Fire in the Gut I

Nutritional Modulation of IBS

KU Clinical Nutrition Seminar 10-12-2012

Gerard E. Mullin MD
Director of Integrative GI Nutrition Services
Johns Hopkins Hospital
600 N. Wolfe Street CARN 464B
Baltimore MD 21205
 Objectives

• To examine the pathophysiology of IBS

• To outline some of the root cause of IBS
• To review the evidence for using nutraceutical
supplements in treating IBS
• To discuss the role of diet in IBS
The Gut-Brain Connection

“The gut is important in

medical research not just for
problems with the the
digestive system but for the
rest of the body” Jay Pasricha
 Rome III Criteria for IBS

• A chronic disorder characterized by abdominal pain or discomfort

associated with disordered defecation
• Symptoms should have developed at least 6 months before the
patient first presents for formal evaluation
• Abdominal pain or discomfort should be present at least 3 days per
month for 3 months and should be associated with two or more of
the following:
– improvement with defecation,
– onset associated with a change in stool frequency, and/or
– onset associated with a change in stool form.
 The Pathogenesis
Fig.2.
of IBS

Mayer, E. A. et al. Am J Physiol Gastrointest Liver Physiol 280: G519-G524 2001

 Genetic
Predisposition
Stress Environmental
Influences
History
Of
Abuse Parental
Modeling
Development
Infection/ Of
Other
Inflammation/ IBS
Factors
SIBO

Anxiety
Stress
Somatization

Poor
Depression
Coping Manifestation
Skills Of
IBS symptoms
 Use of Nutritional Products in IBS

• 40% of patients with IBS claim to

have used some form of herbal
medication in USA
• Herbal products and nutraceuticals
are the most frequent form of
alternative therapies used in IBS

Langmead L., et.al. Inflamm Bowel Dis 2002;8:174-9.

 Emerging Nutritional Approaches
to IBS in 2012

• Supplements
• Gut Microbiome
• Diet
 Herbs Commonly Used for
Gastrointestinal Disease

Herb Indication
Ginger Nausea and vomiting
Berberine Antibacterial
Peppermint IBS
Licorice PUD
Mastic Gum PUD
Tannins Diarrhea
Flaxseed Constipation
 Treatment of IBS with TCM
200
180 N=35

160 N=43
P=0.03
N=38
IBS SYMPTOM INDEX

140 ** P=0.10
120 Placebo
100 Standard
80 Individual
60
40
20
0 Level A
Baseline End of Tx 14 weeks follow up

A Bensoussan, NJ Talley, M Hing et al. Treatment of irritable bowel syndrome with Chinese herbal
medicine. A randomized controlled study. JAMA 1998 280: 1585-1589
Traditional Chinese Herbal Medicine
to Treat IBS

Altern Med Rev. 2011 Jun;16(2):134-51.

Iberogast
 Iberogast Improves IBS
• Commercially available • Research herbal preparation
herbal preparation STW 5):
(STW 5-II):
– bitter candytuft
– bitter candytuft
– chamomile flower
– chamomile flower
– peppermint leaves
– peppermint leaves
– caraway fruit
– caraway fruit
– licorice root
– licorice root
– lemon balm leaves
– lemon balm leaves.
– celandine herbs
– angelica root
– milk thistle fruit.

Alimentary Pharmacology & Therapeutics 2004; 19 (3), 271-279.

 Iberogast
Improves IBS Symptoms
Madisch, A., Holtmann, G., Plein, K. & Hotz, J. Treatment of irritable bowel syndrome with
herbal preparations: results of a double-blind, randomized, placebo-controlled, multi-centre trial.
Alimentary Pharmacology & Therapeutics 19 (3), 271-279.

• Irritable bowel syndrome (IBS)

symptom score ( s.d.) for the various
treatment groups at baseline and after
2 and 4 weeks of treatment. Intention-
to-treat population.
• *P = 0.0033, P = 0.0035, **P = 0.0009
and P = 0.0005 vs. placebo.
• STW 5, commercially available herbal
preparation (nine plant extracts)
• STW 5-II, research herbal preparation
(six plant extracts)
• BCT, bitter candytuft mono-extract.

Level A
 Iberogast
Improves IBS Pain
Madisch, A., Holtmann, G., Plein, K. & Hotz, J. Treatment of irritable bowel syndrome with herbal
preparations: results of a double-blind, randomized, placebo-controlled, multi-centre trial.Alimentary
Pharmacology & Therapeutics 2004; 19 (3), 271-279.

Abdominal Pain score ( s.d.) for the

various treatment groups at baseline
and after 2 and 4 weeks of treatment.
Intention-to-treat population.
*P = 0.0085, P = 0.0006, **P = 0.001 and
P = 0.0003 vs. placebo.
STW 5, commercially available herbal
preparation (nine plant extracts)
STW 5-II, research herbal preparation (six
plant extracts)
BCT, bitter candytuft mono-extract.

