Treatment of GI Dysfunction in the Context of the Functional Medicine Matrix PDF

Treatment of GI Dysfunction in the Context of the Functional Medicine Matrix TOM SULT, MD Applying Functional Medicine in Clinical Practice  Disclosure Tom Sult, MD disclosed he is...

Treatment of GI Dysfunction in the Context of the Functional Medicine Matrix TOM SULT, MD Applying Functional Medicine in Clinical Practice  Disclosure Tom Sult, MD disclosed he is a consultant for Mend After and is on the Scientific Advisory Board of Nutrition Dynamics. ©2021 The Institute for Functional Medicine  Evidence Icons: Key Clinical Disclaimers: Study Types: Association, not causation Animal study Lab test (Labs not generally accepted in conventional care) In vitro study Clinical experience (Intervention warranted by historical clinical experience of ©2021 The Institute for Functional Medicine educator and/or functional medicine community of practitioners in the context of evidentiary paucity) n of 1, or single-case study Clinical judgment (Intervention warranted by clinical judgment of educator and/or functional medicine community of practitioners in the context of evidentiary paucity) In silico (Computerized molecular modeling) Conflict of interest  Performance Objectives Following this activity, successful participants will be able to… 1. Review and clarify the Functional Medicine Timeline, Matrix, and the concepts of Antecedents, Triggers, and Mediators. 2. Discuss the importance of understanding the patient’s individual story. ©2021 The Institute for Functional Medicine 3. Identify key “leverage points” to utilize therapeutically with individual patients.  Performance Objectives Following this activity, successful participants will be able to… 4. Define the components of the 5R framework (Remove, Replace, Re- inoculate, Repair, Rebalance). 5. Select and interpret functional GI laboratory evaluation to help guide personalized implementations of the 5R approach in patient with gastrointestinal dysfunction. ©2021 The Institute for Functional Medicine 6. Develop individual treatment protocols for patients with gastrointestinal dysfunction, using a framework of remove, replace, reinoculate, repair, rebalance. 7. Recognize how laboratory evaluation can help guide the implementation of the 5R approach.  Review The GI system is an integral and central “node” of the complex web of functional medicine. Dysregulation of the GI system can have a ©2021 The Institute for Functional Medicine profound impact on health.  We Have Reviewed the Key Functional Roles of the Gut and How To Evaluate Them: ©2021 The Institute for Functional Medicine  The Case of Joan Recall the case as first presented by Dr. Hughes Recall the case as expanded by Dr. Hanaway Recall the case Timeline ©2021 The Institute for Functional Medicine Recall the case Matrix Gather Oneself & Information Organize on the Matrix, Time Line T O ©2021 The Institute for Functional Medicine I T G O T O I T Gather Oneself & Information Organize on the Matrix, Time Line… Tell the Patient’s Story O ©2021 The Institute for Functional Medicine I T G O T O I T ©2021 The Institute for Functional Medicine Quilligan S, Silverman J. The skill of summary in clinician-patient communication: a case study. Patient Educ Couns. 2012 Mar;86(3):354-9. doi: 10.1016/j.pec.2011.07.009. Finefrock D, et al. Patient-Centered Communication Behaviors That Correlate With Higher Patient Satisfaction Scores. J Patient Exp. 2018 Sep;5(3):231-235. doi: 10.1177/2374373517750414.  Mastering The Story: The Science and Art Of Healing Think deeply about the context of the story. Think deeply about the physiology behind the story. Be patient: allow the story to unfold. Be the audience: don’t interrupt; only at ©2021 The Institute for Functional Medicine appropriate points ask thoughtful probing questions. Help them amplify their story. Muneeb A, Jawaid H, Khalid N, Mian A. The Art of Healing through Narrative Medicine in Clinical Practice: A Reflection. Perm J. 2017;21:17–013. doi:10.7812/TPP/17-013 Zaharias G. What is narrative-based medicine? Narrative-based medicine 1. Can Fam Physician. 2018;64(3):176–180.  Mastering The Story: The Science and Art Of Healing Be inclusive vs. exclusive in the history Look for patterns that connect Retell the story: re-create meaning Connect, educate, inspire, motivate ©2021 The Institute for Functional Medicine Assess the readiness to change Activate nature – the greatest pharmacy  What Is Joan’s Story – How Would You Tell It? ©2021 The Institute for Functional Medicine  What is the conventional retelling of the story? Joan, you appear to have IBS and Depression. The good news is that we have an opportunity to “kill two birds with one stone” so to speak. An antidepressant will help your depression. ©2021 The Institute for Functional Medicine The same antidepressant will also help your IBS. Pick up your med at the pharmacy and let’s follow up in a few weeks If you are not improved, I think a new GI work up is in order.  