When in Doubt, START with the GUT - Amazon S3...When in Doubt, START with the GUT Patrick J....

When in Doubt,START with the GUT

Patrick J. Hanaway, MDSan Diego, CAOctober, 2015

©2014 The Institute for Functional Medicine

Disclosure Statement

Patrick Hanaway, MD has indicated he has no financial relationships with any commercial interest relevant to this activity.


A person whose basic emotional and physical tendencies

are in balance,Whose digestive power

is balanced,Whose bodily tissues,

elimination functions and activities are in balance,

And whose mind, senses and soulare filled with vitality,

That person is said to be healthy.Sushruta Samhita


Avicenna (973-1037):The Prince of Physicians

The knowledge of anything, since all things have causes, is not acquired or complete unless it is known by causes. Therefore, in medicine we ought to know the causes of sickness and health.


Naturopathic maxim …“Death begins in the colon.”

The practical application …“When in doubt, treat the gut.”


Learning Objectives• Identify the role the gastrointestinal tract plays in

many chronic diseases• Organize a framework for evaluation that takes into

account functional gut imbalance (DIGIN) to improve quality of life for patients.

• Organize a framework of treatment that takes integrates the concepts of the ‘5 Rs’ to improve quality of life for patients with gastrointestinal dysfunction and complex chronic disease.


Learning Objectives:Review the key functional roles of the gut:– Digestion/ Absorption– Intestinal Permeability– Gut Microbiota– Immune Regulation– Nervous System – Gut Feelings

Remember the 5 Rs:– Remove – Replace– ReInoculate– Repair– Re-Balance


?Questions?,


“The mammalian gut microbiota interact extensively with the host through metabolic exchange and co-metabolism of substrates. Appropriate consideration of individual human gut microbial activities will be a necessary part of future personalized health-care paradigms.” Nat Rev Microbiol. 2005;3:431-438.

Biochemical Individuality: A Gut Check


Key functional roles of the Gut:

Digestion/AbsorptionIntestinal PermeabilityGut Microbiota/DysbiosisInflammation/ImmuneNervous System


A Healthy Gut• Proper nutritional substrates, micronutrients,

and phytonutrients for: – maintenance of commensal flora, – immune modulation, and – repair and regeneration

• Proper mastication• Adequate digestive juices, enzymes, and pH • Intact intestinal epithelial barrier function• Balanced host-bacteria ecology• Autonomic balance


What May Cause Dysregulation of the GUT Environment?

(Triggers and Mediators)• Nutrient insufficiencies• Food Sensitivities and Allergies• Medications (including: NSAIDs, PPIs,

antibiotics, antacids, SSRIs, etc.)• Infectious agents: viruses, bacteria,

protozoa, helminths-Intestinal dysbiosis• Alcohol and Environmental Toxins• STRESS!!! • Localized free radical production


A Sick Gut• Poor diet• Dehydration• Interaction of medications• Infections• Toxins (metals, molds, foods)• Inadequate digestive enzymes & stomach acid• Imbalanced ecology • Impaired intestinal permeability• Altered neuroendocrine balance and

autonomic function


• The GI system is an integral and central “node” of the complex web of functional medicine.

• Dysregulation of the GI system can have a profound impact on health.

• There are significant inter-relationships between:Digestion/AbsorptionIntestinal PermeabilityGastrointestinal Flora Immune Regulation & InflammationEnteric Nervous System

Understanding ‘Root Cause’


• The gastrointestinal system is an integral and central “node” of the complex web of functional medicine.

• Dysregulation of the gastrointestinal system can have a profound impact on health.

