The Gut and

Autoimmunity Heidi Turner, MS, RDN, CD

The Seattle Arthritis Clinic @

Northwest Hospital/UW Medicine

No conflicts here

Overview Thought process for assessing patients related to diet,

inflammation and the gut

Three pathways of inflammation related to diet

1. Gluten, dairy and food sensitivity

2. Histamines and inflammation

3. Bacterial overgrowth/dysbiosis and gut inflammation

Case Study

Pathway #1

Food Sensitivities: Gluten Elimination of potentially antigenic foods important in reducing GI inflammation

Wheat and dairy most problematic, most consumed

“Intestinal cell damage and systemic immune activation in individuals reporting sensitivity to wheat in absence of Celiac Disease” (1)

Increase in soluble CD14 and lipopolysaccharide-binding protein (1)

Increase antibody reactivity to microbial antigens, indicating systemic immune activation (1)

Elevated levels of fatty acid-binding protein that correlates with the markers of systemic immune activation, suggesting compromised intestinal epithelial barrier integrity. (1)

Gliadin in wheat can increase intestinal permeability (2)

Pathway #1

Food Sensitivities: Dairy Lactose intolerance? Casein sensitivity?

There is research indicating that certain dairy proteins can be inflammatory to the digestive tract

Research on A1 vs A2 beta proteins (3-4)

A1 protein derived from hybridization of Holstein and other cows

A1 has potential to be most inflammatory to the intestinal lining

A2 beta protein from Jersey, Guerney and other cows and others has been shown to be less reactive in those with dairy sensitivities

Goat and sheep are all A2 which may be why we see less reactivity to this dairy

Pathway #2

Histamines Via H1-H4 receptors, histamines impact numerous

systems (5-6)

Summary of histamine-mediated symptoms

Laura Maintz, and Natalija Novak Am J Clin Nutr

2007;85:1185-1196

Assessing for Histamines

Common Symptoms Year round allergy

symptoms (rhinitis, itchy eyes)

Worsening of symptoms with stress

Urticaria

Anxiety

Insomnia

GI issues common

Episodes of tachycardia

Perimenopause: Increase in hot flashes, insomnia, painful menses

Worsening of pain with seasonal change

Hypotension

Headache/migraine

Cause and impact of

histamines in RA Onset of symptoms typically during long period of stress,

illness/infection, trauma. Often combined with perimenopause.

Boiling pot effect, multiple situations occur at once

Excessive histamine production can lead to multiple symptoms including swelling in joints, pain

Research linking histamine (H4 receptors) to RA. (7-8)

H4 antagonist has reduced arthritic pain via reduction IL-17 in vitro. (9)

Studies have shown increase in H4R in synovial fluid cells. (10)

No reliable serum markers (24 hr urinary methylhistamine, tryptase, histamine, etc.)

Low histamine diet

Foods to remove(5-6)

Aged, fermented foods especially high in histamine

Wine, cider, beer

Aged meats/cheese/vinegar/pickled foods

Tomatoes, eggplant, spicy peppers, spinach, pumpkin

Citrus fruit, banana, avocado, strawberries, raspberries

Most nuts

Chocolate, more

Case Study: Histamine 36 yo female

RA dx, seroneg. Onset post partum.

Joint pain in thumb, wrist, shoulder; flares random lasting 3-4 day in duration

GI: Daily diarrhea (watery, urgent). 11 year history of “sensitive stomach” after travel to Panama. GI workups normal.

Sx worsen with menstruation, stress.

Chronic allergy sx including itchy eyes, rhinitis

HCQ reduced the intensity of pain. Declined Humira.

Case Study: 4-Week F/U After one day on low histamine diet, significant

reduction in joint pain

Diarrhea reduced in intensity, now soft stools mixed

with episodes of diarrhea

Introduced both histamines and wheat into the diet and

found reactivity to both, so has kept out/low

About 80% improvement in symptoms with joint flares

less often, less intense. Still present.

Reducing histamine

production Determine personal tolerance threshold to dietary

histamines

Reduction in stress, counseling, meditation

For some women in perimenopause, progesterone

replacement

Medication? H1/H2 may not be effective

Home environment, reducing potential allergens,

chemical sensitivities

Reducing histamine

production Filtered water critical

Supplementation: Vitamin C, quercitin, stinging nettle,

DAO

Assessing for small intestinal bacterial overgrowth or

dysbiosis

Leading to Pathway #3…

Microbiome of the

Small Intestine (11)

Average amount of bacteria in the small intestine in the

100,000’s

Average amount of bacteria in the large intestine

average is 100,000,000,000

Bacteria in the small intestine present as part of

immune system, help with nutrient digestion

Keep balance of the small intestine through peristaltic

waves and pH balance

Small Intestinal Bacterial

Overgrowth (11)

When bacterial concentration increases above normal amounts

Typical causes include post infectious gastroenteritis (food poisoning), c. Dif infection, long term use of PPI’s, antibiotics, long term stress, thyroid, IC valve disruption, adhesions

Symptoms include severe flatulence/belch, abdominal bloat, constipation or diarrhea, heartburn.

