GASTROINTESTINAL HEALTH BEYOND THE GLUTEN-FREE DIET:

Probiotics and Other Therapy

Jacqueline Wolf, M.D.

Associate Professor of Medicine

Beth Israel Deaconess Medical Center

I have no industry or commercial interests to declare that have any

application to my presentation

AT THE END OF THIS PRESENTATION YOU SHOULD:

• Understand some of the roles of intestinal bacteria and how they are altered in irritable bowel disease(IBS) and celiac disease (CD).

• Understand how probiotics (healthy organisms) may be of benefit in IBS and CD

• Understand what other non-traditional therapies may be of benefit for gastrointestinal symptoms in IBS and possibly celiac disease

What is normal gut function?

• Bowel movements 2x/day to 2-3x/week are normal• Stool form varies from person to person. In general the

stool is usually well formed.• Gas occurs in everyone. The amount depends on what

you eat (500mL to 1500mL per day)• Medications including herbs and over-the-counter

medications can sometimes cause constipation, diarrhea or heartburn.

• Most people have rare heartburn

BACTERIA IN YOUR GUT

• 1-2 kilograms x body weight• Cellular content > 10 fold higher than cells in

the body (100,000,000,000,000)• Bacterial microbiome (genes) 100 fold >

human genome• Collective metabolic activity > liver activity• Likely > 1000 different bacterial species in

the gut

Inflamm. Bowel Dis 2004; Science 2005; 308:1635-38; Physiol Rev 2010;90:859-904; Gastroenterology 2014;146:1449-58

BACTERIA IN YOUR GUTWhat do they do?

• Produce carbohydrate-active enzymes that digest carbohydrates

• Break down protein to their component amino acids and then participate in their change to biogenic amines (compounds with another effect on the body), to immunomodulator compounds and to signaling compounds.

• Produce antimicrobial peptides or bacteriocins that may keep harmful organisms at bay.

• Make vitamins such as folate and Vitamin B12• Participate in and stimulate the development and function of

the immune response

Inflamm. Bowel Dis 2004; Science 2005; 308:1635-38; Physiol Rev 2010;90:859-904; Gastroenterology 2014;146:1449-58

BACTERIA IN YOUR GUT

ESOPHAGUS (0-102)

• Limited in diversity• Dominated by Streptococcus• Increased diversity associated with chronic inflammation and dysplasia

STOMACH (0-102)

• Limited in diversity• Helicobacter pylori limits diversity• Without H. pylori dominated by Streptococcus

SMALL INTESTINE (102 duodenum, jejunum; 107-108 distal ileum) Dominated by Streptococcus in duodenum and jejunum

• Increased number and diversity as you travel down the small bowel to the ileum

Gastroenterology 2014;146:1449-1458

BACTERIA IN YOUR GUT

LARGE INTESTINE (COLON) (1011-1012)

• Dominated by phylum Firmicutes (includes Lactobacilli) and phylum Bacteroidetes

• Next most common Actinobacteria (includes Bifidobacteria) and Verrucomicrobia

• Diet can change the microbiome• Ratio of Firmicutes: Bacteroidetes may determine

predisposition to obesity• Proteobacteria small proportion in normal individuals but

may be increased in people with GI diseases

Gastroenterology 2014;146:1449-1458

CELIAC DISEASE AND IRRITABLE BOWEL SYNDROME

What is the possible connection?

• Symptoms of celiac disease and IBS may overlap• People with celiac disease may also have IBS• Studies show a 4.5% prevalence of celiac disease in

people with IBS diagnosed by Rome I or II criteria• Systemic review and meta-analysis showed 4 fold

increase in IBS compared to non-IBS populations of celiac disease with positive serology and biopsies

• 3% of people with a clinical presentation of IBS subsequently diagnosed with celiac disease.

Reviewed in Verdu EF et al. Am J Gastroenterol 2009. 104(6):1587-94

IRRITABLE BOWEL SYNDROME

Can present as:1. Diarrhea predominant (IBS-D)

2. Constipation predominant (IBS-C)

3. Mixed (alternating pattern of diarrhea and constipation)

IRRITABLE BOWEL SYNDROMECriteria for Diagnosis

Rome I Rome II Rome III

Timing >3 months (continuous or recurrent)

>3 months in the last 12 months (does not need to be consecutive)

>3 days in the last 3 months (onset at least 6 months prior to diagnosis)

Criteria Abdominal pain (continuous or recurrent) relieved with defecation or associated with change in stool frequency with2 of the following at least 25% of days:

1. Altered stool frequency2. Altered stool

form/passage3. Passage of mucus4. Bloating or feeling of

abdominal distension

Abdominal pain (continuous or recurrent) in the last year associated with 2 or 3 of the following:

1. Relieved with defecation

2. Onset associated with change of stool form

3. Onset associated with change of stool consistency

Recurrent abdominal pain associated with 2 or more of the following:

