The Arthritis Recovery Plan: Why Healing the Gut Matters and How to Do It

THE ARTHRITIS RECOVERY PLAN: WHY HEALING THE GUT MATTERS AND HOW TO DO IT

Susan S. Blum, MD, MPH Founder and Director Blum Center for Health Rye Brook, NY www.blumcenterforhealth.com Financial disclosure

• No relationship with any commercial interest relevant to the content of this talk • No conflict of interest • Founder and Director of Blum Center for Health, a Functional Medicine and Lifestyle Education Center • Online programs: no conflict for this presentation • Co-Founder of Organic Pharmer, a healthy grab- and-go Juice and Food company. • No conflict for this presentation Affiliations

• Assistant Clinical Professor, Department of Preventive Medicine, Icahn School of Medicine at Mount Sinai, NYC • Integrative Medicine, Greenwich Hospital, CT. • Medical Advisory Board, Dr Oz Show • Senior Teaching Faculty, Center for Mind Body Medicine, Washington • Advisory Board, Institute for Integrative Nutrition • Council of Directors, GLiMMER/True Health Coalition • Certified Practitioner, Institute for Functional Medicine • Board Certified in Preventive Medicine Functional Medicine

• Work at the roots to find and treat the cause of disease • Rule of tacks: • Find and remove triggers of illness • Treatment with: • Food: Nutritional Medicine, Functional Nutrition, Nutrigenomics, Personalized Nutrition • Lifestyle Medicine and health behavior modification: sleep, stress, exercise, detox the environment • Supplements and nutra-ceuticals for targeted treatment • Genetics and deficiencies • Personalized medicine

My Story

• Hashimoto’s

• Worked through all the functional medicine testing and treatment programs to figure out how to cure it

• Within 1 year all my antibodies were gone

• Put together a program I’ve been using for over a decade with my patients

• Share with you today 4 Step Functional Medicine Program to Treat Autoimmune Disease:

1. Using Food As Medicine 2. Balancing Stress Hormones 3. Healing the Gut 4. Supporting the Liver

Arthritis Recovery Plan

• If studies show that Rheumatoid Arthritis (RA) and Spondylarthritis (SpA) are associated with altered gut flora and dysbiosis… • And that dysbiosis and leaky gut can cause systemic inflammation… • And that different probiotic species are active in immune modulation and improvement in arthritis… • Can we create an approach to treating arthritis that is focused on Gut Repair using a Functional Medicine approach? • Yes…and today I will show you the studies and then teach you how to do this What we will discuss today…

• Rheumatoid Arthritis (RA) and Spondylarthritis (SpA) • Clinical features, conventional treatment, microbiome studies • Gut-Arthritis Connection: • Gut Basics • Dysbiosis • Leaky gut syndrome • Restoring gut health to treat arthritis: • Arthritis recovery plan • Case study ARTHRITIS RA, Spondylarthritis Rheumatoid arthritis

• Autoimmune disease: chronic joint inflammation with severe pain and swelling, joint damage and disability • 1% of the world population. • 3:1 women to men • Clinical • Polyarthritis: 5 or more joints • Symptoms of malaise, fatigue, muscle soreness • Monocyclic, polycyclic and progressive • Ultimately joint destruction and loss of function • Labs: diagnostic: Rheumatoid Factor, anti-CCP: anti-citrullinated peptide (CCP ab) • Can be antibody + before disease, and sero-negative with clinical symptoms

• Kerstin Klein; Steffen Gay. Epigenetics in Rheumatoid Arthritis. Curr Opin Rheumatol. 2015;27(1):76-82 RA: Epigenetics

• Cause unknown • Genetic component only explains 20% of RA • Interaction between environmental trigger in genetically susceptible person • Smoking is #1 • Infectious trigger? • Change in DNA methylation and histone acetylation • Studies now underway to understand genetic methylation patterns

• Kerstin Klein; Steffen Gay. Epigenetics in Rheumatoid Arthritis. Curr Opin Rheumatol. 2015;27(1):76-82

RA: Immunology

• Synovial inflammation and hyperplasia • Autoantibody production • Cartilage and bone destruction • Migration and accumulation of immune effector cells • Macrophages and osteoclasts, • Myeloid and plasmacytoid dendritic cells (DCs) • B cells and T cells. • Increased Th17 subsets: inflammatory • Produce interleukin (IL)-17 and IL-21 (cytokines) • Functional impairment in regulatory T cells (Tregs).

• Sue Ellen Verbrugge; Rik J Scheper; Willem F Lems; Tanja D de Gruijl; Gerrit Jansen. Proteasome Inhibitors as Experimental Therapeutics of Autoimmune Diseases. Arthritis Res Ther. 2015;17(17) Gut microbiome in RA

• Rheumatoid arthritis (RA) extensively studied with respect to dysbiosis and deranged microbiome architecture • Missing link to explain pathophysiology of RA • Manipulating the microbes by traditional dietary modifications, probiotics, and antibiotics and by currently employed disease-modifying agents seems to modulate the disease process and its progression

• SANDHYA, Debashish DANDA, Disha SHARMA and Vinod SCARIA. Does the buck stop with the bugs?: an overview of microbial dysbiosis in rheumatoid arthritis. International Journal of Rheumatic Diseases 2015 Does the buck stop with the bugs?: an overview of microbial dysbiosis in rheumatoid arthritis Proposed mechanism of pathophysiology of RA modulated through microbial dysbiosis

International Journal of Rheumatic Diseases 19 SEP 2015 DOI: 10.1111/1756-185X.12728 http://onlinelibrary.wiley.com/doi/10.1111/1756-185X.12728/full#apl12728-fig-0001 Proposed Mechanism for RA

• Gut microbial dysbiosis: • Pro-inflammatory cytokine production • Increased intestinal permeability: bacterial cell wall components (BCWC) in the bloodstream. • BCWC of intestinal bacteria have been identified in joints • Studies have shown destruction of joints in model systems challenged with BCWC • RA patients: immune response against BCWC of the enterobacteria and intestinal Gram-positive bacteria. • Induce inflammation at various sites, including joints.

• Authors created an RA-associated gut microbiome pattern, to be used diagnostically • Discovered a specific pattern of gut and oral microbial dysbiosis in RA patients • Associated with clinical symptoms • RA subjects: consistently enriched with Lactobacillus salivarius and bacteriodes. • Controls: enriched with Hemophilus spp. • Low Hemophilus levels were correlated with serum anti- CCP, RF and CRP.

• Zhang, Xuan. The oral and gut microbiomes are perturbed in rheumatoid arthritis and partly normalized after treatment. Nature medicine VOLUME 21 | NUMBER 8 | AUGUST 2015 Microbiome and RA: Zhang Study

• DMARD treatment partially restored the gut microbiome • Most received MTX and/or glycosides of the traditional Chinese medicinal component Tripterygium wilfordii (thunder god vine). • Both had + effect, separately and together. • Suggest different outcomes for different meds. • Change in microbiome toward healthy controls was correlated with clinical improvement

• Changes in microbiome predicted better outcomes

• Zhang, Xuan. The oral and gut microbiomes are perturbed in rheumatoid arthritis and partly normalized after treatment. Nature medicine VOLUME 21 | NUMBER 8 | AUGUST 2015. Study Conclusion: Zhang

• Conclusion: • RA represents a state of chronic inflammation that might be provoked or aggravated by the overgrowth of pathogenic bacteria or a lack of immune-modulating commensal bacteria • Authors suggest that microbiome profiling will some day be used for: • Patient stratification • Risk prediction • Supplement diagnosis • Early detection and prevention of disease

• Zhang, Xuan. The oral and gut microbiomes are perturbed in rheumatoid arthritis and partly normalized after treatment. Nature medicine VOLUME 21 | NUMBER 8 | AUGUST 2015. Prevotella

• Specific bacterial genes have been implicated in the pathophysiology of disease • Studies have suggested that a low load of Prevotella, can trigger new-onset RA • In a genetically susceptible person • Individuals neg for genetics would need a significantly higher bacterial burden to have the same effect