GI diagnostics typically negative. Dx: “IBS”

SIBO: Link to Autoimmunity Bacterial infection of c. Jejuni, Salmonella, e. Coli, c. Diff,

Shigella can lead to increase in CdtB toxin (12)

Triggers immune response to CdtB toxin GI inflammation (12)

CdtB toxins are structurally similar to vinculin, a protein that helps to manage the MMC (migrating motor complex) which helps to maintain motility (12)

Molecular mimicry leads to creation of anti-Vinculin antibodies (12)

Reduced motility leads to reduced peristaltic/cleansing waves, constipation, increase in bacterial concentration in SI (12,13)

Symptoms and effects Overgrowth increases hydrogen/methane gas and

endotoxin in the GI causing intestinal bloat,

inflammation (11)

Those with IBS have been found to have intestinal

intestinal permeability. Unclear relationship between

SIBO and permeability. (14)

Permeability can lead to translocation of bacteria and

endotoxin (14)

Studies Studies and published case studies linking SIBO to systemic inflammation.

Rosacea (15)

PMR (16)

Sleep apnea (17)

Hepatic encephalopathy and NAFLD (18)

IBS (19)

Parkinson’s Disease (20)

Diabetes (21)

Fibromyalgia (22)

IBD (23)

Pancreatitis (24)

Prostatitis (25)

Hydrogen breath testing Current best way to diagnose bacterial overgrowth is

through lactulose hydrogen breath testing (26)

Available through UW Gastro, VM Gastro, Seattle Children’s (for peds only), Puget Sound Gastro Eastside, external clinics who specialize

Test involves a special prep diet, fast and 3 hour breath collection after drinking lactulose solution

Measures concentration of hydrogen and methane production in the small intestine

Not perfect but best we currently have

Treatment options Antibiotics: Rifaximin (H2) Neomycin Sulfate (CH4) (11,

27, 28)

Herbal antibiotics

Medical food fast x 2 weeks (starve them out)

f/u treatment with prokinetic (Erythromycin) 29

Diet modification: Low FODMAP diet (30)

Diet for SIBO Low FODMAP/starch/sugar diet (30)

Reduces fuel for bacteria

Similar to Paleo/AIP approach but low in fermentable

fruits and vegetables

Broccoli, cauliflower, brussels sprouts, cabbage, garlic,

onion, apples, pears, stone fruits, lactose

Diet consists of high animal protein, vegetable, fruit,

nut, lactose-free dairy

The histamine connection Some species of bacteria have been shown to increase

histamine production: (L. casei and L. bulgaricus) 31

Others have shown to decrease histamines: L.

rhamnosus, B. infantis, L. plantarum 32

SIBO can contribute to histamine production and

contribute to the boiling pot effect

Case Study Continued Patient’s RA pain improved on low histamine diet.

Ordered hydrogen breath test

Positive for hydrogen producing bacteria (37 ppm at 60

mins increasing to 92ppm at 120 mins)

Rifaximin: 550 mg tid x 14d

f/u tx: Erythromycin 250 mg qhs ongoing

Omit fodmaps, starches, limit histamines

First Hydrogen Breath Test

CS: 2 wk follow up

Rifaximin/Erythro tx Complete cessation of joint pain, diarrhea during the

antibiotics

2 weeks post tx: Return of diarrhea, joint pain

completely abated

Tx: Rifaximin 550 mg tid x 14 d

2 weeks post tx: Stools firm, with only occasional

diarrhea, joint pain abated

Ordered follow up HBT

Second Hydrogen Breath Test

Ongoing Treatment Garlic/oil of oregano, probiotics (lactobacillus GG)

Erythromycin 250 mg ¼ cap qhs ongoing. Will likely maintain long term.

f/u HBT still positive, but continues to improve

Rotational herbals (garlic/oo).

Patient continues to do well with no joint pain or diarrhea

Dc’d HCQ without return of joint pain

Slight joint flares with menstruation, which she keeps under control with reduced dietary histamines

Back to grains and FODMAP’s without issue

Self-managed currently

Third Hydrogen Breath Test

Observations and Patterns Clinically, I have observed prevalence of bacterial

overgrowth in patients with EDS, Scleroderma, Crohns, Rheumatoid Arthritis, Ankylosing Spondylitis, reactive arthritis and undetermined inflammatory arthritis

Treating bacterial overgrowth doesn’t always reduce symptoms of joint pain/inflammation but can improve quality of life by improving intestinal function especially in those debilitated by chronic diarrhea or constipation.