• Observe the inter-relationships between:Digestion and absorption Intestinal permeabilityGut microbiota (all types) Inflammation and immune regulationNervous System - gut feelings

Conclusions


Key Functional Roles of the Gut:

Digestion/AbsorptionIntestinal PermeabilityGut Microbiota/DysbiosisInflammation/ImmuneNervous System


Why Focus on the Gut?• 70% of Americans have digestive related

symptoms or diseases• The gut is the most sensitive organ with

multiple common insults that lead to dysfunction

• The gut has perhaps the most diverse and mutable clinical manifestations

• The most effective clinical outcomes across all disease spectrums can result from normalization of gut function


Overview

Primary functions: – Digestion and absorption: organizes,

initiates, and coordinates the metabolism of nutrients

– Intestinal Barrier – selective permeability– Immune sensing: houses and supports

over 70% of our entire immune system– Eliminate waste and start the process of

detoxification


Key Functional Roles of the Gut

Digestion/AbsorptionIntestinal PermeabilityGut MicrobiotaImmune Modulation/InflammationNervous System


DIGESTION/ABSORPTION


Area of Contact with the Outside World

Skin surfacearea: 1.5 m2

Respiratory mucosa area: 100 m2

GI mucosal surface area: 300 m2


We are what we DIGEST & ABSORB

• 630 # of dairy (31# of cheese)• 185 # of meat (beef, chicken, turkey)• 197 # of wheat and grains• 273 # of fruit• 485 # of veggies

• Mostly corn & potatoes• 85 # of fats/ oils• 141 # of sweeteners (including, 42 # of corn syrup!)

2010 USDA DATA

1996 lbs/ year!*


Summary

• Mechanical breakdown• Enzyme hydrolysis of carbohydrates,

proteins, lipids and nucleic acids• Active and passive absorption• Regulation from CNS and ENS integrate

endocrine, exocrine and paracrine hormones to coordinate digestion


Impairments in Digestion

and Absorption • Inadequate mastication• Hypochlorhydria• Pancreatic insufficiency• Bile insufficiency• Brush Boarder Injury• Decreased Vagal tone

Brush Border injury


DIGESTION/ABSORPTIONINTESTINAL PERMEABILITY


Epithelial Barrier


Cell junction

Am J Pathol, 2006; 169(6)

Microvilli

28AFMCP 9‐11

Cell


Why Is This So Important?“the mucosa is directly exposed to the external environment and taxed withantigenic loads consisting of commensal bacteria, dietary antigens, and viruses at far greater quantities on a daily basis thanthe systemic immune system sees in a lifetime”.

Mayer L. Mucosal immunity. Pediatrics. 2003 Jun;111(6 Pt 3):1595-600.


DIGESTION//ABSORPTIONINTESTINAL PERMEABILITY

GUT MICROBIOTA



GUT MICROBIOTAIMMUNE MODULATION AND

INFLAMMATION


Mucosal Immune SystemCritical ‘Line of Defense’


Gut Associated Lymphoid Tissue(GALT)

• Immunological defense• Largest lymph organ in the body: 50-70%

of the immune system and immunoglobulin producing cells are located within the GI tract

• Populated by T cells, B cells, plasma cells, activated TH cells and macrophages in loose clusters


Gut Associated Lymphoid Tissue (GALT)

•The first line of defense to the majority of antigen exposure including dietary molecules and infectious agents

•The primary focus of GALT is two-fold:–determination of ‘Friend or Foe’ –initiating and sustaining an appropriate immune response

Mucosal Immunology, Third Edition, Elsevier Academic Press, 2005

Nat Rev Immunol. 2011 Mar;11(3):221-30


What are the components of GALT that are designed to protect us?

Dendritic cells

Macrophages

Commensal bacteria

Goblet CellsPeyer's Patches

Intra epithelial lymphocytesImmunoglobulinsInterleukins Cytokines

Neutrophils

Toll-Like Receptors

Regulatory T-cells (Th0)

Pattern recognition receptors


With Permission.Mowat AM. 2003;3:332


With Permission.Mowat AM. 2003;3:332.


Immune Tolerance

With Permission. Nature Reviews Immunology 2003;3:338


Rook GA, Brunet LR. Gut 2005;54:317-320.

Contact with “old friends” is greatly diminished in rich countries but increased on farms, in cowsheds, and through contact with pets.


