The document discusses the relationship between compromised intestinal permeability and inflammation, highlighting the prevalence of inflammatory bowel diseases (IBD) in the U.S. and the important role of tight junction proteins in gut health. It reviews literature on the mechanisms of intestinal permeability and the factors contributing to increased permeability, along with diagnostic protocols and natural interventions for treating related disorders. The document concludes by emphasizing evidence-based dietary and supplemental approaches to restore gut health and reduce inflammation.

1. The Role of Compromised Intestinal Permeability
in the Inflammatory Process: Natural Interventions
Ellen Kamhi, PhD, RN, AHG, AHN-BC
www.naturalnurse.com

2. OBJECTIVE I
Investigating the link between intestinal
permeability and inflammation

3. Epidemiology
1.4 million Americans have IBD, evenly split between
Crohn’s and ulcerative colitis. Males and females are
affected equally.
• Crohn’s Disease
– Incidence is highest in developed countries.
– Most commonly diagnosed in young adults (late adolescence to
third decade of life).
• Ulcerative Colitis
– Incidence is highest in developed countries.
– On average people are diagnosed in their mid-30s
– Highest in Jewish populations followed by non-Jewish white
populations.

4. Past literature: the link between intestinal
permeability and inflammation
Parke, A, Gastrointestinal disorders and rheumatic
diseases. Current Opinion in Rheumatology.1991
Feb;3(1):160-5.
“In some instances, the association between
gastrointestinal pathology and extraintestinal disease is so
strong that treatment of gastrointestinal disease cures the
patient of the extraintestinal complaints. maintenance of
the structural and immunologic barriers of the
gastrointestinal tract are vital in determining the
general health of the patient, and the associations
between the gut, arthritis, dermatitis, and autoimmune
disease are much stronger than may appear at first glance. ”

5. Current literature: the link between
intestinal permeability and inflammation
Vandenbroucke RE, et. Al. Matrix metalloproteinase 13
modulates intestinal epithelial barrier integrity in inflammatory
diseases by activating TNF.
EMBO Mol Med. 2013 May 30. doi:10.1002/emmm.201202100.
Wilcz-Villega EM, et. al. Mast Cell Tryptase Reduces Junctional
Adhesion Molecule-A (JAM-A) Expression in Intestinal Epithelial
Cells: Implications for the Mechanisms of Barrier Dysfunction in
Irritable Bowel Syndrome.
Am J Gastroenterol. 2013 Apr 16. doi: 10.1038/ajg.2013.92

7. Intestinal Permeability: a vicious
cycle of inflammation
• mucosal biopsies from IBD and celiac patients
patients shows altered expression of several
critical tight junction proteins, including
upregulation of zonulin and claudin 2
• On this manner, a vicious circle is created, in which
barrier dysfunction allows further leakage of
luminal contents, thereby triggering an
immune response that in turn promotes
further breakdown of the tight junctions.

8. Nature Reviews Immunology
2003;3:528
With Permission

9. Tight junctions are dynamic
structures that are involved in
developmental, physiological and
pathological processes.
Tight junction dysfunction seems to
be the primary defect in
autoimmune diseases.

10. ADHESION MOLECULES
Zonulins, Occludin, Claudins
• Modulate movement of fluid,
macromolecules and leukocytes from
the blood stream to the intestinal
lumen, and vice versa
• Protect the epithelial cells of the
intestine against colonization by
microorganisms

11. Adhesion Molecules
• Zonulin: protein that participates in tight
junctions between cells of the wall of the
digestive tract. Discovered in 2000 as the target
of zonula occludens toxin, secreted by cholera
pathogen Vibrio cholerae,[1] it has been
implicated in the pathogenesis of coeliac
disease[2] and diabetes mellitus type 1.[3]
• ^ Wang, W; Uzzau, S; Goldblum, SE; Fasano, A (2000). "Human zonulin, a potential
modulator of intestinal tight junctions". Journal of Cell Science 113 (24): 4435–40.
PMID 11082037.
• ^ Thomas, KE; Sapone, A; Fasano, A; Vogel, SN (2006). "Gliadin stimulation of
murine macrophage inflammatory gene expression and intestinal permeability are
MyD88-dependent: role of the innate immune response in Celiac disease". Journal of
immunology (Baltimore, Md. : 1950) 176 (4): 2512–21. PMID 16456012.
• ^ Sapone, A; De Magistris, L; Pietzak, M; Clemente, MG; Tripathi, A; Cucca, F;
Lampis, R; Kryszak, D et al. (2006). "Zonulin upregulation is associated with
increased gut permeability in subjects with type 1 diabetes and their relatives".
Diabetes 55 (5): 1443–9. DOI:10.2337/db05-1593. PMID 16644703.

