PATHOGENESIS AND INTEGRATIVE MANAGEMENT OF INFLAMMATORY BOWEL DISEASE

Gerard E. Mullin MD Associate Professor of Medicine

Johns Hopkins University School of Medicine International Congress on Natural Medicine

June 9, 2014

INTERACTION OF VARIOUS FACTORS CONTRIBUTING TO CHRONIC INTESTINAL

INFLAMMATION IN A GENETICALLY SUSCEPTIBLE HOST

PATHOGENESIS OF IBD

NSAIDs Antibiotics Infections

Viral Bacterial Parasitic

Luminal antigens Food antigens

Bacteria Bacterial products

FMLP LPS

PGPS

Th1/Th17 vs. Th2

Translocation of luminal contents

Initiating Events

Mucosal Damage

Abnormal Immune Response

Chronic Inflammation

PATHOGENESIS OF IBD

Macrophage

Inflammation

IL2-R

T9 4F2

Activated Th1 Cell

Ag

Ag

IL-12

Mucosal injury

IL-1 IL-6 TNF-a IL-8, MIP-1a

+ +

IL2-R

T9 4F2

TNF-a

ADCC

Lymphokines

OH. O2

.-

IL-2, IFNg

IL-1

+

+

CD45R

CD4

Memory T Cell

Lymphokines

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)

Enteral > Placebo Enteral < GCS Enteral = TPN

Polymeric = Elemental

SUMMARY: EFFECTIVENESS OF NUTRITIONAL SUPPORT FOR CROHN’S DISEASE

ENTERAL NUTRITION MECHANISMS OF ACTION?

Enteral Nutrition

Gut Permeability

Bowel Rest

Glutamine

Antigenic Load

Fat Composition

Gut Flora

POPULAR DIETS FOR IBD DIET RATIONALE PLAN EVIDENCE Elimination Lower antigenic burden-up to

66% of CD pts. report food intolerances 1

Eliminate known and suspected provocative foods 2-4 weeks then reintroduce: 1 new food per day-process may take 2-3 months

Mishkin S. Am J Clin Nutr. 1997 Feb;65(2):564-7. Giaffer MH, Cann P, Holdsworth CD. Aliment Pharmacol Ther. 1991 Apr;5(2):115-25

Specific Carbohydrate Diet

Eliminate poorly digestible CHO’s to limit fermentation in small bowel. Avoid complex carbohydrates

Allowed: meat, fish, eggs, vegetables, nuts, low-sugar fruits, oils, honey Avoid: starches, grains, pasta, legumes, and breads

none

Maker’s Diet 40 day diet and lifestyle regimen based upon “biblical principles”

Focuses on four components of total health- physical, mental, spiritual, and emotional. Consists of a phased approach. Recommended foods are unprocessed, unrefined, and untreated with pesticides or hormones

none

Anti-inflammatory Diet

Provide foods rich in flavonoids and phytonutrients

Avoid red meat, dairy-favour vegetables, fish, olive oil, walnuts, etc.

none

Brown AC, Roy M. Does evidence exist to include dietary therapy in the treatment of Crohn’s disease? Expert Rev. Gastroenterol. Hepatol.4(2),191–215 (2010).

DIET RESEARCH: ASSOCIATIONS 2011 review article showed associations between dietary intake and risk of IBD Fats and Meats • High dietary intakes associated with an increased risk of IBD Fibre and Fruits • High dietary intakes were associated with decreased risk of CD Vegetables • High dietary intake was associated with decreased risk of UC Limitations with review (different studies, majority were

retrospective).No particular foods, but component common to many foods may have a role. Studies did not explore role of diet on current disease activity.