• Bernard, Nicholas J. Prevotella copri associated with new onset untreated RA. Nature Reviews Rheumatology 10, 2 (2014) • Mohamed K. Bedaiwi; Robert D. Inman. Microbiome and Probiotics: Link to Arthritis. Curr Opin Rheumatol. 2014;26(4):410-415 Mohamed K. Bedaiwi; Robert D. Inman. Microbiome and Probiotics: Link to Arthritis. Curr Opin Rheumatol. 2014;26(4):410-415

• Periodontal disease associated with RA • Prevotella, bacteroides and most commonly P. gingivalis have been observed in RA patients. • Many gut and oral bacteria have enzymes called peptidyl-arginine-deiminase (PAD) and gingipains can cause citrullination of host-proteins, leading to an autoantibody response

• Scher JU, Ubeda C, Equinda M et al. (2012) Periodontal disease and the oral microbiota in new-onset rheumatoid arthritis. Arthritis Rheum 64, 3083–94 Possible mechanism for disease activity

• In the oral cavity Porphyromonas gingivalis: • Peptidyl-arginine-deiminase (PAD) and gingipains cause protein citrullination. • Cigarette smoke could augment the process of citrullination. • A genetically susceptible host mounts an immune response to citrullinated antigens • Causes T cell and B cell activation and subsequent production of anti-citrullinated peptide antibodies.

• Bingham, Clifton O. III and Moni, Malini. Periodontal Disease and Rheumatoid Arthritis: The Evidence Accumlates for Complex Pathobiologic Interactions. Curr Opin Rheumatol. 2013; 25(3):345-35 • Scher JU, Ubeda C, Equinda M et al. (2012) Periodontal disease and the oral microbiota in new-onset rheumatoid arthritis. Arthritis Rheum 64, 3083–94 Oral cavity

• Oral bacteria DNA found in synovial fluid of RA and PsA patients compared to controls • “While it is possible that oral bacterial DNA could translocate to joints, triggering synovial inflammation, it is more likely that inflamed joints could entrap these bacterial DNA, leading to augmentation of inflammation”.

• Moen K, Brun JG, Valen M et al. (2006) Synovial inflammation in active rheumatoid arthritis and psoriatic arthritis facilitates trapping of a variety of oral bacterial DNAs. Clin Exp Rheumatol 24, 656–63 Spondylarthritis (SpA)

• Spondyloarthritis (SpA): family of immune- mediated inflammatory disorders • Includes ankylosing spondylitis (AS), psoriatic arthritis (PsA), juvenile spondyloarthritis (JSpA), and acute anterior uveitis. • Clinical overlap between SpA and inflammatory bowel disease • Microbial dysbiosis of gut commensals implicated • Epithelial permeability: cause or effect of gut inflammation • Implicated in loss of mucosal tolerance • Microbiome research has the potential to revolutionize research, diagnosis, and treatment of SpA

• Tejpal Gill; Mark Asquith; James T. Rosenbaum; Robert A. Colbert. The Intestinal Microbiome in Spndyloarthritis. Curr Opin Rheumatol. 2015;27(4) Psoriatic Arthritis (PsA)

• Systemic inflammatory condition that effects 20-30% of people with psoriasis. • Skin manifestations precede arthritis in >80%, decade or more • Potential involvement of diverse tissues, including peripheral and axial joints, enthesitis, dactylitis and skin and nail disease. Uveitis, iritis. • Peak age 30-50, men and women equal, except axial disease favors men 3:1 • Clinical diagnosis. No markers. ESR and CRP often normal, RF/ACPA can be +

• DoQuyen Huynh; Arthur Kavanaugh. Psoriatic Arthritis: Current Therapy and Future Approaches. Rheumatology. 2015;54(1):20-28 Psoriatic Arthritis (PsA)

• Gastrointestinal involvement with a resemblance to IBD is common • Many patients with psoriasis or psoriatic arthritis have subclinical gut inflammation • Lower commensals: Ruminococcus and Akkermansia in PsA compared to controls. • Organisms play a role in producing SCFA’s that support gut homeostasis

• Scarpa R, Manguso F, D'Arienzo A, et al. Microscopic inflammatory changes in colon of patients with both active psoriasis and psoriatic arthritis without bowel symptoms. J Rheumatol 2000; 27:1241–1246 Bacteria Linked to Arthritis

Bacteria/Bacterial product Disease Reference

Bacteriodetes spp. Arthritis [10]

Klebsiella pneumoniae AS and Crohn's Disease (CD) CD [11]

Flagellin CD [12]

Bacteriodes thetaiotamicron Colitis [13]

Bacteriodes vulgatus Colitis [14] Mycobacteria Psoriasis [15] Prevotella copri Rheumatoid Arthritis (RA) RA [16] Prevotella spp. RA [17] Chlamydia tracomatis Reactive Arthritis (ReA) ReA [18,19] Salmonella Omp ReA [20] Shigella ReA [21,22] Yersinia ReA [21,22]

Tejpal Gill; Mark Asquith; James T. Rosenbaum; Robert A. Colbert. The Intestinal Microbiome in Spndyloarthritis. Curr Opin Rheumatol. 2015;27(4) Ankylosing spondylitis

• Multiple studies looking at microbiome: • There was an increase in the abundance of Lachnospiraceae, Ruminococcaceae, and Prevotellaceae in AS patients • Decreased abundance of Streptococcus and Actinomyces • Increase in sulphate reducing Bacteriodes • Recolonization of the gut of germ-free animals with Bacteroides led to gut inflammation, whereas Lactobacillus and fusiform bacteria did not result in inflammatory lesions • High Klebsiella IgA • Tejpal Gill; Mark Asquith; James T. Rosenbaum; Robert A. Colbert. The Intestinal Microbiome in Spondyloarthritis. Curr Opin Rheumatol. 2015;27(4):319-325 Juvenile spondylarthitis

• Decreased abundance of Clostridium leptum similarly to AS patients. • Another member of the Clostridales family known as Fecalibacterium prausnitzii was also decreased in patients with juvenile SpA compared with healthy controls. • No difference in serum IgA/IgG levels to these org • Study of the microbiota of juvenile SpA patients • Patients could be stratified into two distinct clusters, one dominated by Bacteroides genus members, the other by Akkermansia muciniphila.

• Tejpal Gill; Mark Asquith; James T. Rosenbaum; Robert A. Colbert. The Intestinal Microbiome in Spndyloarthritis. Curr Opin Rheumatol. 2015;27(4): 319-325 Conventional treatment: RA

• DMARDS: disease-modifying anti-rheumatic drugs • Methotrexate (MTX) • Glucocorticoids (steroids) • Biologics: antibodies to the pro-inflammatory cytokines: TNF alpha and IL-6 • Rituximab, Abatacept • Monotherapy with MTX: limited long term efficacy • Combinations of conventional DMARDs, particularly methotrexate, with biological agents: • Clinical remission and prevention of radiological deterioration in approximately 50% of RA patients, but the remaining 50% of patients still experienced insufficient disease activity reduction or sustained active disease.