Inducing Tolerance“We found a lower prevalence of

reported allergy in children aged 7 to 8 years from families who use

hand dishwashing instead of machine dishwashing. This effect

was further potentiated if they also ate fermented food or bought

food directly from farms. We speculate that these lifestyle

factors reduce allergy development via increased or

more diverse microbial exposure stimulating the immune system to

develop in a more tolerant direction.”

Hesselmar B, Hicke-Roberts A, Wennergren G. Allergy in Children in Hand Versus Machine Dishwashing. Pediatrics. 2015 Feb 23. pii: peds.2014-2968. [Epub ahead of print]


Immune Activation

With Permission. Nature Reviews Immunology 2003;3:338


J. Clin. Invest. 119:3502–3511 (2009)

Immune cells encountering {a foreign antigen}…become activated and release an array of factors leading to the

well-known clinical signs of inflammation:rubor, calor, dolor, and tumor.


Biofilms and Inflammation

Gut bacteria, which create a 30 μm “biofilm” barrier, are decreased as inflammation increases. This inflammation increases intestinal permeability.

Gut 2007;56:343-350


Leakage of LPS and other inflammatory factors

Inflammatory Cytokines


The strongest predictor of disease progression is the extent of chronic, systemic immune activation

Mucosal Immunol. 2010 July ; 3(4): 387–398.



GUT MICROBIOTAIMMUNE MODULATION AND

INFLAMMATIONNERVOUS SYSTEM


The enteric nervous system (ENS) is organized in a complex structure that controls motility, blood flow, uptake of nutrients, secretion, and immunological and inflammatory processes in the gut.

In recent years, the role of enteric glial cells (EGCs) has extended from that of simple nutritive support for enteric neurons to that of being pivotal participants in the regulation of inflammatory events in the gut.

World J Gastroenterol 2011; 17(10): 1261-1266World J Gastroenterol 2007; 13(30): 4035-4041Journal of Neuroinflammation 2010, 7:37

What Do We Know about the Enteric Nervous System?


What Do We Know about the Enteric Nervous System?

Enteric glia play a major role in gut pathologies associated with barrier dysfunction by not only protecting enteric neurons, but also by maintaining the integrity of the gut mucosa and in regulating its permeability and turnover.

The ENS is a component of the autonomic nervous system with the unique ability to function independently of the central nervous system (CNS).

Laboratory Investigation (2007) 87, 731–736

Gastroenterology 2007;132:1344–1358

Am J Physiol 2007;292:G231–G241

Journal of Neuroinflammation 2010, 7:37


Nervous System Effect on GI Function

• Alterations in gastrointestinal motility• Increase in visceral perception• Changes in gastrointestinal secretion• Increase in intestinal permeability• Negative effects on regenerative capacity of

gastrointestinal mucosa • Negative effects on intestinal microbiota

Konturek PC(1), Brzozowski T, Konturek SJStress and the gut: pathophysiology, clinical consequences, diagnostic approach and treatment options. J Physiol Pharmacol. 2011 Dec;62(6):591-9.


DIGESTION/ABSORPTIONINTESTINAL PERMEABILITY GUT MICROBIOTAIMMUNE/INFLAMMATIONNERVOUS SYSTEM


Treatment Approaches forGut Dysfunction: The 5R Program

A conceptual framework designed to: – Supply a scaffold to build targeted,

individualized intervention – systematize a process to normalize

critical gastrointestinal functions


The 5R Framework

• Remove• Replace• Reinoculate• Repair• Rebalance


The Conceptual Approach Asks 5 Basic Questions

1. What does this patient need to have Removed?

2. What does this patient need to have Replaced?

3. What does this patient need in terms of support and/or re-establishment of a healthy balance of microflora; that is, what does he/she require to Reinoculate the gut?

4. What does this patient require to support healing and Repair of the GI epithelial barrier and the biofilm?

5. What does this patient need to do to Rebalance their lifestyle; that is, are there ways to modify their attitude and lifestyle to promote a healthier way of living?


