS
SIBO/IBS
29/38
RCT FROM INDIA
N=80
IBS PATIENTS ± GUT ASPIRATE CULTURE PROVEN SIBOIBS-SIBO + NORFLOXACIN 800 mg/day x 10 days
vs
IBS-NO SIBO + PLACEBO
0
10
20
30
40
50
60
70
80
90
IBS-SIBO VS PLACEBO IBS-NO SIBO VS PLACEBO
87.5
25
0 0
%
SYMPTOM RESOLUTION AT 1 MONTH
7/8
0/78/32
0/33
Tilg H, et al. Gut 2016
ANTIBIOTICS
HEPATIC ENCHELOPATHY
29/38INHIBITORY NEUROTRANSMISSION THROUGH
GAMMA-AMINOBUTYRIC ACID (GABA) RECEPTORS
IN THE CENTRAL NERVOUS SYSTEM AND
CHANGES IN CENTRAL NEUROTRANSMITTERS
AND CIRCULATING AMINO ACIDS
Kimer N, et al. Aliment Pharmacol Ther 2014
ANTIBIOTICS
HEPATIC ENCHELOPATHY
29/38
META-ANALYSIS
10 RCTs
n=547
FULL RESOLUTION OF HERIFAXIMIN
vs
PLACEBO/
NON-ABSORBABLE
DISACCHARIDES/
OTHER ANTIBIOTIC
ANTIBIOTICS
POUCHITIS
Shen B, et al. UptoDate 2017
• Inflammatory condition of the ileal pouch
reservoir of an ileal pouch-anal
anastomosis
• Hypothesized to result from an abnormal
immune response to altered luminal
and/or mucosal bacteria in genetically
susceptible hosts
• Acute & Chronic Pouchitis Antibiotics
• Chronic Relapsing Pouchitis?
Gionchetti P, et al. Gastroenterology 2000
POUCHITIS
PROBIOTICS
29/38 30/31
RCT FROM ITALY
n=40
CHRONIC POUCHITIS RELAPSEPROBIOTIC (VSL#3 6 g/day) vs PLACEBO x 9 MONTHS AFTER
REMISSION INDUCED BY CIPROFLOXACIN + RIFAXIMIN
0
10
20
30
40
50
60
70
80
90
100
VSL#3 Placebo
15
100
RELAPSE OF
POUCHITIS
(%)
20/20
3/20
Nobrega FL, et al. Trends Microbiol 2015
Omdorff PE, et al. Curr Genet 2016
Vandenheuvel D, et al. Annu Rev Virol 2015
• Uses naturally occurring bacteriotropic
viruses to target specific members of
disruptive or pathogenic microbiota
• Possible phage resistance due to bacteria
altered surface structure
• More research needed before common in
practice
BACTERIOPHAGES
“Live micro-organisms” which,
when administered in adequate
amounts, confer a health benefit on
the host” - WORLD HEALTH ORGANIZATION
PROBIOTICS
Reid G. Best Pract Res Clin Gastroenterol 2016
PROBIOTICS
1. Suppress growth of epithelial binding/invasion by
pathogenic bacteria
2. Improve intestinal barrier function
3. Modulate immune system:
- Increase protective cytokines (IL-10 & TGF-beta)
- Suppress proinflammatory cytokines (TNF)
4. Modulate pain perception:
- Induce expression of micro-opioid and cannabinoid
receptors in intestinal epithelial cells
POTENTIAL MECHANISMS
Jones SE, et al. BMC Microbiol 2009
Seth A, et al. Am J Physiol Gastrointest Liver Physiol 2008
Yan F, et al. Gastroenterology 2007
Borruel N, et al. Gut 2002
Dalmasso G, et al. Gastroenterology 2006
PROBIOTICS
LACTIC ACID BACILLILACTOBACILLUS AND BIFIDOBACTERIUM
ESCHERICHIA COLI (NON-PATHOGENIC)E. COLI NISSLE 1917
CLOSTRIDIUM BUTYRICUM
STREPTOCOCCUS SALIVARIUS
SACCHAROMYCES BOULARDIINONPATHOGENIC STRAIN OF YEAST
TYPES COMMONLY USED
Macfarlane GT, et al. Curr Opin Infect Dis 2002
Fedorak RN, et al. J Clin Gastroenterol 2008
Kruis W. Dig Dis 2013
Shen J, et al. Inflamm Bowel Dis 2014
PROBIOTICS
VSL#3(Bifidobacterium breve, B. longum, B. infantis, Lactobacillus acidophilus, L. plantarum, L. paracasei, L.
bulgaricus, Streptococcus thermophiles)
ALIGN(B. infantis)
CULTURELLE (L. rhamnosus GG)
DANACTIVE(L. casei)
MUTAFLOR(E. coli Nissle 1917)
FLORASTOR(S. boulardii)
COMMON PRODUCTS
Kruis W. Dig Dis 2013
WHAT ABOUT
YOGURT?