Severe constipation can increase lower back pain

Those with histamine issues don’t always have bacterial overgrowth and vice versa.

Conclusion There is a correlation between diet and inflammation. Food sensitivities,

histamines in foods, or the nutrients that feed bacteria can all impact inflammation in the gut.

Histamines may impact inflammation that leads to inflamed joints and other allergy symptoms. Low histamine diet and stress reduction can help.

Bacterial overgrowth or dysbiosis can increase gases, histamines and endotoxin production that can increase gut permeability, food sensitivities and may increase systemic inflammation.

If patient not responding to Rx treatment, look at other symptoms related to allergy or GI that could help you consider another pathway of inflammation.

If patient has excessive IBS sx, refer to GI doc who specializes in SIBO for treatment or RDN in private practice to help make dietary change

Thank you! Heidi Turner, MS, RDN

The Seattle Arthritis Clinic @ Northwest Hospital/UW

Medicine

www.theseattlearthritisclinic.com

References Gluten and gut/systemic inflammation

• (1) Uhde, M. et al: (2016) Gut Jul 25; Intestinal cell damage and systemic immune activation in individuals reporting sensitivity to wheat in the absence of coeliac disease

(2) Hollon, J, et al (2015): Nutrients Feb 27;7(3):1565-76. Effect of gliadin on permeability of intestinal biopsy explants from celiac disease patients and patients with non-celiac gluten sensitivity.

Dairy and gut inflammation

(3) Jiangin ES, et al. (2016) Effects of milk containing only A2 beta casein versus milk containing both A1 and A2 beta casein proteins on gastrointestinal physiology, symptoms of discomfort, and cognitive behavior of people with self-reported intolerance to traditional cows' milk. Nutr J Apr 2;15:35

(4) Ho, S, et al (2014) Comparative effects of A1 vs A2 beta protein on gastrointestinal measures. Eur J Clin Nutr Sep;68(9):994-1000.

References Overview on histamine intolerance

(5)Skypala IJ et al. Sensitivity to food additives, vasoactive amines and salicylates: a review of

the evidence. Clin Transl Allergy Vol 13, 2015.

(6) Maintz, L and Novak, N. Histamine and Histamine Intolerance. Am J Clin Nutr 2007;85:1185-

1196.

References Histamines and Rheumatoid Arthritis

(7) Abd-Allah AR et al, Involvement of histamine 4 receptor in the pathogenesis and progression of rheumatoid arthritis, Int Immunol 2014 Jun; 26(6):325-40

(8) Tomic, Lucic AP et al, Histamine index and clinical expression of rheumatoid arthritis activity, Vojnosanit Pregl, 2010 Apr; 67(4): 286-90

(9) Cowden, JM, et al, The histamine H4 receptor mediates inflammation and Th17 responses in preclinical models of arthritis Ann Rheum Dis 2014 Mar;73(3):600-8

(10) Nent E et al, Histamine 4 receptor plays an important role in auto antibody induced arthritis, Int Immunol, 2013 Jul; 25(7): 437-43

References SIBO overview

• (11) Rezale, A et al (2016) How to test and treat small

intestinal bacterial overgrowth: an evidence based

approach, Curr Gastroenterol Rep Feb;18(2):8

References SIBO/GI and Autoimmunity

(12) Pimentel, M. et al; Autoimmunity Links Vinculin to the Pathophysiology of Chronic Functional Bowel Changes Following Campylobacter jejuni Infection in a Rat Model. Dig Dis Sci. 2015 May;60(5):1195-205

(13) Jee, SR et al; ICC density predicts bacterial overgrowth in a rat model of post-infectious IBS. World J Gastroenterol. 2010 Aug 7;16(29):3680-6.

Mielants, A et al; Acta Clin Belg.The role of gut inflammation in the pathogenesis of spondyloarthropathies. 1996;51(5):340-9.