Hou JK, et al. Am J Gastroenterol . 2011;

CONTROL IBD SYMPTOMS Avoid “trigger” foods Not all IBD patients are affected by the same foods Common foods that may cause GI discomfort:

• High-fibre foods (e.g., nuts, raw, leafy vegetables) • High-fat foods (e.g., greasy, fried foods) • Caffeine (e.g., coffee, tea, soda, chocolate) • Alcohol • Carbonated beverages • Dairy (lactose) • Sugar alcohols in sugar-free foods (e.g., sorbitol) • Spicy foods

DYSBIOSIS AND IBD

• Illness occurs through changes in gut microbiota from drugs, environmental toxins and climate all stimulate or inhibit different types of microorganisms

• 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

SKEWING THE MICROBIOME AND IBD

Devkota S, Wang Y, Musch MW, Leone V, Fehlner-Peach H, Nadimpalli A, Antonopoulos DA, Jabri B, Chang EB. Nature. 2012 Jul 5;487(7405):104-8

The data provide a plausible mechanistic basis by which Western-type diets high in certain saturated fats might increase the prevalence of complex immune-mediated diseases like inflammatory bowel disease in genetically susceptible hosts.

MILK FAT INDUCES COLITIS IN GENETICALLY SUSCEPTIBLE HOST VIA

DYSBIOSIS

Devkota S, Wang Y, Musch MW, Leone V, Fehlner-Peach H, Nadimpalli A, Antonopoulos DA, Jabri B, Chang EB. Nature. 2012 Jul 5;487(7405):104-8

SCOPE OF PROBIOTIC PRODUCTS AND USES

Sanders M E et al. Gut 2013;62:787-796

PROBIOTICS PREVENTS UC FLARE

POTENTIAL MECHANISMS OF ACTION OF SACCHAROMYCES BOULARDII (SBC).

World J Gastroenterol. 2010 May 14; 16(18): 2202–2222.

BENEFITS OF PROBIOTICS IN IBD: MECHANISMS OF ACTION

INHIBIT PATHOGENIC BACTERIA

IMPROVE EPITHELIAL FUNCTION

IMMUNOREGULATION

pH SCFA’s IL-10, TGF

Bacteriocidal proteins Healing TNF, IL-12

Epithelia binding Mucus sIgA

Epithelial invasion Barrier Integrity NFkB

World J Gastroenterol. 2010 May 14; 16(18): 2202–2222.

SBC does not prevent relapse of post-op CD Clin Gastroenterol Hepatol. 2013 Mar 1. doi:pii: S1542-3565(13)00278-4

RANDOMISED, CONTROLLED TRIALS FOR CHRONIC DISEASE CONDITIONS USING S. BOULARDII

World J Gastroenterol. 2010 May 14; 16(18): 2202–2222.

SUMMARY OF PROBIOTICS IN IBD

• No consistent effects have been noted in treating or preventing relapse of Crohn's disease.

• For ulcerative colitis, benefits have been described for a combination of Lactobacillus, Bifidobacterium and Streptococcus probiotic species or for Escherichia coli Nissle in inducing and maintaining remission of disease activity in mild to moderately severe ulcerative colitis.

• Primary prevention of pouchitis and reducing the likelihood of relapse after successful antibiotic treatment has also been successful, receiving an ‘A’ recommendation.

POSSIBLE EXPLANATIONS AND PROPOSED SOLUTIONS FOR BETTER RESULTS OF PROBIOTICS FOR IBD

Gut 2013;62:787–796. doi:10.1136/gutjnl-2012-30250

PROBIOTIC FOODS Dairy-based • Yoghurt • Cheese • Acidophilus milk • Kefir • Yogurt • Cheese • Acidophilus milk • Kefir

Nondairy-based • Brined olives • Salted gherkins • Sauerkraut • Kimchi • Miso • Natto • Tempeh • Poi • Tanzania Togwa

Lin, D.C. NCP 18:497, 2003 Lipski, E. IN: Integrative Gastroenterology 2011

PREBIOTICS IN UC

AUTHOR YEAR FIBRE STUDY OUTCOME

Fernandez-Banares

1999 Plantago Ovata seed fibre 10 gm

Fiber +/- Mesalamine

= to Mesalamine

Kanauci 2002 2003

30 gm barley Mod to active UC

disease activity

Hallert 2003 Oat bran 60 gm (20gm fibre)

In remission abd pain Increase faecal butyrate

Welters 2002 Inulin 24 gm IAPA pouch inflammation

“Relax, sir. The hair in your soup provides fibre.”