How might you now retell the story? What tools do you use to retell the story? ATMs Timeline ©2021 The Institute for Functional Medicine Matrix ©2021 The Institute for Functional Medicine  Stress as single mom Stress as single mom Weight Weight Weight has has continued continued to Weight gain gain in in “creep up” over the to years college “creep up” over the years college Mother Mother SAD SAD History History of of Depression Depression FmFmHxHxIBS, IBS,Diverticulitis Diverticulitis Bottle @@ Bottle 4 wk; 4 wk;Solid Solidfood food@6mo @6mo “Post “Post partum partum depression” depression” Hx HxOMOMRxRx ABX ABX after after each; each; no no treatment treatment Vag Vag Delivery Delivery Tonsillectomy @ Tonsillectomy @ 4yo 4yo Solid foods at 6 months Vag Vag Delivery Delivery Parents Parents divorced divorced Bottle Bottle fed fed @ @ 4wks 4wks Mother Mother Remarried Remarried Married Married Divorced Divorced membrane rupture prolongedABX dt Vag Birth 3 4 7 9 10 25 27 29 34 44 ©2021 The Institute for Functional Medicine Colic @ 6 weeks Abdominal Abdominal Pain Pain Missed Gas Gas & Bloating, & Bloating, Missed school school GI Frequent Frequent non-bloody non-bloody GI eval, eval, no no scopes scopes stools, “sensitive stools, “sensitive Tonsillectomy @4yo stomach”” stomach Dx Dx as as lactose lactose Feeling Feeling of of incomplete incomplete intolerance intolerance partial partial voiding, voiding, low low energy, energy, 3-5 bouts of OM treated improvement. depressed mood with ABX improvement. depressed mood  Clarifying The Most Important Antecedents, Triggers, And Mediators Antecedents: Triggers: Mediators: Fm Hx IBS, Multiple antibiotics Adiposity Diverticulitis Standard American Depression Bottle @ 4 wk Diet Solid food @ 6 Nutritional Impaired digestion by ©2021 The Institute for Functional Medicine mo insufficiencies lab Hx OM Rx ABX Blastocystis hominis, Tonsillectomy @ dysbiosis presumed 4yo Increased IP  Stress as single mom Stress as single mom Weight Weight Weight has has continued continued to Weight gain gain in in “creep up” over the to years college “creep up” over the years college Mother Mother SAD SAD History History of of Depression Depression Fm Hx IBS, Diverticulitis Fm Hx IBS, Diverticulitis Bottle Bottle @ @44 wk; wk; Solid Solid food food @6mo @6mo “Post “Post partum partum depression” depression” Hx Hx OM OM Rx Rx ABX after ABX Vag after each; each; no no treatment treatment Tonsillectomy Tonsillectomy @@ 4yo 4yo Vag Delivery Delivery Solid foods at 6 months Vag Vag Delivery Delivery Parents Parents divorced divorced Bottle Bottle fed fed @ @ 4wks 4wks Mother Mother Remarried Remarried Married Married Divorced Vag Birth prolongedABX dt Divorced membrane rupture 3 4 7 9 10 25 27 29 34 44 ©2021 The Institute for Functional Medicine Colic @ 6 weeks Abdominal Abdominal Pain Pain Missed Gas Gas & Bloating, & Bloating, Missed school school GI Frequent Frequent non-bloody non-bloody GI eval, eval, no no scopes scopes stools, “sensitive stools, “sensitive Tonsillectomy @4yo stomach”” stomach Dx Dx as as lactose lactose Feeling Feeling of of incomplete incomplete intolerance intolerance partial partial voiding, voiding, low low energy, energy, 3-5 bouts of OM treated improvement. depressed mood with ABX improvement. depressed mood  Retelling the Patient’s Story Physiology and Function: Organizing the Patient’s Clinical Imbalances Antecedents Assimilation Defense & Repair Gas and Bloating SAD (inflammatory diet) Freq stools Mother SAD Fm Hx IBS, Diverticulitis Bottle @ 4 wk; Solid food @6mo Hx OM Rx ABX Stressful job Triggering Events Tonsillectomy @ 4yo Structural Integrity Family Dynamic? Fatigue Energy Parents divorced @7 History of Depression Abdominal pain @10 Lactose Intolerant 2 kids @27&29 wt post part dep. Divorced at 34yo (two teen boys) Depression Mediators/Perpetuators Stress (adrenal reserve) Spiritual Communication Biotransformation & Elimination SAD Transport ©2021 The Institute for Functional Medicine Weight gain in college the problem typically isn't the stressor itself, but our relationship to the stressor Personalizing Lifestyle Factors Sleep & Relaxation Nutrition & Hydration Stress & Resilience Poor quality and quantity; SAD; quick meals due to being Kids are a “handful” Not dating and