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.
•  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
Microbiome and RA: Zhang Study
•  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 antiCCP, 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
© 2014 Lippinco- Williams & Wilkins, Inc. Published by Lippinco- Williams & Wilkins, Inc. 2 Oral cavity
•  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 Mycobacteria Prevotella copri Prevotella spp. Chlamydia tracomatis Salmonella Omp Shigella Yersinia Colitis Psoriasis Rheumatoid Arthritis (RA) RA RA Reactive Arthritis (ReA) ReA ReA ReA ReA [14] [15] [16] [17] [18,19] [20] [21,22] [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
•  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)
Antibacterial action of RX
•  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 antiinflammatory 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
rheuma- toid 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 monocytederived 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
T H E M I C R O B I O TA
Probiotic
Bifidobacterium
Innate immune recognition of the microbiota
Breve increases T promotes host-microbial symbiosis
regulatory cells
and improves
signaling in T regs
to reduce
inflammation.
This is a local and
systemic effect.
npg
© 2013 Nature America, Inc. All rights reserved.
Hiutung Chu & Sarkis K Mazmanian
Chu, Hiutung and
Mazmanian, Sarkis K.
Innate immune recognition
of the microbiota promotes
host-microbial symbiosis.
Nature Immunology 14,
668-675 (2013).
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
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
symbionts and their hosts.
Conventional wisdom suggests that the immune system evolved to
combat infection and that distinguishing between self and non-self
molecules is a basic feature of innate immunity. As Charles Janeway
proposed, the recognition of microbial molecules, termed pathogen-associated molecular patterns (PAMPs), is critical to selectively
drive immune responses to infectious agents1. Studies identifying and
characterizing host receptors that recognize specific PAMPs, called
‘pattern-recognition receptors’ (PRRs), have provided evidence that
PRR signaling is critical in coordinating immune responses and
protection against pathogens2–5. This view, however, has been challenged by the emerging appreciation that animals have a diverse and
complex symbiotic microbiota6–10, which normally does not trigger
inflammation. PAMPs, by definition, are universally conserved, generally invariant and essential in all microorganisms. Thus, PAMPs are
not limited to pathogens but are also common to the microbiota. As
such, it has been proposed that these molecules be renamed microbeassociated molecular patterns (MAMPs)11. Furthermore, host PRRs
are constantly exposed to MAMPs in the absence of infection. These
MAMPs are largely provided by the commensal microbiota that colonize our skin and mucosal surfaces. Despite the continuous presence
of many MAMPs, commensal microbes usually do not elicit inflammatory responses but rather may contribute to various aspects of
host development and enhanced immune function12. To our surprise,
this beneficial influence is mediated, in part, by commensal stimulation of host PRRs13.
How these molecules and receptors can achieve such divergent and
opposing responses between pathogens and symbiosis is a frontier in
Division of Biology and Biological Engineering, California Institute of
Technology, Pasadena, California, USA. Correspondence should be addressed
to S.K.M. (sarkis@caltech.edu).
Received 8 April; accepted 2 May; published online 18 June 2013;
doi:10.1038/ni.2635
668
our understating of innate immunity. It has been proposed that the
context in which the host receives MAMP stimulation dictates the
quality of the immune response. During infection, MAMP signals
are received in the presence of other cues, such as cell damage caused
by infection14 and/or cytosolic detection of MAMPs15, resulting in
inflammation. During symbiosis, not only does the microbiota generally not harm host cells and MAMPs are sensed in the absence
of exposed self antigens, but it appears that some MAMPs directly
promote beneficial outcomes. In this Review, we will focus on how
recognition of MAMPs by PRRs under steady-state conditions promotes immune development, protection from disease and maintains
homeostasis. The concepts presented here collectively demonstrate
that PRRs may have evolved in both the invertebrate and vertebrate
immune systems to communicate with commensals and maintain
beneficial, symbiotic coexistence with the microbiota.
Pattern recognition in Drosophila promotes homeostasis
Extensive work using D. melanogaster as a model system has highlighted the important functions of PRRs in host defense as well as
in homeostasis. Toll, one of the first PRRs to be identified, was initially discovered in D. melanogaster16. However, the realization that
D. melanogaster Toll does not directly recognize MAMPs, unlike the
PRRs in the mammalian Toll-like receptor (TLR) signaling pathway, left the open question of how bacterial ligands are recognized.