• Goekoop-Ruiterman YP, de Vries-Bouwstra JK, Allaart CF, van Zeben D, Kerstens PJ, Hazes JM, et al. Comparison of treatment strategies in early rheumatoid arthritis: a randomized trial. Ann Intern Med. 2007;146:406–15. Psoriatic arthritis treatment

• Target for treatment: ‘minimal disease activity’ • NSAIDS and Corticosteroids • DMARD: • Sulfasalazine: arthritis: 59% improvement with drug:47% controls. No protection for joint damage • Leflunamide: 58.9% LEF/29.7% controls. Increases LFT’s. • Cyclosporin and Tacrolimus: inhibit T cells. Renal toxicity and HTN. Close monitoring • MTX: methotrexate: cornerstone of therapy although not good outcome studies for PsA. • Only + results with >15 mg/week. • Works best when combined with DMARD. • Biologics: TNF inhibitors. • DoQuyen Huynh; Arthur Kavanaugh. Psoriatic Arthritis: Current Therapy and Future Approaches. Rheumatology. 2015;54(1):20-28 Conventional treatment: PI’s

• Newest in autoimmune treatment • Proteosome inhibitors: inhibits NFkB, plasma cell apoptosis • Refractory SLE and hemolytic anemia • Side effects: peripheral neuropathy, thrombocytopenia, diarrhea and an increased risk of developing infectious complications • Not for RA or SpA: other therapies are safer and more effective

• Previously thought anti-inflammatory properties were mechanism for improvement • Now, believe change in microbiome could be at least partly responsible • Sulphasalazine: inhibits non-sporing anaerobes, Clostridia and Enterobacteria. • Tetracyclines previously used in the 1960’s. Minocycline sometimes still used. • Tetracyclines inhibit matrix metalloproteinase and nitric oxide synthase, suppress adaptive immune cells and increase IL-10. • Antimalarials: Plaquenil: similar antimicrobial and anti- inflammatory properties • Pulukool SANDHYA, Debashish DANDA, Disha SHARMA and Vinod SCARIA. Does the buck stop with the bugs?: an overview of microbial dysbiosis in rheumatoid arthritis. International Journal of Rheumatic Diseases 2015 Conventional treatment and microbiome

• RA patients: high levels of Clostridium perfringens vs controls in 4 studies. • SSZ: decreased counts in 2 studies • NSAIDS: 1 study: increased counts • Vegan diet changed flora and improved symptoms

• Pulukool SANDHYA, Debashish DANDA, Disha SHARMA and Vinod SCARIA. Does the buck stop with the bugs?: an overview of microbial dysbiosis in rheumatoid arthritis. International Journal of Rheumatic Diseases 2015 Need for better therapy

• Even when DMARDS and Biologics drive initial remission, long term is of concern

• Studies addressing dose reduction and withdrawal are currently under way.

• High remission in RA, better rates in PsA.

• Despite advances in therapy, there remain patients who fail to respond to classic DMARDs and TNF’s or who have loss of efficacy over time PROBIOTICS AND ARTHRITIS Study review Probiotics and RA: review

• 4 randomized double-blind placebo controlled trials of probiotics in RA • Lactobacillus rhamnosus GG x 12 months. • Improved well being, but no change disease activity scores or inflammatory markers • L. rhamnosus GR-1 and Lactobacillus reuteri RC-14: same results • Bacillus coagulans x 1 month: • improvement in pain scores, patient global assessment scores and reduction in inflammatory markers • L. Casei: 8 weeks. • Improved disease activity and reduced inflammatory markers and cytokine levels

• Vaghef-Mehrabany, Elnaz M.Sc. et al. Probiotic supplementation improves inflammatory status in patients with rheumatoid arthritis. Nutrition (2014) 430-435 Mechanism of action: probiotics

• Microorganisms effect systemic immunity by: • MAMP: microorganism-associated molecular patterns • interact with the pattern recognition receptors (PRPs) such as toll-like receptors (TLRs) on the dendritic cells (DCs) • gut lumen or gut-associated lymphoid tissue (GALT) • Strain-specific: stimulation or down-regulation of immune system function • Effect on T regs • Increase potency: work better • Decrease apoptosis: increase numbers • Suppress bacterial adenosine triphosphate which prevents conversion to Th17 cells: decrease shift into inflammation pathway • Mechanism: probiotics induce enzymes that make all- trans retinoic acid (ATRA). • ATRA induces naïve T cells to T regs. • Vaghef-Mehrabany, Elnaz M.Sc. et al. Probiotic supplementation improves inflammatory status in patients with rheumatoid arthritis. Nutrition (2014) 430-435 RA and Lactobacillus Casei

• Study: The effect of L. casei in RA patients • Significantly lower serum proinflammatory cytokines (TNF-[alpha], IL-6, and IL-12) in the probiotic-treated group • Higher level regulatory cytokine (IL-10) • Clinically, the disease activity score was significantly decreased with L. casei 01 supplementation • Suppresses the type II collagen-reactive effector function of Th1-type cellular and humoral immune responses in arthritic inflammation

• Mohamed K. Bedaiwi; Robert D. Inman. Microbiome and Probiotics: Link to Arthritis. Curr Opin Rheumatol. 2014;26(4):410-415 Effects of Lactobacillus casei supplementation on disease activity and inflammatory cytokines in rheumatoid arthritis patients: a randomized double‐blind clinical trial Effect of probiotic supplementation on cytokine percent changes in the two intervention groups ; statistically significant diff

International Journal of Rheumatic Diseases Volume 17, Issue 5, pages 519-527, 27 MAR 2014 DOI: 10.1111/1756-185X.12333 http://onlinelibrary.wiley.com/doi/10.1111/1756-185X.12333/full#apl12333-fig-0002 RA and Lactobacillus Casei

• L. casei 01 supplementation decreased serum hs-CRP levels, tender and swollen joint counts and GH scores • improved cytokines • improved DAS28 • Decreased number tender and swollen joints • L. casei strains have been shown in several in vitro and animal studies to efficiently regulate immune system function • Dose: 100 million CFU x 8 weeks. 1 capsule/day. • Is more better? Not necessarily. Studies haven’t been done on dosing

• Alipour B, Homayouni-Rad A, Vaghef-Mehrabany E et al. (2014) Effects of Lactobacillus casei supplementation on disease activity and inflammatory cytokines in rheumatoid arthritis patients: a randomized double-blind clinical trial. Int J Rheum Dis 17, 519–27 RA and other Lactobacillus

• Lactobacillus reuteri and Lactobacillus casei, but not Lactobacillus plantarum, prime monocyte- derived DCs to drive the development of Treg cells

• Smits, Hermelijn H, et al. Selective probiotic bacteria induce IL-10-producing regulatory T cells in vitro by modulating dendritic cell function through dendritic cell-specific intercellular adhesion molecule 3-grabbing nonintegrin. Journal of Allergy and Clinical Immunology (2005), 115(6), 1260-1267 RA and L rhamnosis/L reuteri

• 30 subjects, 15 in probiotic group. RA, 3 month double blind, placebo controlled. • L rhamnosis, L reuteri • Inclusion criteria: 4 swollen, 4 tender joints, stable meds, no steroids for at least 1 month prior to and during study • ACR20 responses, serum cytokine levels, safety parameters and HAQ (health assessment questionnaire) • Improvement only in the HAQ. No change in other markers

• Pineda, Maria de los Angeles et al. A randomized, double-blinded, placebo-controlled pilot study of probiotics in active rheumatoid arthritis. Med Sci Monit, 2011; 17(6): CR347-354 Sacharomyces Boulardi

• S. boulardii: influences several important facets of intestinal host-pathogen interaction • Neutralization of bacterial virulence factors • Enhancement of the mucosal immune response • Interference with bacterial adhesion • Strengthening of enterocyte tight junctions • Altering immune cell redistribution • Modulating inflammatory signaling pathways of the host

• Chen X, Yang G, Song J-H, Xu H, Li D, et al. (2013) Probiotic Yeast Inhibits VEGFR Signaling and Angiogenesis in Intestinal Inflammation. PLoS ONE 8(5) REVIEW THE MICROBIOTA

Probiotic Bifidobacterium Innate immune recognition of the microbiota Breve increases T promotes host-microbial symbiosis regulatory cells Hiutung Chu & Sarkis K Mazmanian Pattern-recognition receptors (PRRs) are traditionally known to sense microbial molecules during infection to initiate inflammatory responses. However, ligands for PRRs are not exclusive to pathogens and are abundantly produced by the resident microbiota during normal colonization. Mechanism(s) that underlie this paradox have remained unclear. Recent studies reveal and improves that gut bacterial ligands from the microbiota signal through PRRs to promote development of host tissue and the immune system, and protection from disease. Evidence from both invertebrate and vertebrate models reveals that innate immune receptors are required to promote long-term colonization by the microbiota. This emerging perspective challenges current models in immunology and suggests that PRRs may have evolved, in part, to mediate the bidirectional cross-talk between microbial signaling in T regs symbionts and their hosts.