rarely has time to NONE; “no time” busy has to be up to get the kids Job is stressful as bank exec socialize ready Eats out often asst. Name:____________________________ Date:___________ CC:_____________________________________ © Copyright 2011 Institute for Functional Medicine  What Are The Triggers of Increased IP? Food antigens/other components Increased uptake of food antigens Stress Infections Dysbiosis Immune activation Altered Malabsorption/ Inflammation Intestinal Intestinal inflammation Malnutrition Systemic disease Permeability ©2021 The Institute for Functional Medicine Many diseases Impaired digestion, i.e., low stomach acid, etc. Toxins Increased uptake of Nutritional insufficiencies toxins and Various medications lipopolysaccharides  References: Triggers of Intestinal Permeability > Dietary choices: Kelly JR, Kennedy PJ, Cryan JF, Dinan TG, Clarke G, Hyland NP. Breaking down the barriers: the gut microbiome, intestinal permeability and stress related psychiatric disorders. Frontiers in Cellular Neuroscience. 2015;9:392. doi:10.3389/fncel.2015.00392. > Stress: Vanuytsel T, van Wanrooy S, Vanheel H, et al. Psychological stress and corticotropin releasing hormone increase intestinal permeability in humans by a mast cell dependent mechanism. Gut. 2014 Aug; 63(8):12939. doi: 10.1136/gutjnl 2013305690. > Infection: Kukuruzovic R, Robins, Browne RM, Anstey NM, Brewster DR. Enteric pathogens, intestinal permeability and nitric oxide production in acute gastroenteritis. Pediatr Infect Dis J. 2002 Aug;21(8):730-9. > Dysbiosis: Brown K, DeCoffe D, Molcan E, Gibson DL. Diet induced dysbiosis of the intestinal microbiota and the effects on immunity and disease. Nutrients. 2012;4(8):1095-1119. doi:10.3390/nu4081095 > Inflammation: Michielan A, D’Incà R. Intestinal Permeability in Inflammatory Bowel Disease: Pathogenesis, Clinical Evaluation, and Therapy of Leaky Gut. Mediators of Inflammation. 2015;2015:628157. doi:10.1155/2015/628157 > Systemic Disease: Arrieta MC, Bistritz L, Meddings JB. Alterations in intestinal permeability. Gut. 2006;55(10):1512-1520. doi:10.1136/gut.2005.085373. ©2021 The Institute for Functional Medicine > Impaired Digestion: Centanni M, Marignani M, Gargano L, Corleto VD, Casini A, Delle Fave G,Andreoli M, Annibale B. Atrophic body gastritis in patients with autoimmune thyroid disease: an underdiagnosed association. Arch Intern Med. 1999 Aug 9-23;159(15):1726-30. > Toxins: Pinton P, Nougayrède JP, Del Rio JC, et al. The food contaminant deoxynivalenol, decreases intestinal barrier permeability and reduces claudin expression. Toxicol Appl Pharmacol. 2009 May 15;237(1):41-8. doi: 10.1016/j.taap.2009.03.003. > Nutritional Deficiencies: Tran CD, Hawkes J, Graham RD, et al. Zinc-fortified oral rehydration solution improved intestinal permeability and small intestinal mucosal recovery. Clin Pediatr (Phila). 2015 Jun;54(7):676-82.doi: 10.1177/0009922814562665. > Medications: Dethlefsen L, Relman DA. Incomplete recovery and individualized responses of the human distal gut microbiota to repeated antibiotic perturbation. Proc Natl Acad Sci U S A. 2011 Mar 15;108 Suppl 1:4554 61. doi: 10.107 3/pnas.1000087107. > Food Allergy: Järvinen KM, Konstantinou GN, et al. Intestinal permeability in children with food allergy on specific elimination diets. Pediatr Allergy Immunol. 2013 Sep;24(6):589-95. doi: 10.1111/pai.12106. > Malnutrition: Norman K, Pirlich M, Schulzke JD, Smoliner C, Lochs H, Valentini L, Bühner S. Increased intestinal permeability in malnourished patients with liver cirrhosis. Eur J Clin Nutr. 2012 Oct;66(10):1116-9. doi: 10.1038/ejcn.2012.104. Gather Oneself & Information Organize on the Matrix, Time Line Tell the Patient’s Story Order your Priorities ©2021 The Institute for Functional Medicine I T G O T O I T  Unless there is a compelling reason to do otherwise – TREAT THE GUT. ©2021 The Institute for Functional Medicine  Treatment Approaches for Gut Dysfunction: The 5R Program A conceptual framework designed to: Supply a scaffold to build targeted, individualized intervention Systematize a process to normalize critical ©2021 The Institute for Functional Medicine gastrointestinal functions  The 5R Framework Remove Replace Reinoculate ©2021 The Institute for Functional Medicine Repair Rebalance  The Conceptual Approach Asks 5 Basic Questions: 1. What does this patient need to have Removed? 2. What does this patient need to have Replaced? 3. What does this patient need in terms of support and/or re-establishment of a healthy balance of microflora; that is, what does he/she require to Reinoculate the gut? ©2021 The Institute for Functional Medicine 4. What does this patient require to support healing and Repair of the GI epithelial barrier? 