Figure .. Intestinal Barrier Dysfunction and Systemic Infl ammation. An intact gut barrier is necessary to monitor and keep toxins, allergens, and bacteria from invading the mucosa. Th e gut barrier is a complex system and depends on anatomic tight junc-tions, immune function, antimicrobial chemicals, and digestive enzymes. Disruptions in barrier dysfunction lead to heightened immune activation in the gut, which leads to circulation of cytokines and a systemic infl ammatory response (Neu, Douglas-Escobar, & Lopez, 2007). Pathogenic microbes and intestinal barrier dysfunction may cause an infl ammatory response by interacting and activating lymphocytes, mast cells, and den-dritic cells that mediate release of infl ammatory mediators. Also, abnormal antigen exposure may lead to diseases characterized by local infl ammation (such as IBD, NEC, and celiac), antigenic mimicry (such as Type 1 diabetes), imbalance Th 1/Th 2 (atopic disease), and systemic infl ammation (e.g., systemic infl ammatory response syndrome, sepsis, bad neurologic outcome). Reprinted with permission from Liu Z, Li N, Neu J Acta Paediatr. April 2005; 94(4):386–393.

Barrier dysfunction and inflammatory processes

Cytokines/chemokines

Macrophage

BT PMN

Systemicinflammation

Sepsis SIRS IBD, NEC,Celiac

Type 1diabetes

Atopic disease Bad neurologicaloutcome

Localinflammation

Antigenicmimicry

Th1/Th2imbalance

Lymphocyte

Dendritic cell

Antigen presentation

Abnormal antigen exposure

Mast cellInflammatorymediators

Circulation

Figure .. Interplay of the Emotional Motor System (EMS) and Gastrointestinal Pathophysiology Stress, abuse, and emotional feelings infl uence bowel symptoms via activation of the brain’s central circuitry, called the emotional motor system (EMS), to produce autonomic and neuroendocrine responses. Bowel symptoms then cause more distress, triggering the release of mediators (cytokines, cortisol, and adrenaline) which act on the EMS, producing a feed-forward cycle of bowel symptoms and emotional distress. Reprinted with permission from E.A. Mayer et al., Am J Gastrointestinal Liver Physiology. 2001; 280(4):G519–524.

Life events

EMS+ –

Vigilanceattention

Autonomicresponse

Sensorymodulation

Neuroendocrineresponse

GI pathophysiologysymptoms

StressExteroceptive

StressInteroceptive

Emotional feelingsarousal

Epine

phrin

e

CytokinesCortisol

Figure .. Host Defenses against Small Intestinal Bacterial Overgrowth. Th e upper gastrointestinal tract is sparsely populated with gut coliforms. Th e protective mecha-nisms for maintaining relative gut sterility include: stomach acid; proper absorption of fermentable carbohydrates; gastric, intestinal and pancreatic enzymes; gastrointestinal motility; mucosal immunity; and an intact (competent) ileocecal valve, which serves as a barrier between the terminal ileum and colon.

Natural defense factors that prevention of small intestinalbacterial overgrowth are shown within the circles.

Stomach

Duodenum &Jejunum

Ileum

Acid

Motility

Ileocecalvalve

Enzymes

Absorption

Immunity

Pancreas

Figure .. Small Intestinal Bacterial Overgrowth. In (A) there is a normal distribu-tion of intestinal bacteria that does not ferment poorly digestible starches, such as beans, until they reach the large intestine. In (B) there is small intestinal bacterial over-growth, where the easily (rice) and poorly (beans) digestible carbohydrates are fer-mented in the small intestine by the bacteria, due to their overpopulation. Reprinted with permission from JAMA, 292(7):852–858. Copyright © 2004, American Medical Association. All rights reserved.

A Normal distribution of intestinal bacterial flora

B Small intestinal bacterial overgrowth

Duodenum Jejunum Ileum Colon

Duodenum Jejunum Ileum Colon

Bacterial concentration,organisms/mL

100

103

105

1011

Easily digestiblestarch (eg. Rice)

Poorly digestiblestarch (eg. Beans)

Easily digestiblestarch (eg. Rice)

Poorly digestiblestarch (eg. Beans)

Figure .. Fermentation and Gas Dynamics. Undigested starches are fermented by gut coliforms into hydrogen, methane, and other gases. Th ese gases equilibrate and are absorbed into the blood stream, diff use through pulmonary capillaries, and are excreted in the breath. Th is allows for the detection, by breath testing, of intestinal gases as by-products of fermentation of indigestible starches.

Nutrients in gut

H2

H2

H2

H2

H2

H2

H2

H2

CH4

H2SCH4

H2S

CH4

H2S

Vein

Flatus10%

Tissues1%

Breath89%

Figure .. Role of Alternative Strategies in the Treatment of SIBO-IBS. Dysbiosis of the gut can initiate and drive a proinfl ammatory process that results in systemic neu-roendocrine stress factors to be elaborated. Impairments in the emotional motor system of the brain drive the distorted mind–body processes via altered gut motility, hormones, and sympathetic nervous system overdrive.

IBS pathophysiology-CAM therapy

Physical stressor

Epithelium

Mucosal immune system

+

ACTH/CORTISOLCRF, NE,EPI

IL-1 IL-6 IL-8,TNF-α

Psychosocialstressor

Hypnotherapy

Behavioral TxEmotional motor system

Probiotics,elimination diet

Ag

AgT9

IL2-R

IL-12 IL2-R

T9

4F2

4F2

Macrophage

CRFAVP

LC-NE

IL-10

Figure .. Factors Involved in the Pathogenesis of Interstitial Cystitis. Th e transloca-tion of gastrointestinal bacterial byproducts across a leaky-defective barrier can trigger a mast-cell-centered immune infl ammatory response throughout the common mucosal immune system, including the bladder. Localized production of infl ammatory media-tors (histamine, tryptase, cytokines, prostaglandins) sensitize the pain response.

Altered gutsecretion &motility

Inflammatory mediatorsHistamineTryptaseLipid mediatorsCytokines

Activating factors

IntestinalpermeabilityBacteria andbiproductsFood allergies:IgE & non-IgENeuropeptidesBile acids

Sensory neurons

CNS Stress

Pain

GI Pain

CPPS

Corticotrophinreleasing factor

Mast CellMast Cell

ENS

Neuralcross-talk

Figure .. Clinical Outcome in SIBO-positive and SIBO-negative Patients Treated with Rifaximin . Reprinted with permission from Parodi A, Paolino S, Greco A, et al. Clin Gastroenterol Hepatol. 2008;6(7):759–764.

25 P < .001

n20

15

10

5

ClearedImprovedUnchangedWorsened

SIBO positive SIBO negative0

Current thought process

Individual conditions

SIBO

IBSPi-IBS

Fibromyalgia

IBSPi-IBS

FM, IC, RLS…

SIBO

Future outlook

SIBO overlap

RLS IC

CFSRosacea

Figure .. SIBO as the Root Cause of Functional Digestive Conditions with Systemic Manifestations .

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