Conventional wisdom suggests that the immune system evolved to our understating of innate immunity. It has been proposed that the combat infection and that distinguishing between self and non-self context in which the host receives MAMP stimulation dictates the to reduce molecules is a basic feature of innate immunity. As Charles Janeway quality of the immune response. During infection, MAMP signals proposed, the recognition of microbial molecules, termed patho- are received in the presence of other cues, such as cell damage caused gen-associated molecular patterns (PAMPs), is critical to selectively by infection14 and/or cytosolic detection of MAMPs15, resulting in inflammation. drive immune responses to infectious agents1. Studies identifying and inflammation. During symbiosis, not only does the microbiota gen- characterizing host receptors that recognize specific PAMPs, called erally not harm host cells and MAMPs are sensed in the absence ‘pattern-recognition receptors’ (PRRs), have provided evidence that of exposed self antigens, but it appears that some MAMPs directly PRR signaling is critical in coordinating immune responses and promote beneficial outcomes. In this Review, we will focus on how This is a local and All rights reserved. America, Inc. © 2013 Nature protection against pathogens2–5. This view, however, has been chal- recognition of MAMPs by PRRs under steady-state conditions pro- lenged by the emerging appreciation that animals have a diverse and motes immune development, protection from disease and maintains complex symbiotic microbiota6–10, which normally does not trigger homeostasis. The concepts presented here collectively demonstrate

npg inflammation. PAMPs, by definition, are universally conserved, gen- that PRRs may have evolved in both the invertebrate and vertebrate systemic effect. erally invariant and essential in all microorganisms. Thus, PAMPs are immune systems to communicate with commensals and maintain not limited to pathogens but are also common to the microbiota. As beneficial, symbiotic coexistence with the microbiota. such, it has been proposed that these molecules be renamed microbe- Chu, Hiutung and associated molecular patterns (MAMPs)11. Furthermore, host PRRs Pattern recognition in Drosophila promotes homeostasis are constantly exposed to MAMPs in the absence of infection. These Extensive work using D. melanogaster as a model system has high- Mazmanian, Sarkis K. MAMPs are largely provided by the commensal microbiota that colo- lighted the important functions of PRRs in host defense as well as nize our skin and mucosal surfaces. Despite the continuous presence in homeostasis. Toll, one of the first PRRs to be identified, was ini- of many MAMPs, commensal microbes usually do not elicit inflam- tially discovered in D. melanogaster16. However, the realization that Innate immune recognition matory responses but rather may contribute to various aspects of D. melanogaster Toll does not directly recognize MAMPs, unlike the host development and enhanced immune function12. To our surprise, PRRs in the mammalian Toll-like receptor (TLR) signaling path- this beneficial influence is mediated, in part, by commensal stimula- way, left the open question of how bacterial ligands are recognized. of the microbiota promotes tion of host PRRs13. D. melanogaster has 13 peptidoglycan recognition protein (PGRP) How these molecules and receptors can achieve such divergent and genes that are alternatively spliced into 19 different proteins, which host-microbial symbiosis. opposing responses between pathogens and symbiosis is a frontier in is one of the largest repertoires of PGRPs currently known for any organism17. The role of D. melanogaster PGRPs as PRRs was discov- Division of Biology and Biological Engineering, California Institute of ered during the identification of upstream receptors that activate the 18,19 Nature Immunology 14, Technology, Pasadena, California, USA. Correspondence should be addressed signal-transduction pathways, Toll and Imd (immune deficiency) , to S.K.M. ([email protected]). which are highly similar to the mammalian interleukin 1 (IL-1)–TLR 20 Received 8 April; accepted 2 May; published online 18 June 2013; and tumor necrosis factor (TNF) pathways . However, Toll does not 668-675 (2013). doi:10.1038/ni.2635 function as a PRR because it does not directly recognize MAMPs21.

668 VOLUME 14 NUMBER 7 JULY 2013 NATURE IMMUNOLOGY

Summary and idea…

• Studies have shown that: • Gut microbiome is altered in RA and SpA • Probiotic treatment with specific strains results in clinical and laboratory improvement • Can we apply the Functional Medicine 5 R Gut Repair program to: • Do an even better job at repairing both microbial balance and gut integrity • Use as a primary treatment approach?

• YES! GUT BASICS Dysbiosis and leaky gut

Gut Basics

• Terms: Gut = digestive system = gastrointestinal tract • Mouth to anus • Huge exposure to the environment • Surface area of a tennis court • Stomach is the sterilizer: pH 1.5 • Then immune system takes over: • Innate and Adaptive Immune System

Intestinal Flora

• Diverse community of microorganisms • Human intestine harbors 100 trillion microbes, mainly over 500 species of bacteria • Each species colonizes a specific niche • Mutually beneficial relationship • We provide nourishment • Microbe by-products of digestion provide vitamins, nutrients and help with resistance to colonization by potential pathogens • **see slide 57 for multiple references Intestinal Flora: Immune function

• Antibacterial action against pathogens

• Modulate epithelial cells to increase sIgA

• Enhance intestinal barrier function

• Influence the maturation and phenotype of dendritic cells

• Directs functioning of antigen presenting cells with modulation of T cell responses

• Interact with enteric nervous system which effects immune system

• **see slide 57 for multiple references Dysbiosis

• Imbalance in microbe population of the gut • Can be overgrowth of harmful bacteria, yeast or parasites • And/or too little good bacteria • May or may not have gut symptoms • Caused by: • Stress • Antibiotics • PPI’s and antacids • Gut infections • Diet • Dysbiosis can lead to Leaky Gut • Leaky Gut is associated with RA and SpA • **see slide 57 for multiple references Intestinal Microbiome references

• Denise Kelly et al. Commensal gut bacteria: mechanisms of immune modulation. TRENDS in Immunology. Vol.26 No.6 June 2005 • Macia, L, et al. Microbial influences on epithelial integrity and immune function as a basis for inflammatory diseases. Immunol Rev. 2012 Jan; 245(1):164-76. • Hsin-Jung Wu and Eric Wu. The role of gut microbiota in immune homeostasis and autoimmunity. Gut Microbes 3:1, 1–11; January/February 2012 • Thorens, J et al. Bacterial overgrowth during treatment with omeprazole compared with cimetidine: a prospective randomised double blind study. Gut. 1996 Jul;39(1):54-9 • Pulukool SANDHYA, Debashish DANDA, Disha SHARMA and Vinod SCARIA. Does the buck stop with the bugs?: an overview of microbial dysbiosis in rheumatoid arthritis. International Journal of Rheumatic Diseases 2015 • Stephan C Bischoff et al. Intestinal Permeability – A New Target for Disease Prevention and Therapy. BMC Gastroenterol. 2014;14(189) Laurence Macia* Microbial inﬂuences on epithelial Alison N. Thorburn* integrity and immune function as a Lauren C. Binge Eliana Marino basis for inﬂammatory diseases ‘Dysbiosis contributes to Kate E. Rogers Kendle M. Maslowski Ange´lica T. Vieira compromised epithelial Jan Kranich Integrity and disrupted Charles R. Mackay

Authors’ addresses Summary: Certain autoimmune diseases as well as asthma have Immune tolerance’ 1 1 1 Laurence Macia *, Alison N. Thorburn *, Lauren C. Binge , Eliana increased in recent decades, particularly in developed countries. The 1 1 2 3 Marino , Kate E. Rogers , Kendle M. Maslowski , Ange´lica T. Vieira , Jan hygiene hypothesis has been the prevailing model to account for this 4 1 Kranich , Charles R. Mackay increase; however, epidemiology studies also support the contribution of 1 Department of Immunology, Monash University, Clayton, diet and obesity to inﬂammatory diseases. Diet affects the composition of Victoria, Australia. the gut microbiota, and recent studies have identiﬁed various molecules 2 Department of Biochemistry, University of Lausanne, and mechanisms that connect diet, the gut microbiota, and immune Epalinges, Switzerland. responses. Herein, we discuss the effects of microbial metabolites, such 3 Immunopharmacology Group – Department of as short chain fatty acids, on epithelial integrity as well as immune cell Biochemistry and Immunology, Institute of Biological function. We propose that dysbiosis contributes to compromised epithe- Sciences, Federal University of Minas Gerais, Belo Horizonte, lial integrity and disrupted immune tolerance. In addition, dietary mole- Minas Gerais, Brazil. cules affect the function of immune cells directly, particularly through 4 Immunological Reviews Garvan Institute of Medical Research, Darlinghurst, New lipid G-protein coupled receptors such as GPR43. South Wales, Australia. Keywords: microbiota, epithelium, GPR43, short-chain fatty acids Correspondence to: 2012 Charles R. Mackay Level 3, Building 75 Monash University Wellington Rd Vol. 245: 164–176 VIC 3800, Australia Introduction Tel.: +61 2 9902 9510 Fax: +61 2 9902 4291 A new direction in immunology research has emerged e-mail: [email protected] recently that considers the effects of diet on the gut micro-