D. melanogaster has 13 peptidoglycan recognition protein (PGRP)
genes that are alternatively spliced into 19 different proteins, which
is one of the largest repertoires of PGRPs currently known for any
organism17. The role of D. melanogaster PGRPs as PRRs was discovered during the identification of upstream receptors that activate the
signal-transduction pathways, Toll and Imd (immune deficiency)18,19,
which are highly similar to the mammalian interleukin 1 (IL-1)–TLR
and tumor necrosis factor (TNF) pathways20. However, Toll does not
function as a PRR because it does not directly recognize MAMPs21.
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)
‘Dysbiosis contributes to
compromised epithelial
Integrity and disrupted
Immune tolerance’
Immunological Reviews
2012
Vol. 245: 164–176
Laurence Macia*
Alison N. Thorburn*
Lauren C. Binge
Eliana Marino
Kate E. Rogers
Kendle M. Maslowski
Angélica T. Vieira
Jan Kranich
Charles R. Mackay
Microbial influences on epithelial
integrity and immune function as a
basis for inflammatory diseases
Authors’ addresses
Laurence Macia1*, Alison N. Thorburn1*, Lauren C. Binge1, Eliana
Marino1, Kate E. Rogers1, Kendle M. Maslowski2, Angélica T. Vieira3, Jan
Kranich4, Charles R. Mackay1
1
Department of Immunology, Monash University, Clayton,
Victoria, Australia.
2
Department of Biochemistry, University of Lausanne,
Epalinges, Switzerland.
3
Immunopharmacology Group – Department of
Biochemistry and Immunology, Institute of Biological
Sciences, Federal University of Minas Gerais, Belo Horizonte,
Minas Gerais, Brazil.
4
Garvan Institute of Medical Research, Darlinghurst, New
South Wales, Australia.
Summary: Certain autoimmune diseases as well as asthma have
increased in recent decades, particularly in developed countries. The
hygiene hypothesis has been the prevailing model to account for this
increase; however, epidemiology studies also support the contribution of
diet and obesity to inflammatory diseases. Diet affects the composition of
the gut microbiota, and recent studies have identified various molecules
and mechanisms that connect diet, the gut microbiota, and immune
responses. Herein, we discuss the effects of microbial metabolites, such
as short chain fatty acids, on epithelial integrity as well as immune cell
function. We propose that dysbiosis contributes to compromised epithelial integrity and disrupted immune tolerance. In addition, dietary molecules affect the function of immune cells directly, particularly through
lipid G-protein coupled receptors such as GPR43.
Keywords: microbiota, epithelium, GPR43, short-chain fatty acids
Correspondence to:
Charles R. Mackay
Level 3, Building 75
Monash University
Wellington Rd
VIC 3800, Australia
Tel.: +61 2 9902 9510
Fax: +61 2 9902 4291
e-mail: charles.mackay@monash.edu
*These authors contributed equally.
Acknowledgements
The authors have no conflicts of interest to declare.
This article is part of a series of reviews
covering Microbial Influences on
Immune Function appearing in Volume
245 of Immunological Reviews.
Immunological Reviews 2012
Vol. 245: 164–176
Printed in Singapore. All rights reserved
! 2011 John Wiley & Sons A/S
Immunological Reviews
Introduction
A new direction in immunology research has emerged
recently that considers the effects of diet on the gut microbiota and immune responses. Gastrointestinal microbes have
co-evolved with vertebrates and provide benefits to the host,
including maintenance of epithelial integrity and regulation of
immune responses. However, the composition of the gut microbiota can differ considerably between individuals, and this
difference appears to relate to diet (1–3). This may be particularly relevant to human inflammatory diseases, several of
which associate with western lifestyle and obesity. While several studies and reviews (including by us) have highlighted
the direct effects of dietary molecules on immune cells (4, 5),
a new and possibly equally important element is the gut epithelium. The gut is lined by epithelial cells, which provide an
important physical barrier and defense against pathogens. The
integrity of the epithelial barrier is important to reduce
0105-2896
164
! 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
develop properly
because our
environment is too
clean, which in turn
prevents immune
system from
functioning properly.