Level A
 Iberogast Improves IBS:
Mechanisms of Action
STW 5 plant extracts:
anti-inflammatory, anti-ulcerogenic, carminative and
antibacterial properties.
In vitro studies:
> 10-fold higher affinity of STW 5 to both M3 and 5-
HT4 receptors than to 5-HT3 receptors.
Celandine herb and chamomile flowers are selective to 5-HT4
Licorice root to 5-HT3 receptors
Simmen U, Kelber O, Jäggi R, Büter B, Okpanyi SN, Weiser D. Relevance of the herbal combination of
STW 5 for its binding affinity to the muscarinic M3 receptor. 2003; (Suppl. 1A): R22
Pharmacological Effects of Iberogast
 Peppermint
• Animal model studies demonstrate:
– relaxation effect on gastrointestinal (GI) tissue
– analgesic and anesthetic effects in the central and peripheral
nervous system
– immunomodulating actions
– chemopreventive potential
• Blocks calcium channels in gastrointestinal smoothe muscle to
produce spasmolytic response

Wald A, Rakel D. Nutr Clin Pract. 2008 Jun-Jul;23(3):284-92. Review

Forest plot of randomized controlled trials of
peppermint oil versus placebo
in the irritable bowel syndrome.
Events are number of patients with either global symptoms of irritable bowel
syndrome or abdominal pain unimproved or persistent after treatment

Ford, A. C et al. BMJ 2008;337:a2313

 Efficacy of Therapies for IBS
Therapy Trials NNT

Peppermint 8 2
Oil
Hycosamine 22 11

Alosetron 6 7

Tegaserod 8 17
BMJ 2008;337: TCAs 8 4
a2313
Other Herbal Therapies for IBS

Altern Med Rev. 2011 Jun;16(2):134-51.

 Melatonin

Sleep
Anxiety

Depression IBS???
Is Melatonin involved in IBS?
JOURNAL OF PHYSIOLOGY AND PHARMACOLOGY 2009, 60, Suppl 3, 67-70
Melatonin improves bowel symptoms in
females with IBS:
a double-blind placebo-controlled study

3 mg/D x 8wk, washout, cross over

Lu WZ. Aliment Pharmacol Ther 2005 Nov 15;22;10:927-34.

 Emerging
Complementary Approaches to IBS in 2012

• Supplements
• Gut Microbiome
• Elimination Diets
 Post-Infectious IBS
• May be responsible for up to 30% of all IBS
• Has been reported following food borne illness,
traveler’s diarrhea and outbreaks of Salmonella,
Shigella, Giardia, Campylobacter
• Risk factors: long duration of diarrhea (>3 weeks),
female, psychological factors: anxiety, depression
• IBS may begin up to 4-6 mo. after exposure
 Factors Activating Mucosal
Immune System in IBS
Food Antigens Bacteria EC Cell

Plasma
Cell

Dendritic Activated
Cell T Cells

Mast
Cell
Stress hormones
 Post-infectious IBS
• Increased numbers of T lymphocytes and mast
cells lying in the lamina propria
• Release of tryptase and histamine excite visceral
sensory afferent nerves leading to gut sensory and
motor dysfunction

Red stains tryptase in mast cells

Green stains neuronal specific
enolase

Control Post-I IBS

Barbara, G. et al. Gastroenterology. 2007 Jan;132(1):26-37 c
 Altered Gut Microbiome in IBS
• associated specific microbiome signatures with
pediatric IBS (Saulnier et.al. Gastro
2011;141:1782-91)
• microbiota of IBS had a 2-fold increased ratio of
the Firmicutes to Bacteroidetes (P = .0002).
Correlation analysis of the microbial groups and
IBS symptom scores indicated the involvement of
several groups of Firmicutes and Proteobacteria
in the pathogenesis of IBS (Rajilic-Stojanivoc
Gastro 2011;141:1782-91)
 Altered Gut Microbiome in IBS
• A major functional dysbiosis was observed in
constipated-IBS gut microbiota, reflecting altered
intestinal fermentation.
• Sulphate-reducing population increased in the gut of C-
IBS and were accompanied by alterations in other
microbial groups.
• This could be responsible for changes in the metabolic
output and enhancement in toxic sulphide production
which could in turn influence gut physiology and
contribute to IBS pathogenesis. (Chassard et.al.
Aliment Pharmacol Ther. 2012 Apr;35(7):828-38)
Distribution of Intestinal Bacterial Flora in Normal
Gut and in Small Intestinal Bacterial Overgrowth

Lin, H. C. JAMA 2004;292:852-858.

Origin of gas/bloating of IBS patients with SIBO

 Relationship of SIBO to IBS

Level A
Source: Clinical Gastroenterology and Hepatology 2009; 7:1279-1286 (DOI:10.1016/j.cgh.2009.06.031 )

Copyright © 2009 AGA Institute Terms and Conditions

“Among patients who
had IBS without
constipation, treatment
with rifaximin for
2 weeks provided
significant relief of IBS
symptoms, bloating,
abdominal pain, and
loose or watery stools.
(Funded by Salix
Pharmaceuticals;
ClinicalTrials.gov
numbers,
NCT00731679 and
NCT00724126.)”
Rifaximin Improves IBS
Treatment Options for SIBO
The goal is to treat the underlying
cause(s), eradicate the bacterial
overgrowth, and nutritional support
• Antibiotic therapy
• Prokinetic agents
• Herbs (berberine, oregano oil,
wormwood)
• Diet
• Enzymes/HCl
 Benefits of Probiotics in IBS
potential mechanisms of action
IBS Probiotics
– Post-infectious – Elimination of
– Bacterial overgrowth pathogens
– Qualitative alterations – Modulate
composition of
in fecal flora intestinal flora
– Increased bacterial – Reduce bacterial
fermentation fermentation
– Proinflammatory – Reduce pathogen-
cytokines related inflammation

* Effect on bloating most consistent effect of probiotics

Meta-analysis for Probiotic Use in IBS

Gut. 2010 Mar;59(3):325-32.