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

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 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

• Extracellular matrix

formation • Cell migration • Differentiation • Immune regulation • Tissue remodeling • Regulates inflammation • Promotes healing

TGF-β

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-3 MODULATION OF ARACHIDONIC ACID CASCADE

Cell membrane

Phospholipase A2

Arachidonic Acid

Cyclooxygenase Lipooxygenase

Leukotrienes

SRS-A

Thromboxane

A2

Prostaglandin 2 series

EPA/DHA EPA/DHA

LTB 5 PGE3

DHLA X X

W-6 FA W-6 FA

W-3 FA W-3 FA

FACTOR EFFECT OF 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-kB, PPARs adhesion molecules ↓

EFFECTS OF OMEGA-3 FATTY ACIDS ON FACTORS INVOLVED IN THE

PATHOPHYSIOLOGY OF INFLAMMATION

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

Cochrane Database Syst Rev. 2007 Oct 17;(4):CD005986. * 72% weaned off or reduced medication dose. N=159

STUDY EPA DHA CLINICAL REMISSION

ENDOSCOPIC EVIDENCE

Almallah 1998

3.2 g/d

2.4 g/d p<0.05 p=0.013

Aslan 1992

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

NR

Stenson 1992

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

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.

AN ORAL SUPPLEMENT ENRICHED WITH FISH OIL, SOLUBLE FIBRE AND ANTIOXIDANTS FOR

CORTICOSTEROID SPARING IN ULCERATIVE COLITIS: A RANDOMISED, CONTROLLED TRIAL

UCNS FORMULA PER 8 OZ

• 310 kcal [16.1/49.7/6.5% protein/CHO/lipid]

• Fish oil (1.09 g EPA/0.46 g DHA)

• 3.5 g EPA/DHA per day • FOS 2.9 g • Gum arabic 2.2 g • Calcium (mg)- 432 • Phosphorus (mg)- 300 • Magnesium (mg)- 108

• β-carotene (μg)- 1185 • Vitamin A (IU)- 1320 • Vitamin D (IU)- 192 • Vitamin E (IU)- 72 • Vitamin K (μg)- 32 • Vitamin C (mg)- 156 • Folic acid (μg)- 456 • Zn (mg)- 7 • Se (µg)- 22

AN ORAL SUPPLEMENT ENRICHED WITH FISH OIL, SOLUBLE FIBRE AND ANTIOXIDANTS FOR CORTICOSTEROID SPARING IN

ULCERATIVE COLITIS: A RANDOMISED, CONTROLLED TRIAL

Clin Gastro Hep. 2005;3:358-369.

AN ORAL SUPPLEMENT ENRICHED WITH FISH OIL, SOLUBLE FIBRE AND ANTIOXIDANTS FOR

CORTICOSTEROID SPARING IN ULCERATIVE COLITIS: A RANDOMISED, CONTROLLED TRIAL

CHANGE IN NUTRITION AND DISEASE MEASURES AFTER 4 MONTHS OF SUPPLEMENTATION

Wiese D M et al. Nutr Clin Pract 2011;

26:463-473

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

• 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 sample

Plasma phospholipid FA levels

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

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%

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

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

PREVALENCE OF VITAMIN D DEFICIENCY IN UNSELECTED COHORTS OF PATIENTS WITH IBD

V. P. Mouli and A. N. Ananthakrishnan Alimentary

Pharmacology & Therapeutics Volume 39, Issue 2, Article first published online: 17

NOV 2013

OBSERVATIONAL STUDIES OF THE ASSOCIATION BETWEEN VITAMIN D LEVELS AND OUTCOMES IN

CROHN’S DISEASE AND ULCERATIVE COLITIS 1

V. P. Mouli and A. N. Ananthakrishnan

Alimentary Pharmacology & TherapeuticsVolume 39,

Issue 2, Article first published online: 17 NOV

2013

Higher levels of 25 (OH)D3 predict lower risk of CD and higher use of vitamin D supplementation predicts lower risk of UC

