Small Intestinal Bacterial Overgrowth (SIBO) 3 Hour - Breath (Genova Diagnostics)

Small intestinal bacterial overgrowth (SIBO) is an increase in the number of bacteria and/or the presence of atypical microbiota in the small intestine. 

Gram-positive flora might be present due to failure of the gastric acid barrier, whereas the presence of colonic bacteria may be due to failure of intestinal clearance and small intestinal anatomical alterations. 

The bacteria in SIBO are mainly colonic type bacteria, and it is hypothesized that it is the retrograde bacterial migration from the large intestine into the small intestine that leads to symptoms. These organisms produce gases, including hydrogen (H2), methane (CH4), and hydrogen sulfide (H2 S).

The bacteria commonly found in SIBO include Escherichia coli, Enterococcus spp., Klebsiella pneumonia, and Proteus mirabilis. 

The common methaneproducing organisms include archaea, such as Methanobrevibacter smithii, as well as bacteria, including certain Clostridium and Bacteroides species. There are many natural defense mechanisms against SIBO. These include, but are not limited to: 

- Antegrade peristalsis and the migrating motor complex (MMC)

- Bacteriostatic action of gastric acid, pancreatic enzymes, and bile; bile is an important suppressor of methanogenesis

- Intestinal mucus layer (traps bacteria)

- Ileocecal valve inhibits retrograde translocation of bacteria from the colon to the small intestine

- Immune system, specifically sIgA, prevents bacterial proliferation.

SIBO symptoms are non-specific, including abdominal pain/distention, flatulence, nausea, dyspepsia, constipation, and diarrhea. Post-prandial bloating is a common SIBO symptom due to the bacteria fermenting carbohydrates that produces gas, distension, and bloating. The mechanisms by which diarrhea may occur include bacterial de-conjugation of bile salts, enterotoxic effects of bacterial metabolites, increased small intestinal permeability, decreased vitamin B12, and low grade inflammation resulting from immune activation in the small intestinal mucosa.

Immune activation involves an increased number of intraepithelial lymphocytes, mast cells, and enterochromaffin cells. The mediators of the host immune response trigger the enteric nervous system, which can alter GI motility and visceral hypersensitivity. 

Additionally, lipopolysaccharide (LPS), a gram-negative bacterial endotoxin, can accelerate intestinal transit. Methane (CH4) production has been associated with the pathogenesis of common clinical conditions, such as obesity, irritable bowel syndrome (IBS), and constipation. Methane gas itself may slow intestinal transit, and patients with CH4-predominant bacterial overgrowth have been found to be five times more likely to have constipation compared to individuals with H2-predominant overgrowth. Moreover, the severity of constipation has been found to directly correlate with the CH4 level.

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SIBO Pathophysiology and Symptoms:

Small intestinal bacterial overgrowth (SIBO) is an increase in the number of bacteria and/or the presence of atypical microbiota in the small intestine. Gram-positive flora might be present due to failure of the gastric acid barrier, whereas the presence of colonic bacteria may be due to failure of intestinal clearance and small intestinal anatomical alterations. The bacteria in SIBO are mainly colonic type bacteria, and it is hypothesized that it is the retrograde bacterial migration from the large intestine into the small intestine that leads to symptoms. These organisms produce gases, including hydrogen (H2), methane (CH4), and hydrogen sulfide (H2S). The bacteria commonly found in SIBO include Escherichia coli, Enterococcus spp., Klebsiella pneumonia, and Proteus mirabilis. The common methane- producing organisms include archaea, such as Methanobrevibacter smithii, as well as bacteria, including certain Clostridium and Bacteroides species.

There are many natural defense mechanisms against SIBO. These include, but are not limited to:

- Antegrade peristalsis and the migrating motor complex (MMC)
- Bacteriostatic action of gastric acid, pancreatic enzymes, and bile; bile is an important suppressor of methanogenesis
- Intestinal mucus layer (traps bacteria)
- Ileocecal valve inhibits retrograde translocation of bacteria from the colon to the small intestine
- Immune system, specifically sIgA, prevents bacterial proliferation.

SIBO symptoms are non-specific, including abdominal pain/distention, flatulence, nausea, dyspepsia, constipation, and diarrhea. Post-prandial bloating is a common SIBO symptom due to the bacteria fermenting carbohydrates that produces gas, distension, and bloating.