5. What does this patient need to do to Rebalance their lifestyle; that is, are there ways to modify their attitude and lifestyle to promote a healthier way of living, and thus healthier gut balance?  “Remove” Remove refers to the elimination of factors such as: Foods to which an individual is sensitive, intolerant, or allergic Pathogenic microflora (e.g., bacteria, fungi, parasites) Environmental stressors such as pollutants Stress Clinical approaches may include: ©2021 The Institute for Functional Medicine Oligoantigenic elimination diet Botanical antimicrobials or bacteriostatic/bacteriocidal phytonutrients Antibiotics/Antifungal medications Removal of toxins and stressors  “Replace” Replace refers to the replacement of factors that may be inadequate or lacking. Clinical approaches may include: Digestive factors Hydrochloric acid ©2021 The Institute for Functional Medicine Pancreatic enzymes Bile salts Fiber to support transit and general GI function  “Reinoculate” Reinoculate refers to the reintroduction of desirable GI microflora (prebiotics, probiotics, synbiotics) to obtain a more desirable balance to the intestinal milieu. Clinical approaches may include: Probiotics may include: Bifidobacteria strains Lactobacillus strains Saccharomyces boulardii ©2021 The Institute for Functional Medicine Prebiotics may include: prebiotics are the fertilizing agents for probiotics Inulin or fructooligosaccharides (FOS) Various other soluble fibers Synbiotics may include: Bifidobacteria and FOS Lactobacillus and inulin  “Repair” Repair refers to providing nutritional support for healing and regeneration of the GI mucosa. Clinical approaches may include: Nutrients important for GI repair and healing: glutamine, arginine, vitamin A, vitamin D, vitamin C, zinc, pantothenic acid, vitamin E, carotenoids Mucosal lining support (e.g., phosphatidylcholine) ©2021 The Institute for Functional Medicine Mucosal secretion protectants such as phosphatidylcholine, plantain, polysaccharides Support for GALT function (e.g., lactoferrin, lactoperoxidase, whey immunoglobulins) Antioxidants known to function in the GI (e.g., catechins) Nutritional and phytonutritional anti-inflammatories (e.g., curcumin, EPA, and DHA)  “Rebalance” Rebalance refers to providing support for restorative processes in a patients life. Clinical approaches may include: ‘Scheduling’ relaxation Mindful eating and better choices ©2021 The Institute for Functional Medicine Heart rate variability/ biofeedback Yoga, meditation, prayer, breathing, or other centering practices Psychotherapy ©2021 The Institute for Functional Medicine To Help Joan? How Can We Use The 5R’s Gather Oneself & Information Organize on the Matrix, Time Line Tell the Patient’s Story Order your Priorities ©2021 The Institute for Functional Medicine Initiate Assessment and Care T G O T O I T ©2021 The Institute for Functional Medicine  Practical Applications Using The “5R” Approach What does Joan need to have Removed? Foods to which an individual is sensitive, intolerant, or allergic Pathogenic microflora (e.g., bacteria, fungi, parasites) ©2021 The Institute for Functional Medicine Environmental toxins such as pollutants Stress  Nutrition Therapeutic Nutrition Assessments Interventions Gather Organize The ABCDs of Nutrition Re-Tell ©2021 The Institute for Functional Medicine Evaluation Order/Prioritize Initiate PFC-MVP Biomarkers  Who: Those who haven’t been successful with conventional medical therapy. Expected Length: Short-term (for at least 3 weeks or until symptoms resolve followed by Reintroduction Phase) Aspects of the Diet: gut/microbiome ©2021 The Institute for Functional Medicine healing and support, food trigger identification, reduction of inflammation, DF/GF, increased phytonutrients, toxic burden reduction (from genes, toxic exposures, dietary exposures), increased body awareness of food, no calorie restriction  Introducing the Elimination Diet ©2021 The Institute for Functional Medicine Reducing foods that can trigger systemic reactions in order to reduce inflammation, lower the allergenic load, and provide the gut with a dietary base to allow for restoration See References: Supporting Research for Elimination Diet  References: Supporting Research for Elimination Diet 1. A vegan diet free of gluten improves the signs and symptoms of rheumatoid arthritis: the effects on arthritis correlate with a reduction in antibodies to food antigens. Rheumatology 2001 Oct;40 (10):1175-9 2. Oral cromolyn sodium in comparison with elimination diet in the irritable bowel syndrome, diarrheic type. Multicenter study of 428 patients. Scand J Gastroenterol 1995 Jun;30 (6):535-41 3. The diet factor in pediatric and adolescent migraine. Pediatr Neurol. 