Gastroenterology 2012;142;3:482-489

Gastroenterology 2012;142;3:482-489

UNANSWERED CLINICAL QUESTIONS REGARDING THE ROLE OF VITAMIN D IN INFLAMMATORY

BOWEL DISEASES

V. P. Mouli and A. N. Ananthakrishnan Alimentary Pharmacology &

TherapeuticsVolume 39, Issue 2, Article first published online: 17 NOV

2013

PATHOGENESIS OF IBD

Macrophage

Inflammation

IL2-R

T9

4F2

Activated Th1 Cell

Ag

Ag

IL-12

Mucosal injury

IL-1 IL-6 TNF-a

IL-8, MIP-1a + +

IL2-R

T9

4F2

TNF-a

ADCC

Lymphokines

OH. O2

.-

IL-2, IFN-g

IL-1

+

+

CD45R CD4

Memory T Cell

Lymphokines

ROS

(-)

Nutritional

DNA

NUCLEUS

MITOCHONDRION

PEROXISOMES LYSOSOMES

ENDOPLASMIC RETICULUM

CYTOPLASM

LIPID BILAYER OF ALL CELLULAR MEMBRANES

IMPAIRED CELLULAR DEFENSE MECHANISMS IN IBD

Vitamin E

Catalase

Cu/Zn SOD

Vitamin E + Beta-Carotene Mn

SOD + Glutathione Peroxidase + GSH

Vitamin E

Vitamin C

Glutathione Peroxidase

GSH

Vitamins C and E Beta-Carotene

Beta-Carotene

PHARMACEUTICAL MODULATION OF THE ARACHIDONIC ACID CASCADE

Cell membrane

Phospholipase A2

Arachidonic Acid

Cyclooxygenase Lipoxygenase

Leukotrienes

SRS-A

Thromboxane

A2

Prostaglandin 2 series

Cortisone X

Indomethacin

Aspirin

Ibuprofen

Sulfasalazine

X

Sulfasalazine X

Colchicine X

BOTANICAL MODULATION OF ARACHIDONIC ACID CASCADE

Mullin GE, et al, Expert Review of Gastroenterology and Hepatology, April 2008

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

NF-κB probiotics

NATURAL PRODUCTS WITH ANTI-INFLAMMATORY ACTIONS

NFkB inhibitors: • Curcuminoids • Ginger • Boswellia • Green Tea extract

(EGCG) • Bromelain • Rosemary (carnosol) • Grape Seed Extract • Phytolens (lentils) • VSL#3 • Alpha-lipoic acid

• Caffeic acid phenyl esther (CAPE) Bee Propolis

• Resveratrol • 1,25-(OH)2D3

• GLA (evening primrose oil) • EPA (fish oil)

Inflammatory inhibitors (NFkB-independent):

• DHA (fish oil) • ALA (flax seed oil) • 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

Mullin GE et al . Expert Review in Gastroenterology Expert Rev Gastroenterol Hepatol. 2008 Apr;2(2):261-80. doi: 10.1586/17474124.2.2.261

PROPHYLACTIC AND THERAPEUTIC EFFECTS OF POLYPHENOLS FOR COLITIS

POLYPHENOL N ROUTE, DOSE RESULTS

Resveratrol 2 5-10 mg/kg 2/2 IG

2/2 improvement: clinical, path, mediators, cytokines

EGCG 3 5 g/L, 50 mg/kg/D 1 IP, 2 PO

3/3 improvement: clinical, path, mediators, cytokines

Curcumin 6 2%, 30-300 mg/kg/D 6 PO, 1 IP

6/6, improvement: clinical, path, mediators, cytokines, markers 4/7 ↑ survival

Quercetin 6 5 PO/IG, 0.25-50 mg/kg/D, enema 10-100 mM/D

Overall 3/6 showed efficacy Enema ineffective

Animal Studies

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

TOP FOOD ANTIOXIDANTS

Cinnamon Aronia black chokeberry Dry Small Red Bean Dry Red kidney bean Dry Pinto bean Dry Black bean Prune ½ cup Pecan 1 oz

Wild blueberry Blueberry Cranberry Artichoke hearts Blackberry cultivated Raspberry Strawberry Sweet cherry

Nutrient Data Laboratory, Agriculture Research Service, US Department of Agriculture

PLEASE PASS THE BERRIES!