 Summary of Evidence for Nutritional-
based Therapies for IBS
INTERVENTION BODY OF EVIDENCE
2 meta-analyses of 5 and 4
Peppermint oil
RCTs
Probiotics Meta-analysis of 23 RCTs
Soluble fibre Meta-analysis of 9 RCTs
Iberogast
Artichoke leaf extract 2 RCTs
Tumeric 1 RCT
 Emerging Options for IBS

• Supplements
• Gut Microbiome
• Elimination Diets
 > 60% IBS patients report
worsening symptoms after meals,
28% within 15 minutes, 93% within
3 hours

Eswaran S, Tack J & Chey W. Food: The Forgotten Factor in the Irritable
Bowel Syndrome. Gastroenterol Clin N Am 40 (2011) 141–162
Food Reaction in Patients with IBS
• 25% of Us population claim and they have an
adverse reaction to one or more foods
• IBS 32% claim they have an adverse reaction to a
specific food
• Culprits:
– Carbs
– Allergens
– Lactose, Fructose
– FODMAPs
– Gluten*
*3.6 of IBS patients have Celiac disease vs. 0.7% US population
 Exclusion-Based Diets

• Based on Food Hypersensitivity Testing

Dairy (IgG4, ALCAT, etc)
• Top 8 Food Allergens
• Carbs, Lactose, Fructose, FODMAPs,
Gluten
• Caffeine, Additives, Amines
• Elimination Diet (suspected vs.
restrictive)
Prevalence of Lactose Intolerance in IBS

38%

26%

IBS patients (n=251) Controls (n=174)

Fructose and Fructans As Dietary
Triggers for IBS symptoms
* *
*
Food elimination based on IgG antibodies in
irritable bowel syndrome: a randomized
controlled trial.

P<0.001

Atkinson, W et al. Gut 2004;53:1459-1464

 Results of Studies of Immunoglobulin G (IgG)
Antibody-Elimination Diets for Irritable Bowel
Syndrome (IBS).

Copyright © by The American Society for Parenteral and Enteral Nutrition

Mullin G E et al. Nutr Clin Pract 2010;25:192-198
 Very Low CHO Diet for IBS-D
• 15 females, mean age 46 yrs, BMI 32
• Dietary interventions:
2 wks standard (55% CHO, 30% Fat, 15% Protein)
4 wks VLC (51% Fat, 45% Protein, 4% CHO)
• Responder: Adequate relief of GI symptoms for 2/4
weeks
Responder rate = 13/13 (100%)
10/13 (77%) improved 4/4 weeks
Improvements in stool frequency (p<0.001),
consistency (p<0.001), pain (p<0.001), QoL (p=0.02)
Mean weight loss of 3.1 kg
Austin et al. Clin Gastro Hepatol 2009;7:706
Conclusion: Prevalence of biopsy-proved celiac
disease
in cases meeting diagnostic criteria for IBS was
more
than 4-fold that in controls without IBS.
Arch Intern Med. 2009;169(7):651-658
 Yield of Diagnostic Tests for Celiac Disease in Individuals
With Symptoms Suggestive of Irritable Bowel
Syndrome: Systematic Review and Meta-analysis

Arch Intern Med. 2009;169(7):651-658. doi:10.1001/archinternmed.2009.22

Copyright © 2012 American Medical
Date of download: 9/22/2012
Association. All rights reserved.
 Gluten Sensitivity
• An adverse reaction occurring upon ingestion of gluten in
patients who do not have celiac disease or wheat allergy
and whose symptoms subside after gluten withdrawal’
• Much more commonly seen in adults than in children
• The definition is necessarily broad, as many clinical
manifestations are attributed to gluten sensitivity, ranging
from strictly gastrointestinal to extra-intestinal such as
fatigue, headaches, joint pain….

Curr Gastroenterol Rep 2011 Jul 27

 Gluten Sensitivity
• Up to 10% of the general population
• Encompasses a collection of medical conditions in
which gluten leads to an adverse effect
• Can be clinically indistinguishable from celiac sprue
but testing is negative or inconclusive
• Not associated with increased intestinal permeability
• Innate immunity markers TLR2 & FOXP3 altered in GS
but not Celiac disease
• Improves with a gluten free diet

Eswaren S et al. GI Cl North Am 2011;40:141

Sapone et al. BMC Medicine 2011;9:23
 Is it IBS, Celiac Disease or
Something in Between?
Gluten Sensitivity
IBS symptoms
Motility/Visceral
Spectrum of CD
Sensation
Brain-Gut Interactions Silent CD
Immune activation Latent CD
Altered Gut Microbiome CD &
Altered Permeability
Complications
Participants received either gluten or placebo in the form of two
bread slices plus one muffin per day with a gluten-free diet for up to
6 weeks. Of 19 patients (68%) in the gluten group, 13 reported that
symptoms were not adequately controlled compared with 6 of 15
(40%) on placebo (P=0.0001; generalized estimating equation). On a
visual analog scale, patients were significantly worse with gluten
within 1 week for overall symptoms (P=0.047), pain (P=0.016),
bloating (P=0.031), satisfaction with stool consistency (P=0.024), and
tiredness (P=0.001).
Gluten Induces GI Symptoms