2003 Jan;28(1):9-15. 4. Randomised controlled trial of advice on an egg exclusion diet in young children with atopic eczema and sensitivity to eggs. Pediatr Allergy Immunol. 1998 Feb;9(1):13-9 5. Crohn's disease: maintenance of remission by diet. Lancet 1985 Jul 27;2(8448):177-80 6. Immune sensitization to food, yeast and bacteria in Crohn's disease. Aliment Pharmacol Ther. 2001 Oct;15(10):1647-53 7. Food allergy and adult migraine: double-blind and mediator confirmation of an allergic etiology Allergy 1985 Aug;55(2):126-9 8. Fermentable Oligosaccharides, disaccharides, monosaccharides and polyols ( FODMAPs) and non allergenic food intolerance: FODMAPs or food chemicals? Gastroenterology July 2012;5(4):261-268 9. Practical use of the new American Urological Association Interstitial cystitis Guidelines. Curr Urol Rep July 2012 ©2021 The Institute for Functional Medicine 10. Elimination diet effectively treats eosinophilic esophagitis in adults; food reintroduction identifies causative factors. Gastroenterology June 2012; 142(7):1451-1459 11. Non-Celiac wheat sensitivity diagnosed by the double-blind placebo controlled challenge: exploring a new clinical entity. Am J Gastroenterol Jul 2012 12. Spectrum of gluten related disorders: consensus on new nomenclature and classification. BMC Med 2012 10:13 13. Lucendo et al. Empiric 6-food elimination diet induced and maintained prolonged remission in patients with adult eosinophilic esophagitis: A prospective study on food cause of disease. J Aller Clin Immunol: 2013:131;797-804 14. Irritable Bowel Syndrome: the role of food management in pathogenesis and management. Gastroenterol Hepatol 2014; Mar 10 (3):164-74. 15. Intestinal barrier function and the brain-gut axis.. Adv Exp Med Biol 2014; 817:73-113 16. High Prevalence of abnormal gastrointestinal permeability in moderate severe asthma. Clin Invest Med. 2014;Apr 1;37(2):E53-7. 17. Small Intestinal Permeability in Older Adults. Physiol Rep 2014; Apr 22;2(4) 18. Gastric Barrier and Toxic Damage. Dig Dis 2014;32(3):235-42. 19. Food Allergy in Irritable Bowel Syndrome: The Case of Non-celiac Wheat Sensitivity. World J of Gastroenterol June 21 2015;21(23) 7089-7091  References: Supporting Research for Elimination Diet 1. Gaby AR. The role of hidden food allergy/intolerance in chronic disease. Altern Med Rev. 1998 Apr;3(2):90-100. 2. Sullivan PB. Food allergy and food intolerance in childhood. Indian J Pediatr. 1999;66(1 Suppl):S37-45. 3. Parker SL, Sussman GL, Krondl M. Dietary aspects of adverse reactions to foods in adults. CMAJ. 1988 Oct 15;139(8):711-8. 4. Olendzka-Rzepecka E, Kaczmarski M, Lebensztejn D. Therapeutic effectiveness of treatment with an elimination diet in children with atopic dermatitis of different ages. Rocz Akad Med Bialymst. 1995;40(3):602-6. 5. Wüthrich B, Hofer T. [Food allergies. III. Therapy: elimination diet, symptomatic drug prophylaxis and specific hyposensitization]. Schweiz Med Wochenschr. 1986 Oct 11;116(41):1401-10. 6. Taylor JP, Krondl MM, Csima AC. Assessing adherence to a rotary diversified diet, a treatment for 'environmental illness'. J Am Diet Assoc. 1998 Dec;98(12):1439-44. 7. Bernardini R, Novembre E, Mugnaini L, Vierucci A. Diet regimen in the treatment of food allergy. Ann Ist Super Sanita. 1995;31(4):481-8. 8. Yeung JM, Applebaum RS, Hildwine R. Criteria to determine food allergen priority. J Food Prot. 2000 Jul;63(7):982-6. ©2021 The Institute for Functional Medicine 9. Oranje AP, Wolkerstorfer A, de Waard-van der Spek FB. Natural course of cow's milk allergy in childhood atopic eczema/dermatitis syndrome. Ann Allergy Asthma Immunol. 2002 Dec;89(6 Suppl 1):52-5. 10. Turjanmaa K. "Atopy patch tests" in the diagnosis of delayed food hypersensitivity. Allerg Immunol (Paris). 2002 Mar;34(3):95-7. 11. Kitts D, Yuan Y, Joneja J, Scott F, Szilagyi A, Amiot J, Zarkadas M. Adverse reactions to food constituents: allergy, intolerance, and autoimmunity. Can J Physiol Pharmacol. 1997 Apr;75(4):241-54. 12. Schwartz RH. Allergy, intolerance, and other adverse reactions to foods. Pediatr Ann. 1992 Oct;21(10):654-5, 660-2, 665-74. 13. Nsouli TM, Nsouli SM, Linde RE, O'Mara F, Scanlon RT, Bellanti JA. Role of food allergy in serous otitis media. Ann Allergy. 1994 Sep;73(3):215-9. 14. Sicherer SH. Food allergy: when and how to perform oral food challenges. Pediatr Allergy Immunol. 1999 Nov;10(4):226-34. 15. Niec AM, Frankum B, Talley NJ. Are adverse food reactions linked to irritable bowel syndrome? Am J Gastroenterol. 