1. Improvement with defecation

2. Onset associated with change of stool form

3. Onset associated with change of stool frequency

The microbiome (gut bacteria composition) is altered in IBS

• Bifidobacterium--decreased• Lactobacillus-inconsistent findings with

some studies showing a decrease and others showing an increase

The microbiome (gut bacteria composition) is altered in Celiac Disease (CD)

• Reduced concentration of Bifidobacterium spp. in the feces of untreated CD patients and in both active and nonactive CD as compared to healthy people

• Decreased numbers of Bifidobacterium spp. and increased numbers of Bacteroides spp. In duodenal biopsies of untreated CD

• Treated CD patients with persistent symptoms vs those without symptoms had higher relative abundance of Proteobacteria and lower numbers of Bacteroidetes and Firmicutes with an overall reduction in microbial richness

J Clin Gastroenterol 2013:47;101-103; j Clin Pathol 2009;62:264-9; Am J Gastroenterol 2014:109;1933-1941

WHAT ARE PROBIOTICS

Probiotics are living organisms contained in foods, such as yoghurt, and in other supplements in the form of capsules, powder or tablets, which confer a health benefit when administered in adequate amounts.

Morelli L. J Clin Gastroenterol 2012;46:S1-S2

Some Probiotics on the Market

L. casei

L. casei Shirota

L. johnsonii

Some Probiotics on the Market

L. caseiL. reuteri

L. rhamnosus GG

B. lactis Bb12

PROBIOTICS IN IBSMechanisms of action

• Change gut bacterial composition• Potentially return abnormal gut flora to normal• Competitive interactions with pathogens• Produce chemical products, that are toxic to pathogenic

bacteria or viruses.• Reinforce the mucosal barrier• Inhibit the movement of bacteria across the gut wall• Produce neurotransmitters that influence the motility and

sensation of the gut• Produce cytokines, neuroactive peptides, fatty acids, gas

and other substances.

Reviewed in Gastroenterology 2014; 146 (6)

Probiotics Effective in IBS

Probiotic Targeted Symptom relief Sample Size Weeks

Bifidobacterium Reduced discomfort and bloating 274 3/6animalis in constipation-predominant IBS

Bifidobacterium Reduced abdominal pain and 362 4infantis 35624 other IBS symptoms

Bifidobacterium Alleviated global IBS, improved 122 4bifidum MIMBb75 IBS symptoms and QOL

Escherichia coli Helped in patients with altered 120 12Nissle enteric microflora, for example,

after gastroenterocolitis or use of antibiotics

Lactobacillus Improved abdominal pain and 214 4plantarum 299v bloating

Reviewed in S.S Magge & J.L Wolf . Women’s Health (2013) 9(6), 1-11

Probiotics Effective in IBSProbiotic Targeted Symptom relief Sample Size Weeks

Saccharomyces Improved QOL, but not significantly 67 4boulardii in individual symptoms

Lactobacillus Improved bloating 60 4Acidophilus NCFM

Bifidobacterium Improved bloating 60 4lactis Bi-07

Lactobacillus Reduced frequency and 50 6Rhamnosus GG severity of abdominal pain in

children

Lactobacillus Reduced abdominal pain 40 4acidophilus

VSL#3 Reduced flatulence and retarded 48 4/8 colonic transit

Reviewed in S.S Magge & J.L Wolf . Women’s Health (2013) 9(6), 1-11

S.S Magge & J.L Wolf Women’s Health (2013) 9(6), 1-11

PROBIOTICS IN CELIAC DISEASE• VSL#3 (but not 3 other probiotics) reduced the toxicity of

gluten when used in a fermentation process• Bifidobacterial strains produced less toxic gliadin

peptides in vitro • Saccharomyces boulardii KK1 degraded part of the α-

gliadin. In gluten sensitized mice KK1 decreased the IgA transporter (CD71) and improved the small bowel abnormalities and local cytokines (accelerated hair loss with DC412)

• Bifidobacterium infantis Natren Live Start Super Strain did not improve intestinal permeability, but did improve Gastrointestinal Symptoms and a macrophage inflammatory cytokine, but not other inflammatory markers (# 12 CD; 10 controls)

Biochimica et Biophysica Acta 2006; 1762:80-93; Laboratory Investigation 2012; 92:625-635J Clin Gastroenterol 2013:47;101-103;

Mouse Model for Celiac Disease:Treatment with probiotics

G-mice

D1 D7 D37

Gluten Diet (G+)

Every Day Every 3 days

Sacrifice

Oral delivery of KK1 or DC205 or DC412 or PBS

Laboratory Investigation 2012; 92:625-635

Mouse Model for Celiac Disease:Treatment with probiotics

G- No gluten G+ With glutenKK1 Saccharomyces boulardiiDC205, DC412 Lactobacillus paracasei