Biesiekierski J et. al .
Am J Gastro 2011 106
(3)508-514.
Our data confirm the existence of non-celiac
WS as a distinct clinical condition. We also
suggest the existence of two distinct
populations of subjects with WS: one with
characteristics more similar to
CD and the other with characteristics
pointing to food allergy.
Carroccio et al. Non-Celiac Wheat Sensitivity Diagnosed by
Double-Blind Placebo-Controlled Challenge:
Exploring a New Clinical Entity Am J Gastro In Press 2012.
 Authors Conclusions
• Our results clearly showed that a relevant
percentage — one third of our irritable bowel
syndrome patients who underwent DBPC wheat
challenge were really suffering from WS.
• WS patients were characterized by frequent self-
reported wheat intolerance and coexistent atopy
and food allergy in infancy.
• The main histological characteristic of WS
patients was eosinophil infiltration of the
duodenal and colon mucosa.
 Food Reactions and IBS Summary
• Patients with IBS-D/M should be screened for celiac
disease
• Expected US prevalence in IBS pts is ≤1% but likely varies
based upon population genetics
• Lactose intolerance may be more common in IBS
• Clinical implications of CHO intolerance may be different
in persons with than without IBS
• Food can affect GI function and sensation
• Mounting evidence suggests that dietary & lifestyle
interventions can improve symptoms in a subset of IBS
sufferers
 Fiber
The Forgotten Factor

• Traditional treatment for IBS

• Type of fiber matters
– Insoluble fiber such as wheat bran may exacerbate
IBS symptoms
– Soluble fiber (psyllium husk) more beneficial
• Gradual increase in fiber intake + fluids
 Forest plot of randomized controlled trials of fibre
versus placebo or low fibre diet in IBS

Level A

Ford, A. C et al. BMJ 2008;337:a2313

Copyright ©2008 BMJ Publishing Group Ltd.
 FODMAPs & IBS
• Fermentable Oligo, Di, Monosaccharides And
Polyols
• Family of poorly absorbed, short-chain
carbohydrates
– lactose,
– fructose,
– fructo-and galacto-oliogsaccharides (fructans and
galactans)
– Polyols (sorbitol, mannitol, xylitol and maltitol)
• Highly fermentable in the presence of gut
bacteria (SIBO)
FODMAPs Pathology
Journal of Gastroenterology and Hepatology
25 (2010) 1366–1373
IBS Patients on High FODMAP Diet
Produce Breath Methane
Low FODMAP Diet Improves
IBS Symptoms

Journal of Gastroenterology and Hepatology 25 (2010) 1366–1373

Low FODMAP vs. Standard Diet for IBS

Staudacher HM, et al. J Hum Nutr Diet 2011

 Top FODMAPs Rich-Foods
• Grains: wheat & rye
• Fruits: apples & pears
• Vegetables: onions
• Dairy: milk and soft cheeses
(cottage/ricotta)
• Sweeteners: Agave, honey
• Other: High fructose corn syrup & polyols
FODMAP Fructose Polyols Lactose Fructans and
Galactans
High Apples, pears, Sugar alcohols Milk (cow, Wheat, rye, garlic, onions,
FODMAP watermelon, (sorbitol, goat, artichokes, asparagus, inulin,
food honey, fruit maltitol, sheep), soy, leeks, legumes, lentils,
sources juices, dried mannitol, yogurt, cabbage, Brussels sprouts,
fruits, high- xylitol, soft broccoli
fructose corn and isomalt), cheeses
syrup stone fruits, (ricotta,
avocado, cottage)
mushrooms,
cauliflower
Alternative Citrus, Sweeteners, Lactose- Starches, such as rice, corn,
lower berries, such as sugar, free dairy potato, quinoa. Vegetables,
FODMAP bananas, glucose, other products, such as winter squash,
food grapes, artificial rice milk, lettuce, spinach, cucumbers,
sources honeydew, sweeteners hard bell peppers, green beans,
cantaloupe, not ending in cheeses tomato, eggplant
kiwifruit “-ol” (Stevia)
Mast Cells, CRF and Pain

Although the pathophysiology of visceral

hypersensitivity is still unclear, two key
factors have been identified as playing a
major role in its modulation, namely
peripheral corticotropin-releasing factor
(CRF) and mast cells.
Studies of Mast Cells in IBS

Asia Pac Allergy. 2011 Apr;1(1):36-42

Leaky Gut in IBS-D

Colonic permeability of IBS-D and inactive

UC patients was significantly increased
compared to controls (2.68 ± 0.35 and 3.74
± 0.49 vs. 1.04 ± 0.18%; p < 0.05, p < 0.001).
Colonic permeability of IBS-D patients
correlated with stool frequency
Leaky Gut in IBS-D
 Gut Permeability and Food Allergies

Clinical & Experimental Allergy

Volume 41, Issue 1, pages 20-28, 11 NOV 2010 DOI: 10.1111/j.1365-2222.2010.03639.x
http://onlinelibrary.wiley.com/doi/10.1111/j.1365-2222.2010.03639.x/full#f2
Gut Permeability and Food Allergies