“Remove”Remove refers to the elimination of factors such as: • Foods to which an individual is sensitive,

intolerant, or allergic• Pathogenic microflora (e.g., bacteria, fungi,

parasites)• Environmental stressors such as pollutants• Stress Clinical approaches may include:• Oligoantigenic elimination diet• Botanical antimicrobials or

bacteriostatic/bacteriocidal phytonutrients • Antibiotics/Antifungal medications


“Replace”

Replace refers to the replacement of factors that may be inadequate or lacking. Clinical approaches may include: • Digestive factors

– Hydrochloric acid– Pancreatic enzymes– Bile salts

• Fiber to support transit and general GI function


Supporting Gastric Acidity

• Betaine HCL tablets (350–3500 mg) with protein-containing meal (spaced before & throughout the meal)

• Swedish bitters• Umeboshi plums • Gentian root• Vinegar• Decrease stress!

– Increase vagal tone– Heart rate variability biofeedback


“Reinoculate”Reinoculate refers to reintroduction of desirable GI microflora (prebiotics, probiotics, synbiotics) to obtain a desirable balance to the intestinal milieu.

Clinical approaches may include:– Probiotics:

• Bifidobacteria and Lactobacillus strains• Saccharomyces boulardii• Fermented FOOD!

– Prebiotics:• Inulin or fructooligosaccharides (FOS)• Various other soluble fibers & FOOD!

– Synbiotics:• Bifidobacteria and FOS• Lactobacillus and inulin


Diet/Fermented FoodsSoluble fiberPrebiotics Probiotics

Standard antibiotics Botanical Antimicrobials

Potentially Pathogenic BacteriaNormal Excess

Altering the Intestinal Milieu


“Repair”Repair refers to providing nutritional support for healing and regeneration of the GI mucosa.Clinical approaches may include:• Nutrients important for GI repair and healing:

– Glutamine, arginine, vitamin D, vitamin C, zinc• Mucosal secretion protectants:

– phosphatidylcholine, plantain, aloe, arabinogalactins• Support for GALT function

– lactoferrin, lactoperoxidase, whey immunoglobulins• Antioxidants known to function in the GI • Nutritional and phytonutritional anti-inflammatories

– Curcumin, EPA, and DHA


“Rebalance”Rebalance refers to providing support for restorative processes in a patients life• Clinical approaches may include:

– ‘Scheduling’ and relaxation– Mindful eating and better choices– Heart rate variability/ biofeedback– Yoga, meditation, prayer, breathing, or

other centering practices– Psychotherapy


Integrative TherapiesMind-Body Therapies


‘IBS’ Case #132 yo male, recently returned from traveling in Asia. Had occasional abdominal discomfort before traveling, now present 2-4x/ month over past 3 months.

DIGIN:– Digestion/ Absorption – no issues noted.– Intestinal Permeability – direct testing not performed,– Gut Microbiota – altered with parasite infection

(Entamoeba histolytica); stool test– Immune Regulation/ Inflammation – markers normal– Nervous System – symptoms worsen with family

stressors, poor sleep, and increased sugar


‘IBS’ Case #132 yo male, recently returned from traveling in Asia with E. histolytica.

TREATMENT = 5 R’s– Remove parasites –

• Nitozoxanide 500mg BID x 10 days• Oregano Oil 200mg TID x 10 days

– Replace enzymes & HCl – not necessary– ReInoculate gut flora – probiotics – Repair – no evidence of gut permeability– ReBalance – stress reduction, increase sleep,

relaxing tea = chamomile


‘IBS’ Case #132 yo male, recently returned from traveling in Asia with E. histolytica.

• TREATMENT = 5 R’s– Anti-parasitics– Probiotics– Stress reduction – Diet change

• FOLLOW-UP @ 6 weeks– Symptoms resolved completely– Remained symptom-free @ 1 year


‘IBS’ Case #224 yo female with recurrent abdominal pain/ discomfort x5 years. Also with depression and fatigue. Treated with tri-cyclic anti-depressants.DIGIN

– Digestion/ Absorption – food not completely digested, exocrine pancreatic function decreased

– Intestinal Permeability – Lactulose/Mannitol test elevated; decreased absorption & increased permeability.