The mechanisms by which diarrhea may occur include bacterial de-conjugation of bile salts, enterotoxic effects of bacterial metabolites, increased small intestinal permeability, decreased vitamin B12, and low grade inflammation resulting from immune activation in the small intestinal mucosa. Immune activation involves an increased number of intraepithelial lymphocytes, mast cells, and enterochromaffin cells. The mediators of the host immune response trigger the enteric nervous system, which can alter GI motility and visceral hypersensitivity. Additionally, lipopolysaccharide (LPS), a gram-negative bacterial endotoxin, can accelerate intestinal transit.

Methane (CH4) production has been associated with the pathogenesis of common clinical conditions, such as obesity, irritable bowel syndrome (IBS), and constipation. Methane gas itself may slow intestinal transit, and patients with CH4-predominant bacterial overgrowth have been found to be five times more likely to have constipation compared to individuals with H2-predominant overgrowth. 

Moreover, the severity of constipation has been found to directly correlate with the CH4 level.

Associated Conditions:

Conditions in which a high prevalence of overgrowth are commonly observed include, but are not limited to:

- Functional GI disorders (such as irritable bowel syndrome and gastroparesis)
- Hypothyroidism15
- Neuromuscular diseases (such as restless leg syndrome)
- Inflammatory bowel disease (IBD)
- Pancreatic disease
- Celiac disease
- Liver disease
- Diabetes
- Fibromyalgia
- Rosacea
- Parkinson’s disease
- Obesity
- Interstitial cystitis

Risk Factors:

Decreased intestinal motility is a key factor in the development of SIBO and its recurrence. Out of all the diseases and disorders associated with SIBO, 90% of cases involve either small intestinal motility disorders and/or chronic pancreatitis. 

The migrating motor complex (MMC) describes the waves of electromechanical activity that sweep through the intestines in regular cycles between meals. The MMC triggers waves that move non-digestible substances through the gastrointestinal tract from the stomach distally to the terminal ileum. 

In addition, the MMC is responsible for moving bacteria from the small intestine to the large intestine, as well as inhibiting the migration of colonic bacteria into the terminal ileum. 

Any disorder that impairs MMC function can be a risk factor for SIBO. Gastroenteritis that leads to post-infectious IBS-D is thought to be a risk factor for SIBO. Campylobacter jejuni, Salmonella, E. coli, and Shigella produce cytolethal distending toxin (CDT), and the host can produce an autoimmune response that damages the pacemaker cells for the MMC, resulting in decreased MMC activity.

Other key SIBO risk factors include conditions that result in immunocompromise, decreased bacteriostatic digestive secretions (HCl, pancreatic enzymes, bile acids), and ileocecal valve dysfunction.

Complications of SIBO:

Because SIBO is not consistently characterized by the same species, different symptoms or complications may result, depending on the organisms that are present and their specific function in the GI tract. SIBO can result in damage to the small intestinal mucosa leading to malabsorption and intestinal permeability. Microscopic inflammatory changes in the lamina propria and villous atrophy are common.

Destruction of the intestinal mucosa can result in reduced disaccharidase function and increased intraluminal bacterial carbohydrate degradation, causing SIBO symptoms. The bacteria themselves can consume nutrients, leading to micronutrient deficiencies, and deconjugate bile acids, leading to fat and fat-soluble vitamin malabsorption. Bacteria can produce toxic substances resulting in increased serum endotoxin, stimulating inflammatory cytokine production. 

SIBO complications include:

- Weight loss 
- Steatorrhea
- Vitamin/mineral deficiency
    - Fat-soluble vitamins (A,D,E,K) 
    - Vitamin B12
    - Iron
- Hypoproteinemia/hypoalbuminemia
- Bile acid deficiency
- Anemia
- Osteoporosis
- Neuropathies

Treatment Considerations:

Antibiotics are commonly used to treat SIBO, and studies show normalized breath tests as well as symptomatic relief. The underlying causes of SIBO must be treated properly. Otherwise, the likelihood of SIBO recurrence is very high, even after antibiotic therapy. In general, clinical management of the SIBO patient involves antibiotics and/or natural antimicrobial agents, promotility/prokinetic agents, nutrient supplementation for depleted nutrients and/ or for brush border healing, dietary interventions, meal spacing, and treatment of comorbid conditions.

Treat the Overgrowth:

Antibiotics:

- Rifaximin is a non-absorbable antibiotic that has been FDA-approved for IBS-D, traveler’s diarrhea, and hepatic encephalopathy. It has been extensively studied in functional bowel disorders. It is efficacious against Gram- positive and Gram-negative aerobic and anaerobic bacteria. It can target common SIBO organisms including E. coli, Klebsiella spp., Enterobacter spp., and E. faecalis. In addition to its direct antibiotic effects, rifaximin may also modulate the host inflammatory response with its anti-inflammatory effect. It is best used for hydrogen- predominant SIBO.