*These authors contributed equally. biota and immune responses. Gastrointestinal microbes have co-evolved with vertebrates and provide beneﬁts to the host, Acknowledgements including maintenance of epithelial integrity and regulation of The authors have no conﬂicts of interest to declare. immune responses. However, the composition of the gut microbiota can differ considerably between individuals, and this

This article is part of a series of reviews difference appears to relate to diet (1–3). This may be particu- covering Microbial Inﬂuences on larly relevant to human inﬂammatory diseases, several of Immune Function appearing in Volume which associate with western lifestyle and obesity. While sev- 245 of Immunological Reviews. eral studies and reviews (including by us) have highlighted the direct effects of dietary molecules on immune cells (4, 5), Immunological Reviews 2012 Vol. 245: 164–176 a new and possibly equally important element is the gut epi- Printed in Singapore. All rights reserved thelium. The gut is lined by epithelial cells, which provide an important physical barrier and defense against pathogens. The Ó 2011 John Wiley & Sons A/S Immunological Reviews integrity of the epithelial barrier is important to reduce 0105-2896

164 Ó 2011 John Wiley & Sons A/S • Immunological Reviews 245/2012

SIBO: Small intestinal bacterial overgrowth • Most people are very symptomatic, lots of gurgling, gas and bloating • But more than 20% of apparently healthy controls have been diagnosed with SIBO • FODMAP-restricted diets reduce total bacterial count • Fermentable oligo-di-mono-saccharides and polyols • Rifaximin: rate of success in SIBO eradication is at least 50% across different series • bactericidal action against both aerobic and anaerobic bacteria • best results have been achieved with doses of 1200–1600 mg daily • Recurrence is frequent. Must address underlying cause • Ponziani, Francesca Romana et al. Diagnosis and treatment of small intestinal bacterial overgrowth. Expert Review of Gastroenterology & Hepatology 2015 Dec 4:1-13. [Epub ahead of print] •

Clinic Rev Allerg Immunol (2012) 42:5–15 DOI 10.1007/s12016-011-8285-8

Hygiene Hypothesis and Autoimmune Diseases

Graham A. W. Rook

the gut flora doesn’t Published online: 17 November 2011 # Springer Science+Business Media, LLC 2011 develop properly Abstract Throughout the twentieth century, there were and tarmac” urbanization in the early nineteenth century there striking increases in the incidences of many chronic inflam- has been a progressive increase in immunoregulatory prob- matory disorders in the rich developed countries. These lems attributable to depletion from the urban environment of because our included autoimmune disorders such as Type 1 diabetes and organisms with which mammals co-evolved, and that had multiple sclerosis. Although genetics and specific triggering been tasked by co-evolutionary forces with a crucial role in mechanisms such as molecular mimicry and viruses are likely setting up “normal” background levels of immunoregulation to be involved, the increases have been so rapid that any (this will be explained, expanded and referenced below). It environment is too explanation that omits environmental change is incomplete. would be foolish to suggest that this mechanism is the whole This chapter suggests that a series of environmental factors, explanation for the striking increases in certain autoimmune most of them microbial, have led to a decrease in the diseases (notably Type 1 diabetes (T1D) and multiple sclerosis clean, which in turn efficiency of our immunoregulatory mechanisms because we (MS)) in the twentieth century. On the other hand, the recent are in a state of evolved dependence on organisms with which nature of these increases makes it certain that the major we co-evolved (and that had to be tolerated) as inducers of underlying cause is environmental. The role of genetic factors prevents immune immunoregulatory circuits. These organisms (“Old Friends”) cannot be more than to determine which individuals develop are depleted from the modern urban environment. Rather than the disease after the environmental changes have occurred… a considering fetal programming by maternal microbial expo- classic example of gene-environment interaction. In addition system from sures, neonatal programming, the hygiene hypothesis, gut there are other potential environmental factors that I consider microbiota, and diet as separate and competing hypotheses, I to be subcomponents of the Old Friends hypothesis (such as attempt here to integrate these ideas under a single umbrella delayed exposure to viruses), and others that are entirely concept that can provide the missing immunoregulatory separate in nature (such as deficient Vitamin D3). All of functioning properly. environmental factor that is needed to explain the recent these will exacerbate the immunoregulatory deficit. Figure 1 increases in autoimmune disease. lists some relevant factors, and also emphasizes the immunoregulatory role of the gut. One of the most important Keywords Immunoregulation . “Old Friends” . discoveries in recent years is the fact that manipulations of Microbiota . Treg the immune system (or loss of the Old Friends!) may act indirectly via changes in the gut flora…the microbiota. Wen and colleagues showed that specific-pathogen free (SPF) Introduction non-obese diabetic (NOD) mice that spontaneously develop a condition resembling T1D, are protected from the disease The hygiene hypothesis, recently reformulated as the Old following knockout of the gene encoding MyD88 (an Friends Hypothesis to bring it in line with Darwinian adaptor for multiple Toll-like receptors) [1]. However, this medicine, and with the latest epidemiological and experimen- did not mean that MyD88 was directly involved in the Rook, Graham A. W. tal evidence, suggests that since the start of modern “concrete autoimmune response to β cells in the pancreas. Rather, it emerged that the modification of the immune system G. A. W. Rook (*) resulting from knocking out MyD88 caused profound Hygiene Hypothesis and Department of Infection, Centre for Clinical Microbiology, changes in the interactions between the immune system University College London (UCL), London NW3 2PF, UK and the microbiota. Consequent changes in the composition of Autoimmune Diseases. Clinic e-mail: [email protected] the microbiota were responsible for the immunoregulatory Rev Allerg Immunol (2012) 42:5-15 LEAKY GUT SYNDROME Increased Intestinal Permeability

Nutrients. 2013 March; 5(3): 771–787. What is a leaky gut?

• Intestinal Barrier: the functioning separation of the gut lumen from the host. • Mechanical, humoral, immune, muscular and neurological elements • Intestinal Permeability: normal functioning of the intestinal barrier • Normal: stable; found in healthy people • Impaired Intestinal Permeability = Leaky Gut • Definition: • “disturbed permeability being non-transiently changed compared to the normal permeability leading to a loss of intestinal homeostasis, functional impairments and disease” • Stephan C Bischoff et al. Intestinal Permeability – A New Target for Disease Prevention and Therapy. BMC Gastroenterol. 2014;14(189) What Causes Leaky Gut?