Villous:crypt ratio

Laboratory Investigation 2012; 92:625-635

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*

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*P<0.05 G + to G-, #P<0.05 KK1 to G+

Mouse Model for Celiac Disease:Treatment with probiotics

Positive Cell number

Laboratory Investigation 2012; 92:625-635

* **

*

*

* **

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*

*

*

*

*

*

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*

#

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*P<0.05 G + to G-, #P<0.05 KK1 to G+

Treatment of Celiac Disease with Bifidobacterium infantis

Probiotic Arm (#) Placebo Arm (#)

Syndromes Baseline Final Baseline Final

Indigestion 4.3 (3.4-5.3) 2.9 (2.1-3.7)* 4.0 (2.7-5.3) 3.6 (2.6-4.6)

Diarrhea 3.3 (2.0-4.7) 2.7 (1.6-3.8) 2.9 (1.7-4.0) 1.6 (0.9-2.3)*

Constipation 3.6 (2.2-5.0) 2.5 (1.4-3.5)^ 2.7 (1.5-3.9) 2.4 (1.0-3.7)

GERD Not Significant Not Significant

Abdominal Pain Not Significant Not Significant

Composite Score

Final/baseline ratio Not Significant Not Significant

*P <0.005, ^P<0.05

E. Smecuol et al. J Clin Gastroenterol 2013:47;139-147

Herbal medicines shown to be effective in IBS

Herbal medicines use plant extracts to treat different symptoms and diseases. For effective results the herbs can be used either individually, as a mixture of different herbs or in combination with western medication.

Herbal Medicine Targeted Symptom Relief Length of Study (Wks)

Chinese Herbs Improved IBS global symptoms 16

Padma Lax Improved constipation, abdominal pain, 12 abdominal distension and flatulence

Tong Xie Yao Fang Decrease in activated mast cells present in 4 IBS

STW5,STW5II,placebo Reduced abdominal pain and IBS symptoms 4STW 5/placebo (315) Decreased gastrointestinal symptom score 8

Reviewed in S.S Magge and J.L Wolf. Women’s Health (2013) 9(6), 1-11

The truth about gas…

• When carbohydrates and fat within our food aren’t broken down by the enzymes our bodies make and are not absorbed by the intestines into our bodies, bacteria found in our bowels metabolize them and form gas as a by-product.

• Depending on the type of bacteria residing in your gut and what food you eat, different gases and therefore different odors will be released.

• Gas is often a byproduct of what we eat.

TREATMENT OF GAS AND BLOATING

• Peppermint oil• Simethicone-changes the surface

characteristics of the gas bubbles making it easier to pass

• Activated charcoal-adsorbs the gas. However, it can interfere with medication absorption

Peppermint Oil:Treatment for Gas and Bloating

• A cross between watermint and spearmint

• Menthol is thought to be the active component causing calcium-channel blocking activity

• The blockage of calcium flow into smooth muscle in the intestine decreases muscle contractions thereby reducing pain

• Adverse effects include heartburn, skin rash, perianal burning, bradycardia and muscle tremor.

Reviewed in S.S Magge and J.L Wolf .Women’s Health (2013) 9(6), 1-11

Peppermint Oil in IBS

Study Targeted Relief Symptom Sample Size

Meta-analysis of 8 Significant improvement of IBS symptoms

Trials-5 dble blind

Randomized, Reduced abdominal distension,, 110

Double-blind placebo stool frequency and flatulence

Controlled study-4wks

2007 Double-blind study 75%PO vs 38%PL 57IBS

4 weeks >50% reduction in IBS symptoms

Reviewed in S.S Magge and J.L Wolf .Women’s Health (2013) 9(6), 1-11

Acupuncture not shown to be effective in IBS

• Acupuncture is based on a life force ‘qi’ that runs through the body in channels called meridians

• Disruptions in qi result in disease processes, which can be corrected at the exact anatomical locations using acupuncture

Study Results Sample Size/wks

Real vs Sham acupuncture No significant difference 230/3 wks

vs no treatment in IBS symptoms sham vs real

but better than no treatment

Cochran review-17 random- Many poor quality. 1806/variable

Ized clinical trials Variable results.Same as

Bifidobacteria, psychotherapy

Reviewed in S. S Magge et al. Women’s Health 2013. 9(6):1-11

SUMMARY

• The gut contains numerous bacteria• The bacteria differ in people with Irritable Bowel Syndrome

(IBS) and Celiac disease (CD) from healthy individuals without those conditions.

• Some probiotics have been shown to improve symptoms of patients with IBS

• Some probiotics make gluten less toxic to patients with CD, but to date in people in contrast to animals there are no trials showing benefit.

• Some herbal compounds help IBS patients• Peppermint oil may help bloating and gas• Acupuncture has not shown benefit in IBS