Published online: 17 November 2011
# Springer Science+Business Media, LLC 2011
Abstract Throughout the twentieth century, there were
striking increases in the incidences of many chronic inflammatory disorders in the rich developed countries. These
included autoimmune disorders such as Type 1 diabetes and
multiple sclerosis. Although genetics and specific triggering
mechanisms such as molecular mimicry and viruses are likely
to be involved, the increases have been so rapid that any
explanation that omits environmental change is incomplete.
This chapter suggests that a series of environmental factors,
most of them microbial, have led to a decrease in the
efficiency of our immunoregulatory mechanisms because we
are in a state of evolved dependence on organisms with which
we co-evolved (and that had to be tolerated) as inducers of
immunoregulatory circuits. These organisms (“Old Friends”)
are depleted from the modern urban environment. Rather than
considering fetal programming by maternal microbial exposures, neonatal programming, the hygiene hypothesis, gut
microbiota, and diet as separate and competing hypotheses, I
attempt here to integrate these ideas under a single umbrella
concept that can provide the missing immunoregulatory
environmental factor that is needed to explain the recent
increases in autoimmune disease.
Keywords Immunoregulation . “Old Friends” .
Microbiota . Treg
Introduction
Rook, Graham A. W.
Hygiene Hypothesis and
Autoimmune Diseases. Clinic
Rev Allerg Immunol (2012)
42:5-15
The hygiene hypothesis, recently reformulated as the Old
Friends Hypothesis to bring it in line with Darwinian
medicine, and with the latest epidemiological and experimental evidence, suggests that since the start of modern “concrete
G. A. W. Rook (*)
Department of Infection, Centre for Clinical Microbiology,
University College London (UCL),
London NW3 2PF, UK
e-mail: g.rook@ucl.ac.uk
and tarmac” urbanization in the early nineteenth century there
has been a progressive increase in immunoregulatory problems attributable to depletion from the urban environment of
organisms with which mammals co-evolved, and that had
been tasked by co-evolutionary forces with a crucial role in
setting up “normal” background levels of immunoregulation
(this will be explained, expanded and referenced below). It
would be foolish to suggest that this mechanism is the whole
explanation for the striking increases in certain autoimmune
diseases (notably Type 1 diabetes (T1D) and multiple sclerosis
(MS)) in the twentieth century. On the other hand, the recent
nature of these increases makes it certain that the major
underlying cause is environmental. The role of genetic factors
cannot be more than to determine which individuals develop
the disease after the environmental changes have occurred… a
classic example of gene-environment interaction. In addition
there are other potential environmental factors that I consider
to be subcomponents of the Old Friends hypothesis (such as
delayed exposure to viruses), and others that are entirely
separate in nature (such as deficient Vitamin D3). All of
these will exacerbate the immunoregulatory deficit. Figure 1
lists some relevant factors, and also emphasizes the
immunoregulatory role of the gut. One of the most important
discoveries in recent years is the fact that manipulations of
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)
non-obese diabetic (NOD) mice that spontaneously develop
a condition resembling T1D, are protected from the disease
following knockout of the gene encoding MyD88 (an
adaptor for multiple Toll-like receptors) [1]. However, this
did not mean that MyD88 was directly involved in the
autoimmune response to β cells in the pancreas. Rather, it
emerged that the modification of the immune system
resulting from knocking out MyD88 caused profound
changes in the interactions between the immune system
and the microbiota. Consequent changes in the composition of
the microbiota were responsible for the immunoregulatory
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 has been
demonstrated to
cause autoimmune
Disease
Fasano, Alessio. Leaky Gut and
Autoimmune Diseases. Clinic Rev
Allerg Immunol (2012) 42:71-78
Leaky Gut and Autoimmune Diseases
Alessio Fasano
Published online: 23 November 2011
# Springer Science+Business Media, LLC 2011
Abstract Autoimmune diseases are characterized by tissue
damage and loss of function due to an immune response that is
directed against specific organs. This review is focused on the
role of impaired intestinal barrier function on autoimmune
pathogenesis. Together with the gut-associated lymphoid
tissue and the neuroendocrine network, the intestinal epithelial
barrier, with its intercellular tight junctions, controls the
equilibrium between tolerance and immunity to non-self
antigens. Zonulin is the only physiologic modulator of
intercellular tight junctions described so far that is involved
in trafficking of macromolecules and, therefore, in tolerance/
immune response balance. When the zonulin pathway is
deregulated in genetically susceptible individuals, autoimmune disorders can occur. This new paradigm subverts
traditional theories underlying the development of these
diseases and suggests that these processes can be arrested if
the interplay between genes and environmental triggers is
prevented by re-establishing the zonulin-dependent intestinal
barrier function. Both animal models and recent clinical
evidence support this new paradigm and provide the rationale
for innovative approaches to prevent and treat autoimmune
diseases.