Tobin MC, Moparty B, Farhadi A, et al. Atopic irritable bowel syndrome: a novel
subgroup of irritable bowel syndrome with allergic manifestations. Ann Allergy
Asthma Immunol 2008;100(1):49–53.
J Clin Gastro 2012 Oct;46
Suppl:S52-5
 Mucosal Permeability and Immune Activation as
Potential Therapeutic Targets of Probiotics in Irritable
Bowel Syndrome
“Decreased expression and structural rearrangement of tight junction
proteins in the small bowel and colon leading to increased intestinal
permeability have been observed, particularly in post-infectious IBS and in
IBS with diarrhea.
These abnormalities are thought to contribute to the outflow of antigens
through the leaky epithelium, causing overstimulation of the mucosal
immune system.
Accordingly, subsets of patients with IBS show higher numbers and an
increased activation of mucosal immunocytes, particularly mast cells.
Immune factors, released by these cells, including proteases, histamine, and
prostanoids, participate in the perpetuation of the permeability dysfunction
and contribute to the activation of abnormal neural responses involved in
abdominal pain perception and changes in bowel habits.
All these mechanisms represent new targets for therapeutic approaches in
IBS.”
 Mast Inflammatory
mediators
Activating factors
Cell Histamine
• Intestinal
permeability Tryptase
Bacteria and Lipid mediators
biproducts Cytokines
• Food allergies
(IgE- & non-IgE-
mediated) ENS Altered gut
• Neuropeptides secretion &
motility
• Bile acids
Sensory GI Pain
neurons
CPPS Neural cross-
talk

Corticotrop CNS Stress

hin
Releasing
Factor Pain
 Carminative
A carminative is an herb that relieves flatulence
and/or GI cramping.
 Food Carminatives
Allspice* Cloves Marjoram
Anise seed Coriander Nutmeg
Asafoetida Cumin* Onion
Basil Dill* Oregano
Bergamot Epazote Peppermint*
Chamomile Fennel* Rosemary
Caraway* Ginger * Sage*
Cardamom Lemon balm* Saffron
Cinnamon Licorice Sarsaparilla
Spearmint
Thyme

BMC Complement Altern Med. 2007 Feb 7;7:4

 Nutritional Tools for Your IBS Patient
• Anti-anxiety Herbs • FODMAP restricted
• Anti-microbials for diet
SIBO • Melatonin
• Artichoke leaf • Peppermint Oil
extract • Probiotics
• Elimination Diet • Tumeric
• Fiber
CAM Evidence Ratings for IBS

Nutrition in Clinical Practice. Volume 23 Number 3.

June/July 2008 284-292
• The practice of medicine is an art, not a trade; a
calling, not a business; a calling in which your
heart will be exercised equally with your head.
Often the best part of your work will have nothing
to do with potions and powders, but with the
exercise of an influence of the strong upon the
weak, of the righteous upon the wicked, of the wise
upon the foolish.
~ Sir William Osler, The Three Great Lessons of Life
 Fire in the Gut II
Nutritional Modulation of IBD

KU Clinical Nutrition Seminar 10-12-2012

Gerard E. Mullin MD
Director of Integrative GI Nutrition Services
Johns Hopkins Hospital
600 N. Wolfe Street CARN 464B
Baltimore MD 21205
 Learning Objectives
• Apply knowledge of inflammatory antecedents,
triggers, and mediators to create effective,
individualized treatment plans for patients with
digestive dysfunction.

• Be able to appropriately prescribe diet,

nutraceuticals, and botanicals to decease
inflammation and oxidative stress in the
digestive tract.
© 2006 -
 Outline

• Anti-inflammatories (food, herbs, spices,

nutraceuticals, botanicals)
• Gut repair (food, herbs, spices, nutraceuticals,
botanicals)
• Immune enhancers (food, herbs, spices,
nutraceuticals, botanicals)
• Demulcents (herbs)
Interaction of various factors contributing to
chronic intestinal inflammation in a
genetically susceptible host
 Pathogenesis of IBD
Initiating Mucosal Abnormal Chronic
Events Damage Immune Response Inflammation

NSAIDs Translocation of Th1 vs. Th2 Luminal antigens

Antibiotics luminal contents Food antigens
Infections Bacteria
Viral Bacterial products
Bacterial FMLP
LPS
Parasitic PGPS

Courtesy of R Baldassano, 2000.

 Pathogenesis of IBD
Ag

T9
Ag
T9 IL-12 4F2
4F2 IL-1 IL2-R
IL2-R

+
Activated Th1 Cell Macrophage
+ + CD4
IL-2, IFN Lymphokines TNF-

OH. CD45R
IL-1 IL-6 TNF- O2.-
IL-8, MIP-1 Memory T Cell

ADCC Lymphokines
+

Inflammation
Mucosal injury
ROS
 Inflammatory Bowel Disease

• Chronic inflammation, tissue injury

• Gut repair is multimodal
• Increased oxidative stress both in the gut and
systemically
• Uncontrolled inflammation leads to fibrosis in
Crohn’s disease and higher risk of cancer in
inflammatory bowel disease (IBD)
 Probiotics
• Dysbiosis – unbalanced or
harmful intestinal flora
• Dysbiosis contributes to illness
through changes in intestinal
permeability and altered gut
microbiology
• Stress, food, medical drugs,
environmental toxins and
climate all stimulate or inhibit
different types of
microorganisms
 Benefits of Probiotics in IBD:
Mechanisms of Action
Inhibit Pathogenic Improve Epithelial Immunoregulation
Bacteria Function

pH SCFA’s IL-10, TGF

Bacteriocidal Healing T NF, IL-12

proteins

Epithelia binding Mucus sIgA

Epithelial invasion Barrier Integrity NFkB

 RCTs: CROHN’S DISEASE - Recurrence
PROBIOTIC CONTROL N DURATION REPLAPSE: P AUTHOR
probiotic/
control

