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Definition, Etiology, PathogenesisTop
Small intestinal bacterial overgrowth (SIBO) is a condition in which the small bowel is colonized by excessive numbers of aerobic and anaerobic microbes that normally colonize the colon.
The prevalence of SIBO in the general population is unknown. It is often associated to other disorders and therefore frequently underdiagnosed.
Etiology and pathogenesis: There are several mechanisms that prevent bacterial colonization of the small intestine, such as low gastric pH, gastrointestinal (GI) motility, enzymes in pancreatic and biliary secretions, integrity of the intestinal mucosa, direct effects of commensal bacteria, decreased secretion of IgA, and the ileocecal valve. When any of these mechanisms is altered, the risk for SIBO increases:
1) Alteration of the GI tract: Duodenal or jejunal diverticulosis, fistulas, strictures, inflammatory bowel disease, gastric resection or bypass, blind loop syndrome, resection of ileocecal valve.
2) Decreased gastric acid: Hypochlorhydria or achlorhydria, gastrectomy, vagotomy, inhibitors of acid secretion or acid blockers.
3) Altered GI motility: Functional GI disorders (IBS and functional dyspepsia), gastroparesis, pseudo-obstruction, connective tissue diseases (scleroderma, polymyositis, lupus), medications (opiates, anticholinergics, tricyclic antidepressants), radiation enteropathy, muscular dystrophy, amyloidosis.
4) Decreased pancreatic enzymes or biliary secretion: Chronic pancreatitis, cirrhosis.
Motility disorders, diabetes, and chronic pancreatitis are estimated to account for ~90% of cases of SIBO.
Consequences: SIBO leads to:
1) Deconjugation of bile salts and impaired digestion of fats, with consequent steatorrhea and malabsorption of fat-soluble vitamins (specifically vitamins A, D, and E, but not vitamin K, as it is produced by luminal bacteria).
2) Depletion of vitamin B12, leading to megaloblastic anemia. Vitamin B12 is used by anaerobic bacteria to produce inactive cobamides, which in turn decrease vitamin B12 absorption in the ileum by competing for its binding sites.
3) Protein malabsorption.
4) Inflammation in the small bowel, villous atrophy, and disturbance of disaccharide digestion leading to lactose intolerance, which contributes to diarrhea.
Clinical Features and Natural HistoryTop
SIBO can be asymptomatic or can present with nonspecific symptoms, such as bloating, flatulence, diarrhea, abdominal discomfort, or abdominal pain. These symptoms may mimic irritable bowel syndrome (IBS). In fact, a recent meta-analysis showed that one-third of patients with IBS may test positive for SIBO.Evidence 1Low Quality of Evidence (low confidence that we know true effects of the intervention). Quality of Evidence lowered due to inconsistency, indirectness, and publication bias. Chen B, Kim JJ, Zhang Y, Du L, Dai N. Prevalence and predictors of small intestinal bacterial overgrowth in irritable bowel syndrome: a systematic review and meta-analysis. J Gastroenterol. 2018 Jul;53(7):807-818. doi: 10.1007/s00535-018-1476-9. Epub 2018 May 14. Review. PubMed PMID: 29761234.
Patients with SIBO may develop chronic fatty diarrhea and megaloblastic anemia as well as weight loss and malnutrition. They may have symptoms of vitamin A and D deficiencies (osteomalacia and osteoporosis, tetany, trophic epithelial lesions, night blindness), symptoms of vitamin B12 deficiency (ataxia and peripheral neuropathy), erythema nodosum, and maculopapular rash.
Patients with SIBO may also present glomerulonephritis, hepatitis or hepatic steatosis, and arthritis.
Although there is no perfect test for the diagnosis of SIBO, the current gold standard involves measurement of bacterial concentrations and culture of jejunal aspirate samples taken endoscopically. Because this test is invasive, hydrogen breath testing (HBT) with substrates such as glucose or lactulose has become a widely accepted alternative.
If available, HBT using glucose as the substrate should be considered, with additional measurement of methane concentration to improve the sensitivity of the test. If HBT is not available, culture of small bowel aspirate should be attempted. If clinical suspicion is high and no test is available, empiric antibiotic therapy seems appropriate.
1. Microbiologic test of intestinal contents: Quantitative and qualitative microbiologic examination of samples collected via a nasogastric tube or during endoscopy from jejunal aspirate. This is considered the gold standard for the diagnosis of bacterial overgrowth syndrome; however, the examination is invasive, expensive, and flawed by false-positive results due to contamination with oral and esophageal flora as well as false-negative results due to inability to reach the middle and distal sections of the small bowel. There is a lack of consensus regarding the definition of a positive test. While some studies suggest >103 colony-forming units (CFU)/mL are required to define SIBO, for others >107 CFU/mL are needed. However, most experts have accepted a bacterial count of >103 CFU/mL for the diagnosis of SIBO.
2. HBT: Hydrogen and methane are gas productions from colonic anaerobic bacterial fermentation of carbohydrates used in this test as the substrate for fermentation (eg, glucose or lactulose). These gases can then be measured in exhaled breath using gas chromatography. In patients with SIBO bacteria present in the small intestine produce a premature rise in the concentration of hydrogen, methane, or both following the intake of glucose or lactulose.