PROBIOTICS
NOT ALL LIVE CULTURES SURVIVE
STOMACH ACID
NOT ALL LIVE CULTURES COLONIZE
MICROBIOTA EFFICIENTLY
SOME ARE PASTEURIZED IN U.S.
KILLING BACTERIA
LACTOSE MAY INCREASE SYMPTOMS
YOGURT
Pedrosa MC, et al. Am J Clin Nutr 1995
Kailasapathy K, et al. Immunol Cell Boil 2000
PROBIOTICS
C. DIFFICILE COLITIS
ULCERATIVE COLITIS (NOT CROHN’S DZ)
POUCHITIS
IRRITABLE BOWEL SYNDROME/SIBO
HEPATIC ENCEPHALOPATHY
CELIAC DISEASE
POTENTIAL TREATABLE DISEASES
PROBIOTICS
POTENTIAL ISSUES
SCIENCE LACKING ON MECHANISMS
ENTHUSIASM >>> EVIDENCE
BASED ON MICROBIOTA OF HEALTHY ADULTS
FDA ALLOWS MANY TO FALL UNDER
DIETARY SUPPLEMENTS
MANY PROBIOTICS ON MARKET DO NOT
MEET WHO DEFINITION
“ADEQUATE AMOUNTS” NOT FULLY DEFINED
Reid G. Best Pract Res Clin Gastroenterol 2016
Young VB. BMJ 2017
PROBIOTICS SUMMARY
DISEASE RECOMMENDED BACKGROUND
POUCHITIS YES VSL#3 IN ADDITION TO STANDARD
MEDICAL THERAPY
ULCERATIVE COLITIS LIKELY HELPS MAINTAIN REMISSION IN
ADDITION TO THERAPY
CROHN’S DISEASE NO REMAINS
UNPROVEN
C. DIFFICILE DIARRHEA YES PREVENTION
ONLY
IBS NO MORE RESEARCH
NEEDED
HEPATIC ENCEPHALOPATHY NO NO
BENEFIT
CELIAC DISEASE NO NO
BENEFIT
Louis P, et al. Adv Exp Med Biol 2016
Gibson GR, et al. J Nutr 1995
• Non-digestible carbohydrates that are meant
to be metabolized by specific microbes
to foster their growth
• Examples:– Inulin
– Resistant Starches
• May be diet modification:– Enteral feeding in children with Crohn’s
disease
– Low FODMAP diet in IBS
PREBIOTICS
SYNBIOTICS
PROBIOTIC
PREBIOTIC
+
Young VB. BMJ 2017
• Using diets to promote beneficial microbiota
NUTRITIONAL THERAPIES
LOW FODMAP DIET IN IBS
ENTERAL FEEDING IN
CHILDREN WITH CROHN’S DZ
Young VB. BMJ 2017
ENTERAL FEEDING IN ADULTS
WITH CROHN’S DZ
Dziechciarz P, et al. Aliment Pharmacol Ther 2007
Zachos M, et al. Cochrane Database Syst Rev 2008
INDUCING REMISSION IN CHILDREN WITH CROHN’S DISEASE
Enteral Nutrition vs Steroids
NUTRITIONAL IMPACTIBD
META-ANALYSIS
4 RCTS
N=144
Dziechciarz P, et al. Aliment Pharmacol Ther 2007
Zachos M, et al. Cochrane Database Syst Rev 2008
NUTRITIONAL IMPACTIBD
INDUCING REMISSION IN CROHN’S DISEASE
Enteral Nutrition vs Steroids
ADULTS
OR 0.33 (95% CI: 0.21 – 0.53)
Winner = Steroids
META-ANALYSIS
7 RCTS
N=352
Nguyen DL, et al. Therap Adv Gastroenterol 2015
INDUCING AND SUSTAINING REMISSION IN CROHN’S DISEASE
NUTRITIONAL IMPACTIBD META-ANALYSIS
5 RCTS
n=403
ENTERAL NUTRITION THERAPY WITH INFLIXIMAB(ELEMENTAL OR POLYMERIC FORMULA, WITH OR WITHOUT LOW-FAT
DIET RESTRICTION)
INFLIXIMAB ALONE WITH NO
DIETARY MANIPULATIONvs
INDUCTION OF REMISSION
REMISSION > 1 YEAR
• Restoring deficient microbiota by harvesting
normal microbiota from heathy individual
and give it to another individual
MULTISPECIES
COMMUNITIES
FECAL
MICROBIOTA
TRANSPLANT
Young VB. BMJ 2017
FUTURE
Young VB. BMJ 2017
MICROBIOME IS COMPLEX
MICROBIOME PLAYS A SIGNIFICANT
ROLE IN MANY DISEASES
MICROBIOME MANIPULATION MAY
HELP IN CERTAIN DISEASES
FUTURE IS BRIGHT IN RESEARCH WITH
MICROBIOME AS DISEASE MODIFIERS
SUMMARY
Related Documents