Introduction
Keywords Antigens . Autoimmunity . Gut permeability .
Immune response . Tight junctions . Zonulin
Classical Theories on the Pathogenesis of Autoimmune
Diseases
A. Fasano (*)
Mucosal Biology Research Center,
University of Maryland School of Medicine,
20 Penn Street HSF II Building, Room S345,
Baltimore, MD 21201, USA
e-mail: afasano@mbrc.umaryland.edu
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
often explained by a mechanism known as “molecular
mimicry,” whereby microbial antigens are postulated to
resemble self-antigens [1]. The induction of an immune
response to the microbial antigens results in a cross-reaction
with the self-antigens and the induction of autoimmunity.
The intestinal epithelium is the largest mucosal surface
providing an interface between the external environment
and the mammalian host. Its exquisite anatomical and
functional arrangements and the finely-tuned coordination
of digestive, absorptive, motility, neuroendocrine, and
immunological functions are testimonial of the complexity
of the gastrointestinal (GI) system. Also pivotal is the
regulation of molecular trafficking between the intestinal
lumen and the submucosa via the paracellular space. The
dimensions of the paracellular space are estimated to be
between 10 and 15 Å, suggesting that under physiological
circumstances, solutes with a molecular radius exceeding
15 Å (~3.5 kDa) will be excluded from this uptake route.
Macromolecule trafficking is dictated mainly by intestinal
paracellular permeability, whose regulation depends on the
modulation of intercellular tight junctions (TJ). A fast
growing number of diseases, including autoimmune diseases, are recognized to involve alterations in intestinal
permeability related to changes in TJ competency.
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
the intestinal barrier
in regulating the
innate and adaptive
immune system
Katherine R. Groschwitz, BS,a,b and Simon P. Hogan, PhDa
INFORMATION FOR CATEGORY 1 CME CREDIT
Credit can now be obtained, free for a limited time, by reading the review
articles in this issue. Please note the following instructions.
Method of Physician Participation in Learning Process: The core material for these activities can be read in this issue of the Journal or online at
the JACI Web site: www.jacionline.org. The accompanying tests may only
be submitted online at www.jacionline.org. Fax or other copies will not be
accepted.
Date of Original Release: July 2009. Credit may be obtained for these
courses until June 30, 2011.
Copyright Statement: Copyright ! 2009-2011. All rights reserved.
Overall Purpose/Goal: To provide excellent reviews on key aspects
of allergic disease to those who research, treat, or manage allergic
disease.
Target Audience: Physicians and researchers within the field of allergic
disease.
Accreditation/Provider Statements and Credit Designation: The
American Academy of Allergy, Asthma & Immunology (AAAAI) is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for
physicians. The AAAAI designates these educational activities for a
maximum of 1 AMA PRA Category 1 Credit". Physicians should only
The intestinal epithelium is a single-cell layer that constitutes the
largest and most important barrier against the external
environment. It acts as a selectively permeable barrier,
permitting the absorption of nutrients, electrolytes, and water
while maintaining an effective defense against intraluminal
toxins, antigens, and enteric flora. The epithelium maintains its
selective barrier function through the formation of complex
protein-protein networks that mechanically link adjacent cells
and seal the intercellular space. The protein networks connecting
epithelial cells form 3 adhesive complexes: desmosomes, adherens
junctions, and tight junctions. These complexes consist of
From the Divisions of aAllergy and Immunology and bImmunobiology, Department of
Pediatrics, Cincinnati Children’s Hospital Medical Center, University of Cincinnati
College of Medicine.
Supported in part by a Crohn’s Colitis Foundation of America Career Development
Award, an American Heart Association Grant-in-Aid, and National Institutes of Health
grants R01 (AI 073553), F30 (DK082113), and T32 (GM063483).
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
45229. E-mail: simon.hogan@cchmc.org.
0091-6749/$36.00
! 2009 American Academy of Allergy, Asthma & Immunology
doi:10.1016/j.jaci.2009.05.038
Cincinnati, Ohio
claim credit commensurate with the extent of their participation in the
activity.