• Dysbiosis

• Medication: steroids, antacids, PPI’s, advil

• Alcohol

• Antibiotics

• STRESS

• Acute trauma: emotional or physical

• Toxins

• Infections • Stephan C Bischoff et al. Intestinal Permeability – A New Target for Disease Prevention and Therapy. BMC Gastroenterol. 2014;14(189) Leaky Gut and Immune Function

• Microbial peptides trigger ongoing immune reactions • Increases T effector cell activity: lots of antibodies, and killer cells, inflammation • T regulators aren’t doing their job to turn it off • Fixing the leaky gut will reduce the constant triggering of the immune system • In my opinion, until proven otherwise, everyone with arthritis has a leaky gut • Pulukool SANDHYA, Debashish DANDA, Disha SHARMA and Vinod SCARIA. Does the buck stop with the bugs?: an overview of microbial dysbiosis in rheumatoid arthritis. International Journal of Rheumatic Diseases 2015 Clinic Rev Allerg Immunol (2012) 42:71–78 DOI 10.1007/s12016-011-8291-x

Leaky Gut and Autoimmune Diseases

Leaky gut has been Alessio Fasano demonstrated to cause autoimmune

Published online: 23 November 2011 Disease # Springer Science+Business Media, LLC 2011 Abstract Autoimmune diseases are characterized by tissue Introduction damage and loss of function due to an immune response that is directed against specific organs. This review is focused on the The intestinal epithelium is the largest mucosal surface role of impaired intestinal barrier function on autoimmune providing an interface between the external environment pathogenesis. Together with the gut-associated lymphoid and the mammalian host. Its exquisite anatomical and tissue and the neuroendocrine network, the intestinal epithelial functional arrangements and the finely-tuned coordination barrier, with its intercellular tight junctions, controls the of digestive, absorptive, motility, neuroendocrine, and equilibrium between tolerance and immunity to non-self immunological functions are testimonial of the complexity antigens. Zonulin is the only physiologic modulator of of the gastrointestinal (GI) system. Also pivotal is the intercellular tight junctions described so far that is involved regulation of molecular trafficking between the intestinal in trafficking of macromolecules and, therefore, in tolerance/ lumen and the submucosa via the paracellular space. The Fasano, Alessio. Leaky Gut and immune response balance. When the zonulin pathway is dimensions of the paracellular space are estimated to be deregulated in genetically susceptible individuals, autoim- between 10 and 15 Å, suggesting that under physiological Autoimmune Diseases. Clinic Rev mune disorders can occur. This new paradigm subverts circumstances, solutes with a molecular radius exceeding traditional theories underlying the development of these 15 Å (~3.5 kDa) will be excluded from this uptake route. diseases and suggests that these processes can be arrested if Macromolecule trafficking is dictated mainly by intestinal Allerg Immunol (2012) 42:71-78 the interplay between genes and environmental triggers is paracellular permeability, whose regulation depends on the prevented by re-establishing the zonulin-dependent intestinal modulation of intercellular tight junctions (TJ). A fast barrier function. Both animal models and recent clinical growing number of diseases, including autoimmune dis- evidence support this new paradigm and provide the rationale eases, are recognized to involve alterations in intestinal for innovative approaches to prevent and treat autoimmune permeability related to changes in TJ competency. diseases.

Keywords Antigens . Autoimmunity . Gut permeability. Classical Theories on the Pathogenesis of Autoimmune Immune response . Tight junctions . Zonulin Diseases

Soon after autoimmune diseases were first recognized more than a century ago, it was believed that their development was associated with viral and bacterial infections. The connection between infection and autoimmune disease is A. Fasano (*) often explained by a mechanism known as “molecular Mucosal Biology Research Center, mimicry,” whereby microbial antigens are postulated to University of Maryland School of Medicine, resemble self-antigens [1]. The induction of an immune 20 Penn Street HSF II Building, Room S345, Baltimore, MD 21201, USA response to the microbial antigens results in a cross-reaction e-mail: [email protected] with the self-antigens and the induction of autoimmunity. Alessio Fasano. Zonulin, regulation of tight junctions, and autoimmune diseases. Leaky gut and RA.

Ann N Y Acad Sci. 2012 Jul; 1258:25-33. Leaky Gut References

• Lerner, A. et al. Changes in intestinal tight junction permeability associated with industrial food additives explain the rising incidence of autoimmune disease. Autoimmunity Reviews 14 (2015) 479–489

• Bischoff. Stephan, C et al. Intestinal Permeability – A New Target for Disease Prevention and Therapy. BMC Gastroenterol. 2014;14(189)

• Macia, L, et al. Microbial influences on epithelial integrity and immune function as a basis for inflammatory diseases. Immunol Rev. 2012 Jan;245(1):164-76 Intestinal permeability and SpA

• Epithelium • Physical and chemical barrier between host and microbes: promote tolerance • Provide mucus and metabolites to support colonization • Many studies support increased intestinal permeability in SpA patients. • Loss of integrity can be transient, or subclinical, or overt • “Chicken and egg”: • Local inflammation drives damage to the epithelium itself, causing change in microbes • Dysbiotic changes or a disrupted epithelium promotes a breakdown of mucosal homeostasis with resulting inflammation

• Tejpal Gill; Mark Asquith; James T. Rosenbaum; Robert A. Colbert. The Intestinal Microbiome in Spndyloarthritis. Curr Opin Rheumatol. 2015;27(4): 319-325 Clinical reviews in allergy and immunology

Series editors: Donald Y. M. Leung, MD, PhD, and Dennis K. Ledford, MD

Intestinal barrier function: Molecular regulation and disease pathogenesis The importance of Katherine R. Groschwitz, BS,a,b and Simon P. Hogan, PhDa Cincinnati, Ohio

INFORMATION FOR CATEGORY 1 CME CREDIT claim credit commensurate with the extent of their participation in the the intestinal barrier Credit can now be obtained, free for a limited time, by reading the review activity. articles in this issue. Please note the following instructions. List of Design Committee Members: Authors: Katherine R. Grosch- Method of Physician Participation in Learning Process: The core ma- witz, BS, and Simon P. Hogan, PhD terial for these activities can be read in this issue of the Journal or online at Activity Objectives in regulating the the JACI Web site: www.jacionline.org. The accompanying tests may only 1. To become familiar with the current literature regarding intestinal be submitted online at www.jacionline.org. Fax or other copies will not be epithelial barrier function and disease pathogenesis. accepted. 2. To become familiar with the molecular components of the tight Date of Original Release: July 2009. Credit may be obtained for these junction (TJ) complex and their role in the maintenance of intestinal innate and adaptive courses until June 30, 2011. epithelial barrier function. Copyright Statement: Copyright Ó 2009-2011. All rights reserved. 3. To understand immune-mediated pathways involved in the regulation Overall Purpose/Goal: To provide excellent reviews on key aspects of intestinal epithelial barrier dysfunction. of allergic disease to those who research, treat, or manage allergic 4. To understand endogenous and exogenous factors that influence immune system disease. intestinal epithelial barrier function. Target Audience: Physicians and researchers within the field of allergic 5. To understand the role that altered intestinal barrier function can play disease. in the predisposition to food allergies, inflammatory bowel disease (IBD), Accreditation/Provider Statements and Credit Designation: The celiac disease, and type 1 diabetes. American Academy of Allergy, Asthma & Immunology (AAAAI) is ac- Recognition of Commercial Support: This CME activity has not re- credited by the Accreditation Council for Continuing Medical Educa- ceived external commercial support. tion (ACCME) to provide continuing medical education for Disclosure of Significant Relationships with Relevant Commercial physicians. The AAAAI designates these educational activities for a Companies/Organizations: The authors have declared that they have no maximum of 1 AMA PRA Category 1 Creditä. Physicians should only conflict of interest.

