PATHOGENESIS AND INTEGRATIVE MANAGEMENT OF INFLAMMATORY BOWEL - PowerPoint PPT Presentation

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 Initiating Mucosal Abnormal Chronic Events Damage Immune Response Inflammation NSAIDs Translocation of Th1/Th17 vs. Th2 Luminal antigens luminal contents Antibiotics Food antigens Infections Bacteria Viral Bacterial products FMLP Bacterial LPS Parasitic PGPS

PATHOGENESIS OF IBD Ag T9 Ag 4F2 T9 IL-12 IL-1 4F2 IL2-R IL2-R + Activated Th1 Cell Macrophage + + CD4 TNF-a Lymphokines IL-2, IFNg OH . CD45R IL-1 IL-6 O 2 .- IL-8, MIP-1a Memory T Cell TNF-a Lymphokines ADCC + 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)

SUMMARY: EFFECTIVENESS OF NUTRITIONAL SUPPORT FOR CROHN’S DISEASE Enteral > Placebo Enteral < GCS Enteral = TPN Polymeric = Elemental

ENTERAL NUTRITION MECHANISMS OF ACTION? Bowel Rest Fat Antigenic Composition Load Enteral Nutrition Glutamine Gut Flora Gut Permeability

POPULAR DIETS FOR IBD DIE IET RAT ATIONALE PLA PLAN EVID IDENCE Elimination Lower antigenic burden-up to Eliminate known and suspected provocative Mishkin S. 66% of CD pts. report food foods 2-4 weeks then reintroduce: 1 new Am J Clin Nutr. intolerances 1 food per day-process may take 2-3 months 1997 Feb;65(2):564-7. Giaffer MH, Cann P , Holdsworth CD. Aliment Pharmacol Ther. 1991 Apr;5(2):115-25 Specific Eliminate poorly digestible Allowed: meat, fish, eggs, vegetables, nuts, none Carbohydrate Diet CHO’s to limit fermentation low-sugar fruits, oils, honey in small bowel. Avoid: starches, grains, pasta, legumes, Avoid complex carbohydrates and breads Maker’s Diet 40 day diet and lifestyle Focuses on four components of total none regimen based upon health- physical, mental, spiritual, and “biblical principles” emotional. Consists of a phased approach. Recommended foods are unprocessed, unrefined, and untreated with pesticides or hormones Anti-inflammatory Provide foods rich in Avoid red meat, dairy-favour vegetables, none Diet flavonoids and phytonutrients fish, olive oil, walnuts, etc. 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 Fa Fats and and Me Meat ats • High dietary intakes associated with an increa eased ed risk of IBD Fib ibre re and and Fru ruit its • High dietary intakes were associated with dec ecrea eased sed risk of CD Veg eget etables es • High dietary intake was associated with dec ecrea eased ed 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 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. 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

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 INHIBI BIT P PATHO HOGENIC C IMPROVE VE E EPITHELI LIAL L IMMUNORE OREGULATION ON BACTER ERIA IA FUNCTION ON pH SCFA’s IL-10, TGF Bacteriocidal proteins Healing TNF , IL-12 Epithelia binding Mucus sIgA Epithelial invasion Barrier Integrity NFkB

RANDOMISED, CONTROLLED TRIALS FOR CHRONIC DISEASE CONDITIONS USING S. BOULARDII SBC does not prevent relapse of post-op CD Clin Gastroenterol Hepatol. 2013 Mar 1. doi:pii: S1542-3565(13)00278-4 World J Gastroenterol. 2010 May 14; 16(18): 2202–2222. 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 Nondairy-based Dairy-based • Brined olives • Yoghurt • Salted gherkins • Cheese • Sauerkraut • Acidophilus milk • Kimchi • Kefir • Miso • Natto • Yogurt • Tempeh • Cheese • Poi • Acidophilus milk • Tanzania Togwa • Kefir Lin, D.C. NCP 18:497, 2003 Lipski, E. IN: Integrative Gastroenterology 2011

PREBIOTICS IN UC AUTHO UTHOR YEAR AR FIBRE BRE STUD TUDY OU OUTCO COME Fernandez- 1999 Plantago Ovata Fiber +/- = to Mesalamine Banares seed fibre 10 gm Mesalamine Kanauci 2002 30 gm barley Mod to active UC 2003 disease activity Hallert 2003 Oat bran 60 gm In remission abd pain (20gm fibre) 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

TGF- β TGF • Extrac acell llular ar m matrix ix format ation • Ce Cell m migr gration • Di Diffe fferentiat atio ion • Immun une r e regul ulation • Tissue r remode delin ing • Regu gula lates i infla lammat ation • Promotes h heal aling

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-1 β , IL-8, and IFN- γ • Th The e rel elapse se rate w e was h s high a after er rem emiss ssion achieved eved w with nutritional nal t therapy py 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.