– Gut Microbiota – normal– Immune Regulation/ Inflammation – serum tTG +, confirmed

with endomysial IgA + – Nervous System – labile mood; dull affect


‘IBS’ Case #224 yo female, newly diagnosed with Celiac

disease & pancreatic insufficiency• TREATMENT = 5 R’s

– Remove offending foods = gluten– Replace enzymes & HCl – OTC 10x USP

Pancreatin, take before each meal– ReInoculate gut flora – not necessary– Repair – L-Glutamine 1000mg TID, titrate up to

3000mg TID to repair gut lining– ReBalance – Heart Rate Variability bio-feedback

& exercise program


‘IBS’ Case #224 yo female, newly diagnosed with Celiac disease

& pancreatic insufficiency• TREATMENT = 5 R’s

– Pancreatic supplementation until villous atrophy (2o

celiac disease) resolves– Repair of ‘leaky gut’– Totally, gluten-free diet – lifetime!

• FOLLOW-UP @ 6 & 12 weeks– Symptoms significantly improved– Intermittent dietary indiscretions @ 1 year– Screen for auto-immune diseases


‘IBS’ Case #343yo female with a history of GERD x 3 years, currently using a PPI. Also with IBS x ~ 2 years and recently developing Restless Leg Syndrome.DIGIN

– Digestion/ Absorption – no problems– Intestinal Permeability – IgG testing normal– Gut Microbiota – moderate alterations in bacteria, no

fungal overgrowth, no parasites present, no C. diff. – Immune Regulation/ Inflammation – no elevation in

neutrophilic markers of inflammation– Nervous System – no current issues


‘IBS’ Case #343yo female with a history of GERD, on PPI.

Also with Restless Leg Syndrome.• TREATMENT = 5 R’s

– Remove PPI– Replace HCl – Betaine HCL with each meal– ReInoculate gut flora – 25b cfu BID– Repair – Iberogast (STW 5) 20gtt TID x 4 wks to

stimulate gastric emptying– ReBalance – not necessary, at this time


‘IBS’ Case #343yo female with a history of GERD, on PPI.

Also with Restless Leg Syndrome.• TREATMENT = 5 R’s

– Remove PPI, add Betaine HCl & Iberogast– Probiotics @ 25b cfu BID

• FOLLOW-UP @ 6 weeks– Little improvement in IBS, GERD improved– Consider SBBO

• Lactulose breath testing• Empiric treatment –Rifaxamin 400mg BID x 7 days

– Symptoms resolved @ 12 weeks!


IBS –Understand the ‘root’ cause

Digestion/ Absorption

Intestinal Barrier

GutFlora

Immune/Inflammation

NervousSystem

IBS #1 No No Yes No Yes

IBS #2 Yes Yes No Yes Yes

IBS #3 No No Yes No No


IBS –Treat the ‘root’ cause

Digestion/ Absorption

Intestinal Barrier

GutFlora

Immune/Inflammation

Nervous System

IBS #1 Anti-parasiticsProbiotics

Soothingherbs

IBS #2 Pancreatic enzymes

L-Glutamine

Stop ALLGluten

HRVExercise

IBS #3 Stop PPIBetaine HCL

Iberogast

ProbioticsRifaxamin


When we observe the relationships between:Digestion & AbsorptionIntestinal PermeabilityGut Microbiota (all types)Immune Regulation & InflammationNervous System - Gut Feelings

. . . we move beyond the ICD-10 diagnosis code to a deeper level of understanding that facilitates treatment and healing.

Conclusions –There is No Single ‘IBS’


Conclusions• The GI system is an integral and central

“node” of the complex web of functional medicine.

• Dysregulation of the GI system can have a profound impact on health.

• Consider the inter-relationships of:– Digestion and absorption– Intestinal permeability– GI flora (all types)– Immune regulation and inflammation.– Nervous system relationships


Conclusions

Rx – The 5R Framework• Remove• Replace• Reinoculate• Repair• Rebalance

When in Doubt, START with the GUT - Amazon S3...When in Doubt, START with the GUT Patrick J....

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