E.coli Nissle Placebo 28 12 months 33%/63% <0.05 Malchow

1917 1997

VSL#3 5-ASA 40 12 months 20%/40% <0.05 Campieri

et al. 2000

LGG Placebo 45 12 months 60%/35.3% 0.297 Prantera et

al. 2002

S.boulardii + 5-ASA 32 6 months 6.3%/37.5% <0.05 Guslandi

5-ASA alone et al. 2000
Level A Evidence
 Probiotic Foods
Dairy-based Nondairy-based
• Yogurt • Brined olives
• Cheese • Salted gherkins
• Acidophilus milk • Sauerkraut
• Kim chee
• Kefir
• Miso
• Natto
• Tempeh
• Poi
• Tanzania Togwa

Lin, D.C. NCP 18:497, 2003

Lipski, E. IN: Integrative Gastroenterology 2011
 Prebiotics in UC
Author Year Fiber Study Outcome
Fernandez- 1999 Plantago Ovata Fiber +/- = to
Banares seed fiber 10 gm Mesalamine Mesalamine

Kanauci 2002 30 gm barley Mod to active

2003 UC disease
activity

Hallert 2003 Oat bran 60 gm In remission abd pain

(20gm fiber) Increase fecal
butyrate

Welters 2002 Inulin 24 gm IAPA pouch

inflammation
 “Relax, sir.
The hair in your soup provides fiber.”
 Short Chain Fatty Acids
Malabsorbed carbohydrate and nondigestible fibers are
fermented
by colonic bacteria into short chain fatty acids (SCFA).
•SCFA primary fuel for colon
•SCFA absorbed by colonic mucosa & used as energy in
SBS
•SCFA enhance sodium and water absorption
•SCFA exert trophic effects in SB and colon
•Regulates cell proliferation, differentiation, carcinogenesis
•Role in immunomodulation

Jeppesen et al. JPEN 1999;23:S101-S104

Royall D et al. Am J Gastroenterol 1992;87:751
 SCFA Enemas
(60-100 mmol/100ml 1-2 times/day)
Butyrate, acetate, and propionate are SCFAs, which are
by-products of colonic fermentation.
• Primary fuel for the colon
• Trophic effects, increases sodium/water absorption
• Mucosal levels are decreased in distal ulcerative
colitis
• SCFA enemas are used for refractory distal ulcerative
colitis

Steinhart AH, et al. Am J Gastro. 1994;89(2):179-183.

Patz J, et al. Am J Gastro. 1996;91(4):731-734.
Scheppach W. Dig Dis Sci. 1996;41(11):2254-2259.
Sengore AJ. Dis Col Rectum. 1992;35:923-927.
Scheppach W. Gastroenterol. 1992;103;51-58.
Prospective Studies of SCFA for Left-sided
Ulcerative Colitis
 TGF-β

• Extracellular matrix
formation
• Cell migration
• Differentiation
• Immune regulation
• Tissue remodeling
• Regulates inflammation
• Promotes healing
TGF-β-enriched Formulas for Crohn’s Disease
Using Whey Protein

• 3 cohort studies evaluated TGF-β-enriched formula in patients

with Crohn's disease
• TGF-β diet for 8 weeks as sole nutrition, improvements:
– ESR and CRP levels
– Serum albumin levels
– Mucosal healing, Clinical Disease Activity
– Serum IL-1β, IL-8, and IFN-γ
• The relapse rate was high after remission achieved with
nutritional therapy

Beattie RM, Schiffrin EJ, Donnet-Hughes A, et al. Aliment Pharmacol Ther. 1994;8:609-615.
Fell JM, Paintin M, Arnaud-Battandier F, et al. Aliment Pharmacol Ther. 2000;14:281-289.
Afzal NA, Van Der Zaag-Loonen HJ, et al. Aliment Pharmacol Ther. 2004;20:167-172.
C Hartman, et al, IMAJ, July 2008
 Omega-6 & Omega-3

Proinflammatory Anti-inflammatory

Series 2 Series 3
Prostaglandins Prostaglandins

Series 4 Series 5
Leukotrienes Leukotrienes
 Omega-3, -6 Modulation of
Arachidonic Acid Cascade
Omega-3 Fatty Acids Omega-6 Fatty Acids
• Fish • Corn
• Walnuts • Primrose
• Flax • Safflower oil
• Canola oil • Red meat
 Effects of Omega-3 Fatty Acids
on Factors Involved in the Pathophysiology of
Inflammation
Effect of
Factor Omega-3
Fatty Acid
Platelet activating factor (PAF) ↓
Platelet-derived growth factor (PDGF) ↓
Oxygen free radicals ↓

Lipid hydroperoxides ↓

IL-1, IL-6, and TNF ↓

NF- B, PPARs adhesion molecules ↓
 Fish Oils and IBD:
Animal Studies
6/6 mice models of ulcerative colitis showed
protection from injury and healing with
omega-3 fatty acids.
Proc Natl Acad Sci U S A. 2006;103(30):11276-11281.
Clin Nutr. 2006;25(3):466-476.
Nutrition. 2006;22(3):275-282.
World J Gastroenterol. 2005;11(47):7466-7472.
Proc Natl Acad Sci U S A. 2005;102(21):7671-7676.
Inflamm Bowel Dis. 2005;11(4):340-349.
 Fish Oils & UC
Induction of Remission
Study EPA DHA Clinical Endoscopic
Remission Evidence
Almallah 3.2 g/d 2.4 g/d p<0.05 p=0.013
1998

Aslan 2.7 g/d 1.8 g/d *p<0.05 NR

1992

Stenson 3.24 g/d 2.16 g/d p=0.001 p=0.054

1992

Cochrane Database Syst Rev. 2007 Oct 17;(4):CD005986.