- While rifaximin can be used as an individual agent in patients with methane positive breath-testing, an additional agent may be a more effective treatment in instances of constipation-predominant symptomology or when both H2 and CH4 are present. Rifaximin plus neomycin, both non-absorbable antibiotics, have been described as an effective treatment for constipation-predominant cases.

- A variety of other antibiotics have been studied for SIBO with varying efficacy. These include metronidazole, ciprofloxacin, norfloxacin, amoxicillin-clavulanic acid, cefoxitin, and doxycycline.

Natural Agents:

- In addition to pharmaceutical agents, limited evidence suggests a possible role for natural anti-microbial agents such as berberine, allicin (a component of garlic), oregano oil, and/or neem. One study showed that herbal therapies are at least as effective as rifaximin for SIBO resolution confirmed by lactulose breath test. The herbal products used in this study were a combination of Dysbiocide and FC Cidal (Biotics Research Laboratories) or Candibactin-AR and Candibactin-BR (Metagenics, Inc.).

Elemental Diet:

- Elemental formulas are medical foods that provide nutrition that is absorbed in the proximal small intestine, thus limiting the delivery to the bacteria residing in the distal small intestine.

- This diet may be an alternative to antibiotics in patients with allergies to antibiotics or who cannot tolerate antibiotics.8

Provide Nutritional Support:

Numerous nutritional consequences have been associated with SIBO including: weight loss, fat soluble vitamin deficiency, vitamin B12 deficiency, iron deficiency, hypoproteinemia, and low serum bile acids. Any patient with such secondary consequences may warrant nutraceutical support until SIBO has been addressed. Dietary adjustments to support the management of bacterial overgrowth are also commonly utilized in SIBO. Because no dietary approach has been found to be uniformly effective for the management of symptoms, ongoing dietary modifications, based on patient feedback, is imperative. 

Common dietary SIBO interventions include the Specific Carbohydrate Diet (SCD), Low FODMAPs, SIBO Specific Diet (a combination of low FODMAPs and SCD designed by Allison Siebecker, ND), SIBO Bi-Phasic Diet (designed by Australian clinician Nirala Jacobi, ND), a liquid elemental diet, GAPS Diet, the Cedars-Sinai Medical Center’s Low Fermentation/SIBO Diet (Mark Pimentel, MD), and the Fast Tract Diet (designed by Norman Robillard, PhD).

Probiotics may be beneficial, but further studies are needed to determine the dose and strain. Prebiotics, often added to probiotic supplements, are fermentable foods for bacteria and can encourage overgrowth; these should be avoided during treatment. Other supplements used by functional medicine key opinion leaders include hydrochloric acid, digestive enzymes, and brush border healing supplements, including mucilaginous herbs (licorice, slippery elm, aloe vera, marshmallow), colostrum, L-glutamine, zinc carnosine, vitamins A and D, curcumin, resveratrol, glutathione, and N-acetylcysteine.

Correct the Underlying Cause:

While it may not always be possible, depending on the condition, treatment should include strategies to minimize any risk factors or comorbid conditions for SIBO. Patients with impaired GI motility that affects the migrating motor complex (MMC), or anatomical abnormalities of the digestive tract, are particularly susceptible to SIBO.

Optimal functioning of the MMC may be supported in the following ways:

- Meal spacing every 4 – 5 hours and an overnight fast. The MMC is active during fasting states and is stopped by feedings.

- Use of prokinetic/promotility agents:

    - Pharmaceutical agents include low-dose erythromycin, low-dose naltrexone (LDN), and others. Erythromycin is a motilin agonist and can increase the frequency of phase III of the MMC. LDN is an opioid antagonist and can stimulate peristalsis and increase transit.
    - Natural agents include the botanical product Iberogast, ginger, and others. Iberogast consists of 9 herbs and, when compared with the prokinetics metoclopramide and cisapride, there was comparable effectiveness in the treatment of dyspepsia. Ginger increases motility during phase III of the MMC.

Retesting:

In a patient treated for SIBO, many variables affect the decision of when to retest, including the patient’s underlying condition and its severity, and the length and type of treatment. The North American consensus group suggests that breath tests may be performed shortly after cessation of antibiotic therapy to confirm eradication.

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