1998 Nov;93(11):2184-90. ©2021 The Institute for Functional Medicine  How will an Elimination Diet help Joan? What parts of the Functional Medicine Matrix will an Elimination Diet touch? ©2021 The Institute for Functional Medicine ©2021 The Institute for Functional Medicine An touches the entire Matrix Elimination Diet  Elimination Diet “It’s hard to do an elimination diet.” Actually it is relatively easy but requires planning. Most don’t plan to fail, they fail to plan. Plan your work and work your plan! More discussion with Dr. Boham about the Comprehensive ©2021 The Institute for Functional Medicine Elimination Diet in the presentation titled “Prescribing an Elimination Diet” We recommend you experience an elimination diet YOURSELF; watch for communications regarding opportunities for Elimination Diet experientials  Laboratory: What do we know about Joan? Primary Care CBC: WNL Ferritin: 75 mg/dl TSH: 2.1 25 OH vitamin D: 47 ng/dl preferrably above 50 Gastroenterologist Celiac Serology ©2021 The Institute for Functional Medicine IGA/Immunoglobulin A (IgA): normal TTGA / Tissue Transglutaminase (tTG) IgA: negative Gliadin (Deaminated) IgA: negative Endomysial Antibody IgA: negative SIBO breath testing: WNL  Can we rule out Celiac disease? Can we rule out wheat allergy? ©2021 The Institute for Functional Medicine Can we rule out non-Celiac gluten sensitivity?  Practical Applications Using The “5R” Approach What does Joan need to have Removed? Foods to which an individual is sensitive, intolerant, or allergic Pathogenic microflora (e.g., bacteria, fungi, parasites) ©2021 The Institute for Functional Medicine Environmental toxins such as pollutants Stress ©2021 The Institute for Functional Medicine  What do we know about Blastocystis hominis? Can we link Joan’s symptoms to Blastocystis in particular? ©2021 The Institute for Functional Medicine  How Common is Blastocystis? In 2000, a study found that B. hominis infected 23% of the 2,896 patients throughout the US. It is the most prevalent mono-infection in symptomatic patients in the US. Studies using DNA-based methods to assess the positive rate in different cohorts have seen prevalence rates ranging from about 50% in healthy adults in highly industrialized countries to 100% in healthy Senegalese children. Statistics from one lab revealed 23.5 % of clinical samples tested positive for at least one parasite (3,223/13,857) ©2021 The Institute for Functional Medicine Blastocystis hominis (12.5%) Dientamoeba fragilis (3.8%) Entamoeba spp. (3.4%) Endolimax nana (2.2%) Giardia lamblia (0.7%) See References: How Common is Blastocystis?  References: How Common is Blastocystis? 1. Amin OM. Seasonal prevalence of intestinal parasites in the United States during 2000. Am J Trop Med Hyg. 2002 Jun;66(6):799-803. 2. Scanlan PD, et al. 15 September 2014. The microbial eukaryote Blastocystis is a prevalent and diverse member of the healthy human gut microbiota. FEMS Microbiol Ecol doi:10.1111/1574- ©2021 The Institute for Functional Medicine 6941.12396. 3. El Safadi D, et al. 2014. Children of Senegal River Basin show the highest prevalence of Blastocystis sp. ever observed worldwide. BMC Infect Dis 14:164. doi:10.1186/1471-2334-14-164.  Is Blastocystis a Pathogen? Screening of a large population group for protozoa infections revealed that 515 were infected with the single protozoa Blastocystis hominis. However, only 239 (46%) were found to be symptomatic, suggesting differential pathogenicity. ©2021 The Institute for Functional Medicine 43 of these symptomatic patients were treated with metronidazole. All patients became asymptomatic with negative stools on follow-up. Qadri SM, al-Okaili GA, al-Dayel F. Clinical significance of Blastocystis hominis. J Clin Microbiol. 1989 Nov;27(11):2407-9.  Is Blastocystis a Pathogen?: Update Human pathogenicity of Blastocystis sp. remains controversial as it can be found in both symptomatic and asymptomatic patients. It may be associated with certain subtypes of organism which impacts Blastocystis protease activity. The host specificity and the pathogenic potential of different B. hominis isolates correlate with sequence variations in the SSU-rRNA gene. Additional Considerations: The occurrence of gut microbiota appears to be ©2021 The Institute for Functional Medicine important for the pathogenic countenance of Blastocystis infections. Gut microbiota influences the survival and outcome of many parasitic infections. Commensal yeasts and bacteria can play an important role in reducing pathogenicity of parasites as they prevent the colonization of pathogenic agents on intestinal mucosa. See References: Is Blastocystis a Pathogen? Update  References: Is Blastocystis a Pathogen? Update 1. Skotarczak B. Genetic diversity and pathogenicity of Blastocystis. Ann Agric Environ Med. 2018 Sep 25;25(3):411-416. doi: 10.26444/aaem/81315. 