12. •
•

13. Intestinal fortitude….
• The strength of the intestines depends on the
effectiveness of the matrix that keeps its
framework intact.
• In a healthy intestine, few unwanted molecules
can penetrate the cell membranes of the small
or large intestine, or escape between intestinal-wall
cells because of the tight seal created by
the intracellular “glue” which forms a barrier.

14. GALT
• The Gastrointestinal lining contains most
of the immune cells in the body (Gut
Associated Lymphoid Tissue (GALT)
• It engages in a continuous fight with
potentially pathogenic bacteria, fungi,
parasites, lectins, allergens, while leaving
symbiotic bacteria unscathed.

15. GALT
http://origin-ars.els-cdn.com/content/image/1-s2.0-S089990079800029X-gr1.gif

16. Periodontal disease is really a
Periodontal infection
Science is showing that the gums are a
major entry point for microorganisms to
invade the rest of the body.
Candida
Helicobacter
Pylori

17. • . The small and large
intestines measured
together and laid flat
equal about 25 feet in
length.
• The total surface area
of villi and microvilli in
the intestines that is
capable of absorbing
nutrients is about the
size of a tennis court.

18. Intestinal Permeability
• Note the severe
damage to the
intestinal microvilli

19. Candidiasis Infection
• IMAGE CREDIT: http://www.dietsforweightloss.net/wp-content/uploads/2010/02/candida.jpg

20. Structure and function of tight junctions are altered by direct pathogen binding to tight junction
proteins, PKC ( protein kinase enzymes) , and protease-mediated disruption of actomyosin
Kunzelmann K , McMorran B Physiology 2004;19:240-244
©2004 by American Physiological Society

21. http://www.fmp-berlin.de/schmieder/research/jpg/img_tight_junction.jpg

23. OBJECTIVE II
Diagnostic protocols and tools to
determine functional gastro-intestinal
disorders & intestinal permeability

24. Pathophysiological regulation of tight junctions is
influenced by many factors, including:
• Secretory IgA
• Enzymes
• Neuropeptides &neurotransmitters
• Dietary peptides
• Lectins
• Yeast, aerobic and anaerobic bacteria
• Parasites
• Proinflammatory cytokines
• Free radicals , oxidative damage
• Regulatory T-cell dysfunction
• Psychological Factors- Stress
(Buret, Andre. How Stress Induces Intestinal Hypersensitivity. American Journal of
Pathology. 2006 Jan; 168(1): 3-5 PMC1592668)

25. Factors that can increase the permeability of the intestinal barrier:
• Food sensitivity
• Celiac disease
• Acute Gastroenteritis
• Chronic intestinal
infections
• Inflammatory bowel
disease
• Surgery
• Exercise
• Psychosocial stress
• Nutrient Deficiency(often
secondary to
pharmaceutical depletion)
• Excessive radiation
• Extensive burns
• Septicemia shock
• Hypovolumetric shock
• Neurotransmitter
imbalance
• Malnutrition
• Secretory IgA deficiency
• Anti-inflammatory drugs
• Viral infection

26. • NSAIDS
perpetrate
inflammation
via increasing
intestinal
permeability

27. ROME III Criteria (2006)
The Rome III criteria system was developed to classify the
functional gastrointestinal disorders based on clinical symptoms.
Each disorder has its own set of criteria.
For example, the Rome III criteria for
irritable bowel syndrome (IBS) :
Symptoms of recurrent abdominal pain or discomfort and a marked
change in bowel habit for at least six months, with symptoms
experienced on at least three days of at least three months.
Two or more of the following must apply:
Pain is relieved by a bowel movement
Onset of pain is related to a change in frequency of stool
Onset of pain is related to a change in the appearance of stool.

28. Intestinal Permeability
• Measurement of urinary clearance post
challenge drink.
– Lactulose
– Mannitol
– Lactulose/Mannitol Ratio

29. Normal Gut
Mucosa

30. Intestinal Permeability
Intestinal Permeability

31. Permeability can occur between
juntions or transcellularly
• Altered permeability
between tight
junctions
• {tested with
Lactulose, a dimer }
• Altered permeability
transcellularly (thru
the cell)
• {Use Mannitol, a
monosaccharide}

33. http://www.undergroundwellness.com/images/mucosal_barrier_degradation.png

34. • Once tight junctions are compromised bacterial
toxins, xenobiotics and food antigens enter the
circulation
• These stimulate the immune system , which
attempts to remove them from circulation, thus
forming ANTIGEN-ANTIBODY/CIRCULATING
IMMUNE COMPLEXES which trigger additional
inflammation.
• The heightened activation of inflammatory
cascades results in further production of
proinflammatory cytokines TNF-alpha, IL-6 and
IL-1B
• As immune complexes are deposited in
Connective tissue, activation of the complement
and alternate complement pathway