Breath testing to measure hydrogen and methane concentrations after the intake of glucose or lactulose as substrates is a noninvasive and relatively inexpensive tool to diagnose SIBO. There is, however, a lack of standardization regarding indications and methodology for testing as well as interpretation of results. A recent North American consensus has proposed a rise ≥20 ppm from baseline in hydrogen concentration within 90 minutes or ≥10 ppm at any moment of the test in methane concentration using a glucose or lactulose substrate for the diagnosis of SIBO, which is different than the Rome protocol (50 g glucose, >12 ppm hydrogen and methane increase after glucose), although the characteristics of these tests are unclear and likely poor.Evidence 2Low Quality of Evidence (low confidence that we know true effects of the intervention). Quality of Evidence lowered due to inconsistency, indirectness, and publication bias. Rezaie A, Buresi M, Lembo A, et al. Hydrogen and Methane-Based Breath Testing in Gastrointestinal Disorders: The North American Consensus. Am J Gastroenterol. 2017 May;112(5):775-784. doi: 10.1038/ajg.2017.46. Epub 2017 Mar 21. PubMed PMID: 28323273; PubMed Central PMCID: PMC5418558. The sensitivity and specificity of HBT is variable, with studies reporting a sensitivity range from 31% to 68% and a specificity range from 44% to 100%. When using glucose as a substrate, HBT is more specific but not as sensitive, as glucose is absorbed mainly in the proximal bowel and can therefore miss distal SIBO. On the other hand, the lactulose breath test is more sensitive than specific, but lactulose is an osmotic laxative, which accelerates transit and may lead to false-positive results and overtreatment.
3. Laboratory tests: There is no specific laboratory test to diagnose SIBO. Indirect findings may be macrocytic anemia, hypoalbuminemia, and other abnormalities depending on clinical manifestations and target organ damage.
4. Radiography of the GI tract is not routinely performed. Radiographs may reveal impaired intestinal passage or anatomical defects (eg, diverticulum, duplication, “blind loop,” intestinal stricture).
5. Stool fat analysis: Microscopic examination of a freshly prepared stool specimen stained with a 1% solution of Sudan III may reveal an increased number of fat droplets in the stool. The examination is not done routinely.
Other causes of chronic diarrhea (see Diarrhea).
SIBO often presents with other concomitant conditions such as functional GI disorders, diabetes, celiac disease, or IBS, or after a GI surgery. Concomitant celiac disease and SIBO commonly manifest as a lack of an adequate response to a gluten-free diet. In patients with other underlying diseases, like Crohn disease or pancreatitis, SIBO may present as unexplained clinical deterioration. Patients with IBS with predominant constipation (IBS-C) have higher risk of methane-dominant SIBO than patients with IBS with predominant diarrhea (IBS-D) or those with inflammatory bowel disease.
Treatment of SIBO involves modification of risk factors, correction of nutritional deficiencies, and oral antibiotics.
1. Treatment of the underlying diseases or correcting factors promoting bacterial overgrowth: This is the most important part of SIBO treatment. However, because it is not always possible to completely control the underlying condition, the risk of recurrence remains high.
2. Nutritional management:
1) Formulas containing medium-chain triglycerides (MCTs) may facilitate the absorption of fats.
2) In the case of disaccharide intolerance, dietary lactose restriction may contribute to better symptom control.
3) Supplementation of vitamins A, D, E, and, B12 in patients with deficiencies.
4) A diet low in fermentable oligosaccharides, disaccharides, monosaccharides, and polyols (FODMAPs) may improve clinical symptoms.
3. Antimicrobial treatment: Wide-spectrum antimicrobial drugs against gram-negative aerobic and anaerobic bacteria may be used. The most commonly used antibiotics and doses:
1) Amoxicillin/clavulanate 500/125 mg tid.
2) Ciprofloxacin 250 to 500 mg bid.
3) Doxycycline 100 mg bid.
4) Metronidazole 250 mg bid or tid.
5) Neomycin 500 mg bid.
6) Norfloxacin 400 mg bid.
7) Rifaximin 550 mg bid or tid.
8) Tetracycline 250 to 500 mg bid or qid.
9) Sulfamethoxazole/trimethoprim 800/160 mg bid.
Most guidelines recommend administering treatment for 7 to 10 days as a single treatment course or as a cyclic therapy.
Rifaximin is the most studied antimicrobial drug for SIBO. It has been preferred over other antibiotics because of its limited absorption and systemic effects. Furthermore, it is probably the only antibiotic capable of achieving a long-term favorable clinical effect in patients with IBS and SIBO.Evidence 3Low Quality of Evidence (low confidence that we know true effects of the intervention). Quality of Evidence lowered due to severe inconsistency, indirectness, and imprecision. Gatta L, Scarpignato C. Systematic review with meta-analysis: rifaximin is effective and safe for the treatment of small intestine bacterial overgrowth. Aliment Pharmacol Ther. 2017 Mar;45(5):604-616. doi: 10.1111/apt.13928. Epub 2017 Jan 12. Review. PubMed PMID: 28078798; PubMed Central PMCID: PMC5299503. However, the drug is expensive and not widely available. Adding neomycin to rifaximin is recommended for the treatment of intestinal methanogen overgrowth.
4. Probiotics for SIBO: Different probiotic strains have shown benefits in reducing abdominal pain as well as decreasing hydrogen concentration and may help to restore microbial balance in patients with SIBO. However, they do not seem effective in preventing SIBO.Evidence 4Low Quality of Evidence (low confidence that we know true effects of the intervention). Quality of Evidence lowered due to inconsistency, indirectness, imprecision. Zhong C, Qu C, Wang B, Liang S, Zeng B. Probiotics for Preventing and Treating Small Intestinal Bacterial Overgrowth: A Meta-Analysis and Systematic Review of Current Evidence. J Clin Gastroenterol. 2017 Apr;51(4):300-311. doi: 10.1097/MCG.0000000000000814. Review. PubMed PMID: 28267052.
SIBO is considered a relapsing condition, with up to 44% of patients having a recurrence of symptoms at 9 months after initial successful antibiotic treatment. Therefore, multiple cycles of antibiotics may be needed. The role of retesting after a course of an antibiotic is currently unknown.