References SIBO and intestinal permeability

• (14) Jung ho Park, et al (2009) The relationship

between small intestinal bacterial overgrowth and

intestinal permeability in patients with irritable bowel

syndrome. Gut Liver Sep; 3 (3):174-179

References: SIBO SIBO and Systemic Inflammatory Conditions

• (15) Agnoletti, AF Pathogenesis of rosacea: a prospective study with three year follow up, G Ital

dermatol Venereol, 2016 Feb 18

• (16) Traussnigg S, et al, Difficult case of Cronkhite-Canada Syndrome with small intestinal bacterial

overgrowth, Clostridium difficile infection and polymyalgia rheumatica, BMJ Case Rep, 2016 Jan

27;2016

• (17) Weinstock, LB et al Identification and treatment of new inflammatory triggers for complex regional

pain syndrom: small intestinal bacterial overgrowth and obstructive sleep apnea; AA Case Rep, 2016

May 1; 6(9):272-76

• (18) Kapil, S et al, Small intestinal bacterial overgrowth and toll like receptor signaling in patients with

non-alcoholic fatty liver disease. J Gastroenterol Hepatol, 2016 Jan; 31(1):213-21

• (19) Chu H, et al, Small intestinal bacterial overgrowth in patients with Irritable Bowel Syndrome:

Clinical characteristics, psychological factors and peripheral cytokines; Gastroenterol Res Pract, 2016

References SIBO and other conditions

• (20) Fasano A et al, (2013) The role of small intestinal bacterial overgrowth in Parkinson’s

Disease, Mov Disord, Aug;28(9):1241-9

• (21) Ojetti V, et al (2009), Small bowel bacterial overgrowth and type 1 diabetes, Eur Rev Med

Pharmacol Sci Nove-Dec; 13(6) 419-23

• (22) Pimentel, et al (2004), A link between irritable bowel syndrome and fibromyalgia may be

related to findings on lactulose breath testing, Ann Rheum Dis Apr;63(4):450-2

• (23) Rana SV et al (2013) Small intestinal bacterial overgrowth and orocecal transit time in

patients of inflammatory bowel disease. Dig Dis Sci Sep;58(9):2594-8

• (24) Kim DB et al (2015) Breath hydrogen and methane are associated with intestinal

symptoms in patients with chronic pancreatitis, Pancreatology Sep-Oct;15(5):514-8

References SIBO and other inflammatory conditions

• (25) Weinstock LB, et al (2011) Chronic prostatitis and

small intestinal bacterial overgrowth: effect of rifaximin

Can J Urol Aug;18(4):5826-30

SIBO and breath testing

(26) Rana, SV et al; Hydrogen breath tests in

gastrointestinal diseases. Ind J Biochem: 2014

Oct;29(4):398-405

References SIBO and Antibiotics

(27) Pimentel, M. Review article: potential mechanisms of action of rifaximin in the management of irritable bowel syndrome with diarrhoea. Aliment Pharmacol Ther. 2016 Jan;43 Suppl 1:37-49.

(28) Shah, SC: Meta-analysis: antibiotic therapy for small intestinal bacterial overgrowth. Aliment Pharmacol Ther. 2013 Oct;38(8):925-34

(29) Pimentel, M (2009) Low dose nocturnal tegaserod or erythomycin delays symptom recurrence after treatment of irritable bowel syndrome based on presumed bacterial overgrowth, Gastroenterol Hepatol June 5(6) 435-442

SIBO and low FODMAP diet

(30) Halmos EP, et al; A diet low in FODMAPs reduces symptoms of irritable bowel syndrome. Gastroenterology 2014 Jan;146(1):67-75.e5. doi: 10.1053/j.gastro.2013.09.046. Epub 2013 Sep 25.

References Bacteria that increase/decrease histamines

(31) Dev, S., et al. Suppression of histamine signaling

by probiotic Lac-B: a possible mechanism of its anti-

allergic effect. Journal of Pharmacological Sciences,

2008;107(2):159-166.

(32) Priyadarshani, D., et al. “Screening selected

strains of probiotic lactic acid bacteria for their ability to

produce biogenic amines (histamine and tyramine).”

International Journal of Food Science & Technology.

2011;46:2062–2069.

References Histamines and Autoimmunity (cont)

• Schneider E, et al, Histamine, immune cells and autoimmunity, Adv Exp Med Biol, 2010; 709:

81-94

Herbal remedies to reduce mast cell activation, histamine

production

Kaiser, MS, et al, Anti-Allergic Effects of Herbal Product from Allium Cepa (Bulb),

Journal of Medicinal Food, April 2009, 12(2): 374-382.

Hogberg, Bertil, “Inhibitory action of allicin on degranulation of mast cells produced

by compound 48/80, histamine liberator from ascaris, lecithinase A and antigen”

Acta Physiologica Scandinavia 44.2 (1958) 157-162.

References Diet and Microbiome

• Silvio at al, Diet, Microbiota and Autoimmune Disease,

Lupus, 2014 May; 23(6): 518-526

• Maslowski KM, et al. Regulation of inflammatory responses

by gut microbiota and chemoattractant receptor GPR43.

Nature. 2009; 461:1282-6