The intestinal epithelium is a single-cell layer that constitutes the transmembrane proteins that interact extracellularly with largest and most important barrier against the external adjacent cells and intracellularly with adaptor proteins that link environment. It acts as a selectively permeable barrier, to the cytoskeleton. Over the past decade, there has been permitting the absorption of nutrients, electrolytes, and water increasing recognition of an association between disrupted while maintaining an effective defense against intraluminal intestinal barrier function and the development of autoimmune toxins, antigens, and enteric flora. The epithelium maintains its and inflammatory diseases. In this review we summarize the selective barrier function through the formation of complex evolving understanding of the molecular composition and protein-protein networks that mechanically link adjacent cells regulation of intestinal barrier function. We discuss the and seal the intercellular space. The protein networks connecting interactions between innate and adaptive immunity and intestinal epithelial cells form 3 adhesive complexes: desmosomes, adherens epithelial barrier function, as well as the effect of exogenous junctions, and tight junctions. These complexes consist of factors on intestinal barrier function. Finally, we summarize clinical and experimental evidence demonstrating intestinal epithelial barrier dysfunction as a major factor contributing to From the Divisions of aAllergy and Immunology and bImmunobiology, Department of the predisposition to inflammatory diseases, including food Pediatrics, Cincinnati Children’s Hospital Medical Center, University of Cincinnati allergy, inflammatory bowel diseases, and celiac disease. College of Medicine. Supported in part by a Crohn’s Colitis Foundation of America Career Development (J Allergy Clin Immunol 2009;124:3-20.) Award, an American Heart Association Grant-in-Aid, and National Institutes of Health grants R01 (AI 073553), F30 (DK082113), and T32 (GM063483). Key word: Intestinal epithelium Received for publication March 12, 2009; revised May 22, 2009; accepted for publication May 27, 2009. Reprint requests: Simon P. Hogan, PhD, Division of Allergy and Immunology, Cincinnati Children’s Hospital Medical Center, 3333 Burnet Ave, ML7028, Cincinnati OH The intestinal epithelium is a single layer of cells lining the gut 45229. E-mail: [email protected]. 0091-6749/$36.00 lumen and has 2 critical functions. First, it acts as a barrier to Ó 2009 American Academy of Allergy, Asthma & Immunology prevent the passage of harmful intraluminal entities, including 1,2 doi:10.1016/j.jaci.2009.05.038 foreign antigens, microorganisms, and their toxins. Its second

3 MICROBIOME TESTING AND TREATMENT Testing: Assessing the Flora

• Testing:

• Dysbiosis self-test: symptoms and triggers

• Urine test looking for dysbiosis markers

• Genova, Metametrix, Great Plains

• Stool testing: Genova, Metametrix, Doctors Data, Diagnostechs, Great Plains

• Some limitations in NY, but available.

• If no access to testing, treat for dysbiosis anyway

• Asymptomatic dysbiosis is common in autoimmune disease and arthritis. Therefore stool testing or treatment is mandatory XXXXX XXXXX

Immune Health: Fix the Flora

• Treat dysbiosis and improve the microbiome balance is the first goal of treatment • Giving probiotics isn’t enough for remission • Functional Medicine 5 R GUT program • Remove: bad food and harmful microbes • Replace: digestive enzymes, bile, stomach acid • Reinoculate: the good bacteria • Regenerate: a healthy intestinal lining/barrier • Retain: long term health and resiliency • Textbook of Functional Medicine. Institute for Functional Medicine, Gig Harbor, Washington. C 2005. Pp 462-468 Step 1 Remove: Herbal Antibiotics

• Herbal treatment of dysbiosis • Recommend for 2 months initially; often repeating treatment 6 months later. • Combination formulas • Berberine • Joshi PV, Shirkhedkar AA, Prakash K, Maheshwari VL. Antidiarrheal activity, chemical and toxicity profile of Berberis aristata. Pharm Biol. 2011;49(1):94–100 • Han, Junling et al. Modulating gut microbiota as an anti-diabetic mechanism of berberine. Med Sci Monit, 2011; 17(7): RA164-167 • Chedid, V, et al. Herbal therapy is equivalent to rifaximin for the treatment of small intestinal bacterial overgrowth. Glob Adv Health Med 2014 May;3(3):16-24 • Artemesia • Juteau F, Jerkovic I, Masotti V., et al. Composition and antimicrobial activity of the essential oil of Artemisia absinthium from Croatia and France. Planta Med. 2003;69(2):158–61 Herbal Antibiotics Cont’d

• Uva Ursi • Tolmacheva, Anna A, et al. Antibacterial and quorum sensing regulatory activities of some traditional Eastern-European medicinal plants. Acta Pharmaceutica. Volume 64, Issue 2 (June 2014 • Black Walnut and Sea Buckthorn • Abidi, SH, et al. Synergy between antibiotics and natural agents results in increased antimicrobial activity against Staphylococcus epidermidis. J Infect Dev Ctries. 2015 Sep 27;9(9):925-9. • Grapefruit seed extract • Heggars, JP et al. The effectiveness of processed grapefruit-seed extract as an antibacterial agent: II. Mechanism of action and in vitro toxicity. J Altern Com[lement Med 2002 Jun;8(3):333-40 • Oregano: • Saeed S, Tariq P. Antibacterial activity of oregano (Origanum vulgare Linn.) against gram positive bacteria. Pak J Pharm Sci. 2009;22(4):421–4 SIBO: Herbs vs Rifaximin Study

• The high prevalence rate for SIBO of 64% in a tertiary care referral gastroenterology practice. • The response rate for normalizing breath hydrogen testing in patients with SIBO was 46% for herbal therapies vs 34% for Rifaximin. • Study herbs: mixture of >20 herbs in 4 different supplements given at the same time. • Herbal treatment as effective as Rifaximin • Advantages: cost, does not promote yeast, well tolerated

• Chedid, V, et al. Herbal therapy is equivalent to rifaximin for the treatment of small intestinal bacterial overgrowth. Glob Adv Health Med 2014 May;3(3):16-24 Step 2: Replace

• Digestive enzymes: • Clinical evaluation: GERD, gas and bloating after meals • Laboratory: low nutrients on testing despite a good diet. Low levels on stool testing • Options: • Plant based • Pancreatin from animals • Apple cider vinegar before meals • Test for and treat hypochlorhydria • Bile acids: especially if gall bladder has been removed or trouble digesting fat • Option to use a combination enzyme formulas that have ox bile in it • Textbook of Functional Medicine, Copyright 2005, Institute for Functional Medicine. Pp 436-7

Step 3: Reinoculate with Probiotics

• Combination formulas: 100 billion for 6 months. • Strains researched in Arthritis: • Lactobacillus casei • Alipour B, Homayouni-Rad A, Vaghef-Mehrabany E et al. (2014) Effects of Lactobacillus casei supplementation on disease activity and inflammatory cytokines in rheumatoid arthritis patients: a randomized double-blind clinical trial. Int J Rheum Dis 17, 519–27 • Amdekar, Sarika, et al. Lactobacillus Casei Reduces the Inflammatory Joint Damage Associated with Collagen Induced Arthritis by reducing the Pro- Inflammatory Cytokines. J. Clin Immunol. 2011; 31: 147-54 • Vaghef-Mehrabany, Elnaz M.Sc. et al. Probiotic supplementation improves inflammatory status in patients with rheumatoid arthritis. Nutrition (2014) 430-435 • J.-S. So et al. Lactobacillus casei suppresses experimental arthritis by down- regulating T helper 1 effector functions. Molecular Immunology 45 (2008) Probiotics for Arthritis cont’d

• Lactobacillus acidophilus • Amdekar, Sarika et al. Lactobacillus acidophilus Protected Organs in Experimental Arthritis by Regulating the Pro-inflammatory Cytokines. Ind J Clin Biochem (Oct-Dec 2014) 29 (4): 471-478 • Lactobacillus rhamnosis and reuteri • Pineda, Maria de los Angeles et al. A randomized, double-blinded, placebo- controlled pilot study of probiotics in active rheumatoid arthritis. Med Sci Monit, 2011; 17(6): • Lactobacillus GG • Baharav, Ehud et al. Lactobacillus GG Bacteria Ameliorate Arthritis in Lewis Rats. J Nutrition 2004 Aug;134(8):1964-9 • Lactobacillus salivarius • O’Callaghan, John et al. Influence of Adhesion and Bacteriocin Production by Lactobacillus salivarius on the Intestinal Epithelial Cell Transcriptional Response. Applied and Environmental Microbiology p. 5196–5203 Probiotics for Arthritis cont’d

• Bifidobacterium Bifidum • Al-Okbi SY. Nutraceuticals of anti-inflammatory activity as complementary therapy for rheumatoid arthritis. Toxicol Ind Health 2014 Sep;30(8):738-49

• S. Boulardi • Beneficial to microbiome, but no direct studies showing helpful in arthritis patients. • Moew, MI and Swidsinski, A. Saccharomyces boulardii CNCM I-745 supports regeneration of the intestinal microbiota after diarrheic dysbiosis- a review. Clin Exp Gastroenterol 2015 Aug 14; 11:237-55 • Citation: Chen X, Yang G, Song J-H, Xu H, Li D, et al. (2013) Probiotic Yeast Inhibits VEGFR Signaling and Angiogenesis in Intestinal Inflammation Improve the Flora with Food

• Cultured foods: non-dairy yogurt, kefir • With live active cultures of lactobacillus, bifidobacteria and sacharomyces boulardi • Fermented foods: kimchi, sauerkraut, other vegetables • Prebiotics: vegetables and fiber. • Fructo-oligo-sacharides (FOS), which are compounds found in onions, garlic, leeks, rye, chicory, blueberries, and bananas. • Inulins, which are found in chicory and artichokes.