2. Noël C, et al. Molecular phylogenies of Blastocystis isolates from different hosts: implications for genetic diversity, identification of species, and zoonosis. J Clin Microbiol. 2005 Jan;43(1):348-55. 3. Berrilli F, Di Cave D, Cavallero S, D’Amelio S. Interactions between parasites and microbial communities in the human gut. Front Cell Infect Microbiol. 2012; 2: 141. doi:10.3389/fcimb.2012.00141 4. Lepczyńska M, Białkowska J, Dzika E, Piskorz-Ogórek K, Korycińska J. Blastocystis: how do specific ©2021 The Institute for Functional Medicine diets and human gut microbiota affect its development and pathogenicity? Eur J Clin Microbiol Infect Dis. 2017 Sep;36(9):1531-1540. doi: 10.1007/s10096-017-2965-0.  B. Hominis Differential pathogenicity Blastocystis: 17 subtypes, immunosuppressed patients most affected Treatment should be considered if patients are symptomatic OR if one of the more virulent subtypes is detected by PCR: > Sub-Type 3 had a strong correlation with symptomatic disease. > Sub-Type 1, 2, 4 and 6 have also been isolated from symptomatic patients. ©2021 The Institute for Functional Medicine Symptoms: IBS and/or cutaneous (uticaria, pruritus- perianal, intense palmoplantar itching) Mast cell degranulation: ↑ histamine release Short-term exacerbation with die off is not uncommon 1. Roberts T, Stark D, Harkness J, Ellis J. Update on the pathogenic potential and treatment options for Blastocystis sp. Gut Pathog. 2014;6:17. doi:10.1186/1757-4749-6-17 2. Tan KS. New insights on classification, identification, and clinical relevance of Blastocystis spp. Clin Microbiol Rev. 2008; 21(4):639-65. doi: 10.1128/CMR.00022-08. 3. Yakoob J, et al. Irritable bowel syndrome: is it associated with genotypes of Blastocystis hominis. Parasitol Res.2010;106(5):1033-8. doi: 10.1007/s00436-010-1761-x. 4. Kick G, Rueff F, Przybilla B. Palmoplantar pruritus subsiding after Blastocystis hominis eradication. Acta Derm Venereol. 2002;82(1):60.doi:10.1080/000155502753600948 5. Kurt Ö, Doğruman Al F, Tanyüksel M. Eradication of Blastocystis in humans: Really necessary for all? Parasitol Int. 2016 Dec;65(6 Pt B):797-801. doi: 10.1016/j.parint.2016.01.010. 6. El Safadi D, et al. (2013) Molecular epidemiology of Blastocystis in Lebanon and correlation between subtype 1 and gastrointestinal symptoms. Am J Trop Med Hyg 88:1203–1206. doi:10.4269/ajtmh.12-0777 ©2021 The Institute for Functional Medicine Lab Test for B. hominas Subtypes  B. Hominis Sub-type Differences of Pathogenicity Blastocystis exhibits host specificity and strain-to-strain variation in pathogenicity. The subtype (ST) differences are an important factor affecting the pathogenesis of Blastocystis sp. ST6, which is reported limitedly in our country, was found in patients with GIS complaints. ©2021 The Institute for Functional Medicine ST1 and ST2: higher in the patient group Blastocystis ST-7 (but not ST-4) significantly increased apoptosis in enterocytes, suggesting that Blastocystis exhibits host specificity and strain- to-strain variation in pathogenicity. 1. Cakir F, Cicek M, Yildirim IH. Determination the Subtypes of Blastocystis sp. and Evaluate the Effect of These Subtypes on Pathogenicity. Acta Parasitol. 2019 Mar;64(1):7- 12. doi: 10.2478/s11686-018-00002-y. 2. Wu Z, Mirza H, Teo JD, Tan KS. Strain-dependent induction of human enterocyte apoptosis by blastocystis disrupts epithelial barrier and ZO-1 organization in a caspase 3- and 9-dependent manner. Biomed Res Int. 2014;2014:209163. doi: 10.1155/2014/209163.  Does Blastocystis Have Systemic Effects? Does it Increase Intestinal Permeability? Increased intestinal permeability in patients with protozoan infections vs. controls, especially in the Giardia and Blastocystis groups (not in Entamoeba coli group). The increase in intestinal permeability in patients with Blastocystis hominis suggests that it can be a pathogenic protozoal infection and have systemic consequences. ©2021 The Institute for Functional Medicine Blastocystis spp. also have immuno-modulatory effects: Degradation of IgA Inhibition of iNOS Upregulation of proinflammatory cytokines 1. Dagci H, Ustun S, Taner MS, Ersoz G, Karacasu F, Budak S. Protozoon infections and intestinal permeability. Acta Trop. 2002 Jan;81(1):1-5. 2. Ajjampur SS, Tan KS. Pathogenic mechanisms in Blastocystis spp. – Interpreting results from in vitro and in vivo studies. Parasitol Int. 2016 Dec;65(6 Pt B):772-779. doi: 10.1016/j.parint.2016.05.007.  