List of Design Committee Members: Authors: Katherine R. Groschwitz, BS, and Simon P. Hogan, PhD
Activity Objectives
1. To become familiar with the current literature regarding intestinal
epithelial barrier function and disease pathogenesis.
2. To become familiar with the molecular components of the tight
junction (TJ) complex and their role in the maintenance of intestinal
epithelial barrier function.
3. To understand immune-mediated pathways involved in the regulation
of intestinal epithelial barrier dysfunction.
4. To understand endogenous and exogenous factors that influence
intestinal epithelial barrier function.
5. To understand the role that altered intestinal barrier function can play
in the predisposition to food allergies, inflammatory bowel disease (IBD),
celiac disease, and type 1 diabetes.
Recognition of Commercial Support: This CME activity has not received external commercial support.
Disclosure of Significant Relationships with Relevant Commercial
Companies/Organizations: The authors have declared that they have no
conflict of interest.
transmembrane proteins that interact extracellularly with
adjacent cells and intracellularly with adaptor proteins that link
to the cytoskeleton. Over the past decade, there has been
increasing recognition of an association between disrupted
intestinal barrier function and the development of autoimmune
and inflammatory diseases. In this review we summarize the
evolving understanding of the molecular composition and
regulation of intestinal barrier function. We discuss the
interactions between innate and adaptive immunity and intestinal
epithelial barrier function, as well as the effect of exogenous
factors on intestinal barrier function. Finally, we summarize
clinical and experimental evidence demonstrating intestinal
epithelial barrier dysfunction as a major factor contributing to
the predisposition to inflammatory diseases, including food
allergy, inflammatory bowel diseases, and celiac disease.
(J Allergy Clin Immunol 2009;124:3-20.)
Key word: Intestinal epithelium
The intestinal epithelium is a single layer of cells lining the gut
lumen and has 2 critical functions. First, it acts as a barrier to
prevent the passage of harmful intraluminal entities, including
foreign antigens, microorganisms, and their toxins.1,2 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 rheuma- toid 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 ProInflammatory 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 downregulating 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 dysbiosisa 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
months
RF
Arthritis sx
Gut sx
Visit 2 (1st follow up
with results)
32
8/10. Pain in feet
Gas and bloating Yersinia
Cipro 5 d x 2
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
Visit 4
16.8
Slightly Improved
7/10
Gas and bloating Visit 5
16.4
Slightly Improved
5/10
improved
Probiotic with boulardi.
Glutamine.
Visit 6
Not tested
Continues to
Resolved improve slowly, 5/10
Probiotic with boulardi.
Glutamine.
Visit 7
Not tested
Improved but not
resolved 3/10
pending
Oregano,
Berberine herbal blend
(didn’t take)
Resolved
Stool test
Gut Treatment given
Boulardi and diflucan
(didn’t take)
Culturelle
Probiotic with boulardi.
Glutamine.
Treatment history chart for patient Deb I. (continued)
Visit 8
RF: 14.6
Improved but not
resolved 2/10
none
Candida
Bacterial dsybiosis
Oregano,
Berberine herbal blend
(didn’t take) Probiotics + glutamine
Visit 9
RF: 14.8
2/10
none
Candida gone
Bacterial dysbiosis
improved but not
resolved
Change to different
Mild Berberine herbal
blend.
Change probiotic, stop
boulardi. Visit 10
STRESS; daughters
bat mitzvah
2/10
New psoriasis
Still mild joint pain
when stressed or
sick
Arthritis is resolved
Psoriasis gone
Heartburn, noisy,
gurgly
Send stool and
SIBO
Digestive enzymes,
probiotics, glutamine
Resolved
SIBO negative
Candida
Bacterial dysbiosis
Stronger herbal blend x
3 weeks
Oregano x 2 m
Nystatin x 2m
Glutamine and probiotics
Resolved
Resolved
Stool test is
improved. No
candida
Probiotics
Glutamine
Visit 11
**finally willing to
do a full dose gut
treatment regimen
Visit 12
RF: 12.8
ANA and CCP still
neg
Visit 13
Gas and bloating Candida
Nystatin 1 m
Bacterial dysbiosis Rifaximin 1 m
Glutamine and probiotics
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