• *References on next slide References: food and microbiome

• Everard A, et al. Cross talk between Akkermansia muciniphila and intestinal epithelium controls diet-induced obesity. Proc Natl Acad Sci USA 2013 May 28. • Wlodarska M, Willing BP, Bravo DM, Finlay BB. Phytonutrient diet supplementation promotes beneficial Clostridia species and intestinal mucus secretion resulting in protection against enteric infection. Sci Rep. 2015 Mar 19;5 • Tilg H, Moschen AR. Food, immunity, and the microbiome. Gastroenterology. 2015 May;148(6):1107‐19 • Johanna Maukonen and Maria Saarela. Human gut microbiota: does diet matter? Proceedings of the Nutrition Society (2015), 74, 23–36 • Jens Kjeldsen-Kragh. Rheumatoid arthritis treated with vegetarian diets. Am J Clin Nutr 1999;70(suppl):594S–600S Step 4: Regenerate: Heal the lining

• Repair the lining with food: permanent • Ghee (butyrate) • Coconut oil and medium chain triglycerides • Glutamine: found in all animal protein, such as chicken, beef, and dairy, but also in beans, cabbage, beets, spinach, and parsley, so don’t focus only on animal sources. • Turmeric and cinnamon • Supplementation: 1 year minimum • Glutamine: loose powder is best: 7-8 grams/day • Whey protein is also gut healing • Jin, CJ et al. Supplementation of sodium butyrate protects mice from the development of non-alcoholic steatohepatitis (NASH). Br J Nutr 2015 Dec;114(11):1745-55 • Rapin JR, Wiernsperger N. Possible links between intestinal permeablity and food processing: a potential therapeutic niche for glutamine. Clinics. 2010;65(6):635-43 Step 5: Retain

• Long term treatment: protocol used at our Clinic: • Repeat 30 day herbal treatment every 4-6 months until stool testing is normalized. • Rotate formulas • 1-2 years of high dose probiotics (100 billion) and glutamine (4-7 grams) • Prebiotics and enzymes: use supplements for 6 months, then taper off and use Food as Medicine Terroir de Gut

• Recommendations based on experience • For long term gut health, focus on the ‘soil’ • Nutrition: vegetable based diet rich in prebiotic fiber • Identify and lessen all the damaging behavior: • Stress: direct effect on gut micro-environment • Ingested Toxins • Alcohol • Medication: PPI’s, antacids, steroids, NSAIDS • Oral microbiome: bacteria seed the gut Fecal Transplant: FMT

• C Difficile: FMT is the first conv treatment to alter the intestinal microbiome • Falls under US Food and Drug Admin: biologic product and a drug. • No double blind randomized control studies, so not approved yet. Investigational new drug status. unregulated • Study review: • Whole stool preps. Working on encapsulated formulas • Donor eligibility • Delivery method: NG tube, colonoscopy, duodenal infusion, rectal catheter, enema • Long term safety? Few short term adverse effects • Transmission of infectious agents. (think Hep C from transfusions) • Goal: defined microbial consortia targeted to treat specific diseases.

• Colleen R. Kelly, Stacy Kahn, Purna Kashyap, Loren Laine, David Rubin, Ashish Atreja, Thomas Moore, Gary Wu. Update on Fecal Microbiota Transplantation 2015: Indications, Methodologies, Mechanisms, and Outlook. Gastroenterology, Volume 149, Issue 1, 2015, 223–237 Figure 1. Mechanisms underlying successful treatment of recurrent CDI with FMT. Improvement in symptoms after FMT has been associated with changes in microbial community structure, such as a decrease in Proteobacteria as well as restoration of microbial divers...

Colleen R. Kelly, Stacy Kahn, Purna Kashyap, Loren Laine, David Rubin, Ashish Atreja, Thomas Moore, Gary Wu. Update on Fecal Microbiota Transplantation 2015: Indications, Methodologies, Mechanisms, and Outlook Gastroenterology, Volume 149, Issue 1, 2015, 223–237

Gastroenterology, Volume 149, Issue 1, 2015, 223–237 http://dx.doi.org/10.1053/j.gastro.2015.05.008 CASE STUDY

Case Study: Deb I.

• 51 year old woman, new dx of RA with RF of 32. • Doesn’t want medication • Pain in feet and toes. Fatigue • Long history of gut issues: • antibiotics for strep • Travelers diarrhea multiple times beginning at age 13 • 10 years of gas and bloating; constipation; • Chronic vaginal yeast infections and gum inflammation • Saw another FM doc before me: diet and detox helped energy but not joint pain. Case Study: Deb I.

• I have seen her every 3-4 months for 3 years • She is a good example of a patient who improves slowly because they need to do the program their way • For the first 2 years she was able to follow maybe 50% of my recommendations. • Slowly improving but not resolving. • However in the past year she finally felt able to do the treatment I recommended and her arthritis finally resolved completely with normalizing of her RF. • Reminder that the terrain of the gut/immune system takes time to shift and heal. Treatment history chart for patient Deb I.

Visit every 3-4 RF Arthritis sx Gut sx Stool test Gut Treatment given months

Visit 2 (1st follow up 32 8/10. Pain in feet Gas and bloating Yersinia Cipro 5 d x 2 with results) Candida Undecylenic Acid x 1 Bacterial dysbiosis mo Boulardi and diﬂucan (didn’t take) Culturelle

Visit 3 Not tested Pain 8/10 no change resolved Boulardi and diﬂucan (didn’t take) Culturelle Visit 4 16.8 Slightly Improved Gas and bloating Probiotic with boulardi. 7/10 Glutamine.

Visit 5 16.4 Slightly Improved improved Probiotic with boulardi. 5/10 Glutamine.

Visit 6 Not tested Continues to Resolved Probiotic with boulardi. improve slowly, 5/10 Glutamine.

Visit 7 Not tested Improved but not Resolved pending Oregano, resolved 3/10 Berberine herbal blend (didn’t take) Treatment history chart for patient Deb I. (continued)

Visit 8 RF: 14.6 Improved but not none Candida Oregano, resolved 2/10 Bacterial dsybiosis Berberine herbal blend (didn’t take) Probiotics + glutamine

Visit 9 RF: 14.8 2/10 none Candida gone Change to diﬀerent Bacterial dysbiosis Mild Berberine herbal improved but not blend. resolved Change probiotic, stop boulardi.

Visit 10 STRESS; daughters Heartburn, noisy, Send stool and Digestive enzymes, bat mitzvah gurgly SIBO probiotics, glutamine 2/10 Visit 11 New psoriasis Gas and bloating Candida Nystatin 1 m **ﬁnally willing to Still mild joint pain Bacterial dysbiosis Rifaximin 1 m do a full dose gut when stressed or Glutamine and probiotics treatment regimen sick Visit 12 RF: 12.8 Arthritis is resolved Resolved SIBO negative Stronger herbal blend x ANA and CCP still Psoriasis gone Candida 3 weeks neg Bacterial dysbiosis Oregano x 2 m Nystatin x 2m Glutamine and probiotics

Visit 13 Resolved Resolved Stool test is Probiotics improved. No Glutamine candida We can help…

• The Immune System Recovery Plan: • 4 Step Do-it-With-Us! Free Program: • http://blumcenterforhealth.com/online-programs/ do-it-with-us/ • Step 1: Using Food As Medicine, with recipes • Step 2: Balancing Your Stress Hormones • Step 3: Healing Your Gut • Step 4: Supporting Your Liver If you do not change direction, you may end up where you are heading.” --Lao Tzu