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

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 • Randomised, multicentre, 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

Madisch et al 2007

DBRCT Collagenous colitis

Placebo 6 wks Maintenance of remission superior with Boswellia

Gupta et al 2001

Randomized IBD Sulfasalazine 6 wks

Induction of remission superior with Boswellia

Gupta et al 2001

Randomized UC Sulfasalazine 6 wks Induction of remission not different

Gerhardt et al 2001

DBRCT CD Mesalamine 8 weeks Boswelia H15 36% Meslamine 31% remission

Holtmeirer er al 2011

DBRCT CD Placebo 52 weeks Boswellia PS0201Bo 60%vs. P 55% remission at 52 wks

The herbal preparation of myrrh, chamomile extract and coffee charcoal is well tolerated and shows a good safety profile. We found first evidence for a potential efficacy non-inferior to the gold standard therapy mesalazine, which merits further study of its clinical usefulness in maintenance therapy of patients with ulcerative colitis.

EudraCT-Number 2007-007928-18. Aliment Pharmacol Ther 2013; 38: 490–500

Aliment Pharmacol Ther. 2013 Oct;38(8):854-63. doi: 10.1111/apt.12464. Epub 2013 Aug 2

SYSTEMATIC REVIEW: THE EFFICACY OF HERBAL THERAPY IN INFLAMMATORY BOWEL DISEASE

Alimentary Pharmacology & Therapeutics 25 AUG 2013 DOI: 10.1111/apt.12464 http://onlinelibrary.wiley.com/doi/10.1111/apt.12464/full#apt12464-fig-0001

Alimentary Pharmacology & Therapeutics 25 AUG 2013 DOI: 10.1111/apt.12464 http://onlinelibrary.wiley.com/doi/10.1111/apt.12464/full#apt12464-fig-0001

Aliment Pharmacol Ther. 2013 Oct;38(8):854-63. doi: 10.1111/apt.12464. Epub 2013 Aug 2

FLOW DIAGRAM OF THE STUDY SELECTION PROCESS. ASA: AMINOSALICYLIC ACID

RESULTS FOR OUTCOMES INVESTIGATED FOR EACH

INCLUDED STUDY

Rahimi et al. World Journal of Gastroenterology Sept 14, 2013; 19;34:5738-5749.

RESULTS OBTAINED FROM SUB-ANALYSES BASED ON PLANT TYPE

Rahimi et al. World Journal of Gastroenterology Sept 14, 2013; 19;34:5738-5749.

INDIVIDUAL AND POOLED RELATIVE RISK (A), HETEROGENEITY INDICATORS (B) AND PUBLICATION BIAS INDICATORS (C) FOR THE OUTCOME OF “CLINICAL

REMISSION” IN THE STUDIES CONSIDERING HERBAL MEDICINES COMPARING TO PLACEBO THERAPY IN INFLAMMATORY BOWEL DISEASE (IBD) PATIENTS.

Rahimi et al. World Journal of Gastroenterology Sept 14, 2013; 19;34:5738-5749.

INDIVIDUAL AND POOLED RELATIVE RISK (A), HETEROGENEITY INDICATORS (B) FOR THE OUTCOME OF “CLINICAL REMISSION” IN THE STUDIES CONSIDERING

HERBAL MEDICINES COMPARING TO PLACEBO THERAPY IN ULCERATIVE COLITIS (UC) PATIENTS.

Rahimi et al. World Journal of Gastroenterology Sept 14, 2013; 19;34:5738-5749.

INDIVIDUAL AND POOLED RELATIVE RISK (A), HETEROGENEITY INDICATORS (B) AND PUBLICATION BIAS INDICATORS (C) FOR THE OUTCOME OF

“CLINICAL RESPONSE” IN THE STUDIES CONSIDERING HERBAL MEDICINES COMPARING TO PLACEBO THERAPY IN IBD PATIENTS.

Rahimi et al. World Journal of Gastroenterology Sept 14, 2013; 19;34:5738-5749.

Rahimi et al. World Journal of Gastroenterology Sept 14, 2013; 19;34:5738-5749.

INDIVIDUAL AND POOLED RELATIVE RISK (A), HETEROGENEITY INDICATORS (B) FOR THE OUTCOME OF “CLINICAL RESPONSE” IN THE STUDIES CONSIDERING HERBAL MEDICINES COMPARING TO PLACEBO THERAPY FOR CROHN’S DISEASE CD (LEFT) AND UC (RIGHT) PATIENTS

INDIVIDUAL AND POOLED RELATIVE RISK (A), HETEROGENEITY INDICATORS (B) FOR THE OUTCOME OF “ENDOSCOPIC REMISSION” IN

THE STUDIES CONSIDERING HERBAL MEDICINES COMPARING TO PLACEBO THERAPY FOR UC PATIENTS.