Can Other Protozoal Infections Increase Intestinal Permeability? Adhesion of Giardia duodenalis trophozooites to intestinal cells was shown to induce disturbances of their tight, adherens, and desmosomal junction proteins. Giardia Cysteine Proteases (CPs) are directly involved ©2021 The Institute for Functional Medicine in intestinal epithelial junctional complex disruption, intestinal epithelial cell apoptosis, and degradation of host immune factors, including chemokines and immunoglobulins. 1. Maia-Brigagao C, Mordgado-Diaz JA, De Souza W. Giardia disrupts the arrangement of tight, adherens and desmosomal junction proteins of intestinal cells. Prasitol Int. 2012;61(2), 280-7. doi: 10.1016/j.parint.2011.11.002. 2. Allain T, Fekete E, Buret AG. Giardia Cysteine Proteases: The Teeth behind the Smile. Trends Parasitol. 2019 Aug;35(8):636-648. doi: 10.1016/j.pt.2019.06.003  Other Protozoal Infections and Intestinal Permeability In vitro study: Protozoan parasite Cryptosporidium parvum (CP) infection increased paracellular permeability in Caco-2 cell monolayers and substantially decreased the protein levels of occludin, claudin 4, and E-cadherin. Animal study: A mouse model of malaria/NTS co-infection showed increased gut mastocytosis and increased ileal and plasma histamine levels that were temporally associated with ©2021 The Institute for Functional Medicine increased gut permeability and bacterial translocation. Malaria/NTS co-infection in mast cell-deficient mice was associated with a reduction in gut permeability and bacteremia. Antihistamine treatment reduced bacterial translocation and gut permeability in mice with malaria, suggesting a contribution of mast cell-derived histamine to GI pathology and enhanced risk of bacteremia during malaria/NTS co-infection. 1. Kumar A, et al. Cryptosporidium parvum disrupts intestinal epithelial barrier function via altering expression of key tight junction and adherens junction proteins. Cell Microbiol. 2018 Jun;20(6):e12830. doi: 10.1111/cmi.12830. 2. Potts RA, et al. Mast cells and histamine alter intestinal permeability during malaria parasite infection. Immunobiology. 2016 Mar;221(3):468-74. doi: 10.1016/j.imbio.2015.11.003.  Is Inflammation Linked To Increased Intestinal Permeability? ©2021 The Institute for Functional Medicine  Leakage of LPS Inflammatory and other ©2021 The Institute for Functional Medicine Cytokines inflammatory factors Michielan A, D’Incà R. Intestinal Permeability in Inflammatory Bowel Disease: Pathogenesis, Clinical Evaluation, and Therapy of Leaky Gut. Mediators of Inflammation. 2015;2015:628157. doi:10.1155/2015/628157  Is Inflammation Linked To Depression? 1. Miller AH, Maletic V, Raison CL. Inflammation And Its Discontents: The Role Of Cytokines In The Pathophysiology Of Major Depression. Biological Psychiatry. 2009;65(9):732-741. doi: 10.1016/j.biopsych.2008.11.029. 2. Leonard B, Maes M. Mechanistic explanations how cell-mediated immune activation, inflammation and oxidative and nitrosative stress pathways and their sequels and concomitants play a role in the pathophysiology of unipolar depression. Neurosci Biobehav Rev. 2012;36(2):764-85. doi: 10.1016/j.neubiorev.2011.12.005. 3. Slavich GM, Irwin MR. From Stress to Inflammation and Major Depressive Disorder: A Social Signal Transduction ©2021 The Institute for Functional Medicine Theory of Depression. Psychological bulletin. 2014;140(3):774-815. doi:10.1037/a0035302. 4. Akhondzadeh S, et al. Clinical trial of adjunctive celecoxib treatment in patients with major depression: a double blind and placebo controlled trial. Depress Anxiety. 2009;26(7):607-11. doi: 10.1002/da.20589. 5. Köhler O, et al. Effect of anti-inflammatory treatment on depression, depressive symptoms, and adverse effects: a systematic review and meta-analysis of randomized clinical trials. JAMA Psychiatry. 2014 Dec 1;71(12):1381-91. doi: 10.1001/jamapsychiatry.2014.1611.  So… can intestinal permeability be linked to depression… and potentially some of Joan’s health issues? Intestinal mucosal dysfunction characterized by increased LPS translocation may induce specific “sickness behavior” including symptoms of depression. ©2021 The Institute for Functional Medicine Maes M, Kubera M, Leunis J. The gut-brain barrier in major depression: Intestinal mucosal dysfunction with an increased translocation of LPS from gram negative enterobacteria (leaky gut) plays a role in the inflammatory pathophysiology of depression. Neuroendocrinology Letter. 2008; 29(1):117-24.  Triggers of Increased IP: Joan’s Joan’sCase Case Food antigens/other components Increased uptak