36. Food Sensitivities
“IgG-mediated immunologic adverse
reactions to foods”
Food allergies cause the immune
system to synthesize and release
reactive chemical agents including:
– Cytokines and lymphokines
– Interferon
– IgG antibodies

37. Associate Conditions
•Celiac Disease
•IBD
•IBS
•Food Allergy
•Atopic Dermatitis, Eczema
•Ankylosing Spondylitis
•Inflammatory Joint Disease
•Rheumatoid Arthritis
Fasano A. Surprises from Celiac Disease. Scientific American 2009(Aug):54-61.
Associated Conditions

38. OBJECTIVE III
Incorporating low risk- high efficacy
evidence based natural interventions
in patient protocols

39. ••
Treatment Protocol
••4R program
• Dr Jeff Bland
• Remove
• Replace
• Reinoculate
• Repair

40. Functional Assessment Resource Manual
1999 Great Smokies Diagnostic Laboratory ,
Ashville, NC

41. Gluten Free Diet
Vazquez-Roque MI , et. Al. Gastroenterology.
2013 Jan 25. pii: S0016-5085(13)00135-2.
A Controlled Trial of Gluten-Free Diet in Patients with
Irritable Bowel Syndrome-Diarrhea: Effects on
Bowel Frequency and Intestinal Function.
CONCLUSION:: Gluten alters bowel barrier functions
in patients with IBS-D, particularly in HLA-DQ2/8-
positive patients. These findings reveal a reversible
mechanism for the disorder.

42. Gluten Free Diet
• A gluten free diet reduced diarrhea in
patients with IBS
• There was a measurable increase
in intestinal permeability in those eating
gluten.
• Gluten caused an increased production of
inflammatory markers
• Worse in patients who had positive gene
markers for gluten sensitivity.
http://www.glutenfreesociety.org/gluten-free-society-blog/ibs-reversable-on-a-gluten-free-diet/

43. Antimicrobials to Reduce
Intestinal Microbe Overgrowth
Sweet wormwood herb (Artemisia annua) 400 mg
Olive leaf extract (Olea europaea) 300 mg
Berberine sulfate 200 mg
Oregano leaf (Origanum vulgare) 200 mg
Thyme leaf extract (Thymus vulgaris) 200 mg
Grapefruit seed extract (Citricidal spp.) 150 mg
Black walnut hull extract (Juglans nigra) 100 mg
Uva ursi leaf extract (Arctostaphylos uva ursi) 100 mg
Cat's Claw (Uncaria tomentosa) 100 mg

44. Probiotics to Reinoculate
Friendly Microbiota
Acidophilus, Bifidus and other beneficial species
can be given orally to help re-establish healthy
gut flora.
J Neurogastroenterol Motil. 2011 Jul;17(3):252-66. doi:
10.5056/jnm.2011.17.3.252. Irritable bowel syndrome, gut
microbiota and probiotics. Lee BJ, Bak YT.

45. Normal Flora & Probiotics
Decrease Inflammation
• Bennet JD, Brinkman M. Treatment of
ulcerative colitis by implantation of normal
colonic flora. Lancet 1989;1:164.
• Borody TJ et al. Treatment of ulcerative
colitis using fecal bacteriotherapy. J Clin
Gastroenterol. 2003; 37(1):42-47.
• Gionchietti P et al. Prophylaxis of pouchitis
onset with probiotic therapy.
Gastroenterology. 2003;124:1202-1209.

46. Repair
GLUTAMINE - most abundant amino acid
involved in more metabolic processes than
any other amino acid.
Directly used by cells lining the intestines to
rebuild villi. Also used by white blood
cells, supporting immune function.

47. Foods For Repair
• Okra
• Cabbage
• Onion
• Garlic
• Artichokes
• Jerusalum Artichokes ( Sunchokes)
• Turmeric/Ginger
http://fixyourdigestion.com/top-ten-best-foods-for-digestive-health/

48. Repair Vegetable Soup Recipe

49. Repair Typical Supplement Protocol
L-Glutamine 1500 mg
N-Acetyl Glucosamine 1000 mg
Citrus Pectin 1000 mg
Deglycyrrhizinated Licorice (DGL) (Glycyrrhiza
glabra) 400 mg
Slippery Elm (bark) (Ulmus pulmila) 200 mg
Marshmallow (root) (Althea officinalis) 100 mg
Chamomile (Matricaria chamomilla) 100 mg
Okra (pod) (Hibiscus esculentus) 100 mg
Cat's Claw (bark) (Uncaria tomentosa) 100 mg
Quercetin 100 mg
Prunus (Concentrate) 100 mg
Zinc-Carnosine 75 mg

50. Information Sources
www.naturalstandard.com
www.restorativemedicine.org
www.functionalmedicine.org
www.naturalnurse.com
Link: education
www.gdx.net (Genova Diagnostics)