Rahimi et al. World Journal of Gastroenterology Sept 14, 2013; 19;34:5738-5749.

INDIVIDUAL AND POOLED RELATIVE RISK (A), HETEROGENEITY INDICATORS (B) FOR THE OUTCOME OF

“ENDOSCOPIC REMISSION” IN THE STUDIES CONSIDERING HERBAL MEDICINES COMPARING TO

PLACEBO THERAPY FOR UC PATIENTS.

Rahimi et al. World Journal of Gastroenterology Sept 14, 2013; 19;34:5738-5749.

INDIVIDUAL AND POOLED RELATIVE RISK (A), HETEROGENEITY INDICATORS (B) AND PUBLICATION BIAS INDICATORS (C) FOR THE OUTCOME OF “ANY ADVERSE EVENTS”(LEFT)

AND “SERIOUS ADVERSE EVENTS “ (RIGHT) IN THE STUDIES CONSIDERING HERBAL MEDICINES COMPARING TO PLACEBO THERAPY IN IBD PATIENTS.

Rahimi et al. World Journal of Gastroenterology Sept 14, 2013; 19;34:5738-5749.

An improvement in hemoglobin level (11.8±1.6 g/dL vs. 13.4±1.2 g/dL, P<0.05) and erythrocyte sedimentation rate (23.7±11.5 mm/h vs.10.8±3.2 mm/h, P<0.05) was observed in the silymarin group but not in the placebo group. DAI significantly decreased in the silymarin group and reached from 11.3±3.5 to 10.7±2.8 (P<0.05). Thirty-five out of 38 patients in the silymarin group were in complete remission with no flare-up after 6 months as compared to 21 out of 32 patients in the placebo group (P=0.5000). CONCLUSION: Silymarin as a natural supplement may be used in UC patients to maintain remission.

NUTRACEUTICALS & IBD NOT READY FOR PRIME TIME

• Alpha Lipoic Acid 500 mg 2-3/D • NAC 800 mg/D • L-Carnitine 1,000 mg/D • Vitamin E enemas 800 IU/D • Phosphatidyl choline 500 mg QID delayed

release

NUTRITIONALS SHOWING EFFICACY IN IBD

MULTIPLE STUDIES • Elemental Diet • Modulen • Prebiotics • Probiotics • Turmeric • Fish Oils • Artemesia absinthium • Triticum Aestivum

SINGLE STUDIES • Boswellia serrata • Lycopene • Aloe vera • Andrographis paniculata

extract (HMPL-004) • Ginger • Wheatgrass juice • Silymarin • UCNS • CDNS

CONCLUSION

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

A B high

Aminosalicylates A moderate

Corticosteroids A high

* Transforming growth factor

THERAPEUTIC MODALITIES FOR IBD

Azathioprine

TAKE HOME POINTS • Polyphenols, fish oils, probiotics, vitamin D,

antioxidants: downregulate inflammation to “cool the fire in the gut”

• Short chain fatty acids are colonic-specific anti-inflammatory nutrients

• SBC, arabinogalactans, MCTs, whey, raw milk, pre- and probiotics - Immune Modulators

• High ORAC foods, wild cold-water fish, etc. Think of food as medicine first!

Pt with diarrhoea, wt. loss, abd pain,

inflammatory markers

Evaluate for Inflammatory Bowel Disease

Other Diagnoses IBD Localisation, colitis vs. enteritis

Colitis

Short Chain Fatty Acid Enemas

Prebiotics, Ca Mg Butyrate

Anti-inflammatory Diet

Enteritis

Glutamine, Aloe, zinc-L-carnosine

SCD, low FODMAPs

Dysbiosis, Immune Regulators

Systemic Inflammation. Fish Oil, Curcumin, Bowsellia, Vitamin D, Elimination diet

Consider Coeliac Disease and/or other

Dx

Symptoms Persist

Serology, Radiology, WCE

“Let medicine be thy food and let food be thy medicine”

Hippocrates