* 72% weaned off or reduced medication dose. N=159
Level A Evidence
Fish Oil for the Maintenance of
Ulcerative Colitis

Turner, D et al Inflamm Bowel Dis. 2011 Jan;17(1):336-45

Fish Oil for the Maintenance of CD

Turner, D et al Inflamm Bowel Dis. 2011 Jan;17(1):336-45

Combined oral supplement to determine
whether enteral nutrition can provide
steroid sparing effect (n=121, 86
completed study) for 6 months
18 oz. of either:
• Nutritionally balanced oral
supplement (UCNS)
• CHO-based placebo
Clin Gastro Hep. 2005;3:358-369.
 UCNS Formula per 8 oz.
• 310 kcal [16.1/49.7/6.5% • β-carotene (μg)- 1185
protein/CHO/lipid]
• Vitamin A (IU)- 1320
• Fish oil (1.09 g EPA/0.46 g
• Vitamin D (IU)- 192
DHA)
• Vitamin E (IU)- 72
• 3.5 g EPA/DHA per day
• Vitamin K (μg)- 32
• FOS 2.9 g
• Vitamin C (mg)- 156
• Gum arabic 2.2 g
• Folic acid (μg)- 456
• Calcium (mg)- 432
• Zn (mg)- 7
• Phosphorus (mg)- 300
• Se ( g)- 22
• Magnesium (mg)- 108
Clin Gastro Hep. 2005;3:358-369.
Change in Nutrition and Disease Measures After 4
Months of Supplementation.

After 4 months, those patients with higher EPA levels had a significantly higher
IBDQ (mean ± SD, 179.1 ± 26.6 vs 114.6 ± 35.9; P < .001) and lower CDAI (116 ±
94.5 vs 261.8 ± 86.5; P = .005) compared with those with lower levels of EPA

Wiese D M et al. Nutr Clin Pract 2011;26:463-473

 The Effects of an Oral Supplement Enriched With
Fish Oil, Prebiotics, and Antioxidants on Nutrition
Status in Crohn’s Disease Patients

Vitamin D and PTH levels

• increased fat-free and fat mass
deposition,
•improved vitamin D status
• improvement in quality of life and lower
disease activity
•open label; high drop out rate; small
Plasma phospholipid FA levels sample
Wiese D M et al. Nutr Clin Pract 2011;26:463-473
 Inflammatory Bowel Disease Questionnaire (IBDQ) and Crohn’s
Disease Activity Index (CDAI) during treatment with IBD Nutritional
Formula (IBDNF) supplementation in patients with final
eicosapentaenoic acid (EPA) >2%

There was a significant increase in IBDQ (+41.4 [23.1, 47.0]; P = .002) and
decrease in CDAI (−47.8 [−65, −37.8]; P = .05) in patients with higher EPA levels

Wiese D M et al. Nutr Clin Pract 2011;26:463-473

Clinical trial: vitamin D3 treatment in Crohn’s disease – a
randomized double‐blind placebo‐controlled study

108 patients with Crohn's disease in remission, of which fourteen were excluded later.
Patients were randomized to receive either 1200 IU vitamin D3 (n = 46) or placebo (n = 48)
once daily during 12 months. The primary endpoint was clinical relapse.

Alimentary Pharmacology & Therapeutics Volume 32, Issue 3 pages 377-

383, 11 MAY 2010
 Pathogenesis of IBD
Ag

T9
Ag
T9 IL-12 4F2
4F2 IL-1 IL2-R
IL2-R

+
Activated Th1 Cell Macrophage
+ +
IL-2, IFN- Lymphokines
IL-8, MIP-1 CD4 CD45R
OH.
IL-1 IL-6 O2.-
Memory T Cell
TNF-
TNF-
ADCC Lymphokines
+
(-)
Mucosal injury Inflammation
ROS
 Impaired Cellular Defense
Mechanisms in IBD
Nutritional
Vitamin E

Beta-Carotene Vitamins C and E

NUCLEUS Beta-Carotene

ENDOPLASMIC RETICULUM
DNA
LYSOSOMES
Catalase PEROXISOMES GSH
Cu/Zn SOD Glutathione
CYTOPLASM
MITOCHONDRION
Peroxidase
LIPID BILAYER OF ALL CELLULAR
MEMBRANES
Vitamin C
Vitamin E +
Beta-Carotene
Vitamin E
Mn
SOD + Glutathione Peroxidase
+ GSH
 Pharmaceutical modulation of the
Arachidonic Acid Cascade
Cell
membrane

X Phospholipase A2 X Sulfasalazine
Cortisone

Arachidonic Acid
Indomethacin
Aspirin
Ibuprofen X Cyclooxygenase Lipoxygenase
Sulfasalazine X Colchicine

Thromboxane Leukotriene
Prostaglandin 2 s
series A2
SRS-A
 Botanical Modulation
of Arachidonic Acid Cascade

Mullin GE, et al, Expert Review of Gastroenterology and Hepatology, April 2008
 NF-κB probiotics

Singarelli B. CCM. 2005;33:S414-416

 Natural Products with
Anti-inflammatory Actions
NF-κB inhibitors: – Caffeic acid phenyl ester (CAPE)
bee propolis
– Curcuminoids
– Resveratrol
– Ginger
– 1,25-(OH)2D3
– Boswellia
– GLA (evening primrose oil)
– Green tea extract (EGCG) – EPA (fish oil)
– Bromelain
– Rosemary (carnosol) Inflammatory inhibitors
– Grape seed extract (NF-κB independent):
– Phytolens (lentils) – DHA (fish oil)
– Probiotics – ALA (flaxseed oil)
– Alpha-lipoic acid – White willow bark
– Devil’s claw
 Phytonutrients and Botanicals
Likely to be Useful in Inflammatory
Conditions of the GI Tract
 Polyphenols
• Phytochemicals found in food and beverages that are
derived from plants
• Nonessential
• Anti-inflammatory and vasculoprotective properties
• Four polyphenols with anti-inflammatory properties
have been studied in human and animal models of
colitis:
• Curcumin (turmeric)
• Resveratrol (grapes, wine)
• EGCG (green tea)
• Quercetin (apples, onions, leafy veggies, tea)
 Polyphenols Attenuate
Inflammation and Injury
Prophylactic and Therapeutic Effects of
Polyphenols for Colitis
Polyphenol N Route, dose Results

Resveratrol 2 5-10 mg/kg 2/2 improvement: clinical,

2/2 IG path, mediators, cytokines

EGCG 3 5 g/L, 3/3 improvement: clinical,

50 mg/kg/D path, mediators, cytokines
1 IP, 2 PO
Curcumin 6 2%, 30-300 6/6, improvement: clinical,
mg/kg/D path, mediators, cytokines,
6 PO, 1 IP markers 4/7 ↑ survival
Quercetin 6 5 PO/IG, 0.25-50 Overall 3/6 showed efficacy
mg/kg/D, enema Enema ineffective
10-100 mM/D
Animal Studies
 Please Pass
the Berries!

J Med Food. 2007;10;2:258-265.

 Foods associated with a decrease in inflammatory
markers in human interventional studies
Food Duration Effect
Extra virgin olive oil Single meal ↓ TXB2 and LTB4
Tomato juice 10 days ↓neutrophil airway influx in asthmatics
Tomato drink 26 days ↓TNFalpha production by whole blood
Whole tomatoes 28 days No change in CRP
Walnuts Single meal ↓monocyte mRNA for TNFa & IL-6
Red wine 4 weeks Reduced CRP and fibrinogen
Garlic powder 3 months No effect on CRP, TNF-a
Flaxseed flour 2 weeks ↓CRP, fibronectin & serum amyloid A in
obese subjects
Tea, black 12 weeks 40-50% ↓ CRP in subjects w/CRP>3mg/L.
Tea, black 6 weeks ↓CRP & platelet aggregation in healthy men
Tea, green 4 weeks No effect on CRP in men; no significant
effect on CRP in male smokers
Cherries, sweet 4 weeks ↓ CRP and CCL5, no effect on IL-6 in healthy
adults
Red Wine Cools Colonic Inflammation
in UC

Digestion 2011 Aug 26;84(3):238-244.

 Turmeric (Curcuma longa)
Mechanism of action:
• Inhibits TNF-α
• Dual inhibitor
of arachidonic acid
metabolism
• Cortisone-like
inhibitory action
on phospholipases
• Antioxidant activity
Note: Turmeric is a
potent inhibitor of transcription factor NF-κB
 Turmeric (Curcuma longa): Maintenance
Therapy for Ulcerative Colitis
• Randomized, multicenter, double-blind, placebo-
controlled trial from Japan
• 97 patients enrolled, 89 completed study
• All took mesalamine/sulfasalazine
• Curcumin 1 g BID vs. placebo
• Clinical and endoscopic activity index (CAI, EI) end
points:
• Recurrence @ 6 mo (on drug), 12 mo (off)
• CAI, EI

Hanai H, et al. Clinical Gastro Hepatol. 2006;4:1502-1506.

 Curcumin
in Ulcerative Colitis

Hanai H, et al. Clinical Gastro Hepatol. 2006;4:1502-1506.

 Boswellia and IBD
Author Design/# Disease Control Duration Results

Madish et al DBRCT Collagenous Placebo 6 wks Maintenance

(31) colitis of remission
superior with
Boswellia
Gupta et al Randomized IBD Sulfasalazine 6 wks Induction of
(30) remission
superior with
Boswellia
Gupta et al Randomized UC Sulfasalazine 6 wks Induction of
(30) remission
not different

World J Gastroenterol 2010 September 28; 16(36): 4504-4514

 Nutritionals Showing Efficacy in IBD

Solid Evidence Single Studies

• Elemental Diet • Lycopene
• Modulen • Aloe vera
• Prebiotics • Ginger
• Probiotics • Wheatgrass juice
• Turmeric
• UCNS
• Boswellia
• CDNS
• Fish Oils
 Conclusion
Therapeutic Modalities for IBD
Modality Level of Evidence Risk
Omega-3 fatty acids B Low
Modulen (TGF-b)* B na
Curcumin B na
Probiotics A low
Butyrate enemas B na
Diet B na
Azathiopurine
A B high
Aminosalicylates A moderate
Corticosteroids A high

* Transforming growth factor

 Nutritional Modulation of IBD
Take Home Sticky Points
• Polyphenols, fish oils, probiotics, vitamin D,
antioxidants: down regulate inflammation to
“cool the fire in the gut”
• Short chain fatty acids are colonic –specific
anti-inflammatory nutrients
• High ORAC foods, wild cold-water fish, etc.
Think of food as medicine first!
“Let medicine be thy food and let food be thy medicine”
Hippocrates