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Small intestinal bacterial overgrowth: diagnosis and treatment

Small Bowel
Small Intestinal Bacterial Overgrowth:
Diagnosis and Treatment

Antonio Gasbarrini Ernesto Cristiano Lauritano Maurizio Gabrielli Emidio Scarpellini Andrea Lupascu Veronica Ojetti Giovanni Gasbarrini Internal Medicine Department, Gemelli Hospital, Catholic University of Sacred Heart, Rome , Italy Key Words
Small intestinal bacterial overgrowth ؒ Antibiotics ؒ Breath tests ؒ Irritable bowel syndrome Adult humans live in symbiosis with several bacteria species exceeding the number of host somatic cells by at least one order of magnitude [1] . Intestinal microflora is Abstract
a complex microbiological system composed of parasites, Small intestinal bacterial overgrowth (SIBO) is a clinical con- viruses, yeast and, above all, bacteria. The bacterial con- dition characterized by a malabsorption syndrome due to an centration varies along the gastrointestinal tract increas- increase in microorganisms within the small intestine. The ing from 10 3 colony-forming units (CFU)/ml in the upper main mechanisms restricting bacterial colonization in the intestinal tract to 10 14 CFU/ml in the colon.
upper gut are the gastric acid barrier, mucosal and systemic Intestinal ecoflora is responsible for integrity and immunity and intestinal clearance. When these mechanisms function of the gastrointestinal tract. It plays a role in the fail, bacterial overgrowth develops. Diarrhea, steatorrhea, defense from pathogenic microorganisms, in the stimu- chronic abdominal pain, bloating and flatulence are com- lation of the immune system, in the control of metabolic mon symptoms and are similar to those observed in irritable and trophic function of epithelial cells and in the synthe- bowel syndrome. Breath tests (glucose and/or lactulose sis of vitamins and nutrients [2] . It also exerts remarkable breath tests) have been proposed as a sensitive and simple effects in the development and maintenance of gut sen- tool for the diagnosis of bacterial overgrowth, being non- sory and motor functions, including the promotion of invasive and inexpensive compared to the gold standard represented by the culture of intestinal aspirates. Antibiotic There is emerging evidence indicating that quantita- therapy is the cornerstone of SIBO treatment. Current SIBO tive and qualitative changes in intestinal flora contribute treatment is based on empirical courses of broad-spectrum to the pathogenesis of intestinal and extraintestinal dis- antibiotics since few controlled studies concerning the eases. Small intestinal bacterial overgrowth (SIBO) is a choice and duration of antibiotic therapy are available at condition associated with the presence of 1 10 6 CFU/ml of intestinal aspirate and/or the presence of colonic-type species [3] . Normally, SIBO is prevented by action of the Internal Medicine Department, Catholic University of Sacred Heart Tel. +39 06 3015 4294, Fax +39 06 3550 2775, E-Mail angiologia@rm.unicatt.it intestinal immune system, gastric acid, pancreatic en- Diagnosis of Bacterial Overgrowth
zymes, small intestinal motility and the ileocecal valve. When one or more of these mechanisms fail, SIBO can Aspiration and direct culture of jejunal contents are considered the gold standards for the diagnosis of SIBO [10] . These procedures have some limitations, such as in-vasivity, possible contamination by oropharyngeal bacte- Metabolic Effects of Bacterial Overgrowth
ria, low reproducibility and presence of non-culturable bacteria. For this reason, non-invasive tests are common- Bacteria in excess can interfere with the metabolism ly used for the diagnosis of SIBO (breath tests). These are and the absorption of many substances such as carbohy- based on production of hydrogen and methane by bacte- drates, proteins, lipids and vitamins. The loss of activity ria as a consequence of carbohydrate fermentation [11] . of brush-border disaccharidases due to mucosal injury The diagnosis of SIBO is established when the exhaled and the bacteria fermentation of sugars such as sorbitol, hydrogen level increases by 1 10 parts per million greater fructose and lactose could be responsible for carbohy- than baseline (for glucose breath test) or when though drate malabsorption [4] . Enterocyte injury may alter the double peaks (SIBO and colonic peaks) have been clearly gut permeability, predisposing to the development of a found after lactulose ingestion. The specificity and sen-protein-losing enteropathy. Moreover, bacteria may com- sitivity of breath tests are not excellent but they are a non- pete with the host for protein and lead to the production invasive, simple and inexpensive tool for the diagnosis of of ammonia [5] . Deconjugation of bile acids in the proxi- mal gut induces fat and lipophilic vitamin (A, D, E) mal-absorption and leads to the production of lithocholic acid, which is poorly absorbed and may be directly toxic Treatment of Bacterial Overgrowth
to enterocytes [6] . Cobalamin (vitamin B 12 ) deficiency can occur in SIBO as a result of use of the vitamin by an- SIBO therapy is based on two different approaches: aerobic bacteria. Levels of both folates and vitamin K, treatment of predisposing conditions and antibiotic ad-however, are usually normal or increased in SIBO as a ministration. Little evidence exists for the efficacy of pro-result of bacterial production.
kinetics and probiotics in SIBO treatment.
Clinical Aspects of Bacterial Overgrowth
Small intestinal bacterial overgrowth is generally con- Although ideally the antibiotic choice should reflect in sidered a malabsorption syndrome, although clinical vitro susceptibility testing, this is usually difficult in manifestations can be largely different in each subject. SIBO because of the presence of several bacterial species This variability is caused by many factors including the with different antibiotic sensitivities. Therefore, antibi-entity of contamination, the extension of intestinal tract, otic treatment requires the administration of wide-spec- the predisposing factors causing SIBO and the bacterial trum antibiotics, also if the best pharmacological ap-species involved. Common SIBO symptoms are diarrhea, proach in terms of drug, dosage and duration of therapy steatorrhea, chronic abdominal pain, bloating and flatu- lence, although asymptomatic cases have been described Tetracyclines have been used for a long time; however, this class of drugs is associated with several side effects SIBO symptoms are similar to those observed in pa- and a low eradication rate (about 30%) since they do not tients affected by irritable bowel syndrome (IBS). Recent have a direct activity against anaerobes and may be inef-findings suggest that SIBO could play a role in the patho- genesis and clinical manifestations of IBS and eradication Metronidazole has been used with satisfying results as of SIBO is associated with a significant improvement of an alternative to tetracycline. In a study on patients with IBS symptoms [8, 9] . However, further studies are needed blind-loop syndrome, metronidazole showed a higher to confirm this clinical association. Unusual SIBO pre- therapeutic efficacy than a non-absorbable antibiotic, ri- sentations include megaloblastic anemia, osteomalacia, faximin [13] .
neuropathy, weight loss and peripheric edema.
Gasbarrini/Lauritano/Gabrielli/Scarpellini/Lupascu/Ojetti/Gasbarrini Attar et al. [14] compare the efficacy of amoxicillin- patient showed any side effect in the rifaximin group. clavulanic acid, norfloxacin, and Saccharomices boular- Recently, Lauritano et al. [17] showed that higher doses dii for the treatment of SIBO-related diarrhea. A statisti- of rifaximin (1,200 mg/day) were associated with a sig- cally significant improvement in mean daily number of nificantly higher therapeutic efficacy (60% of glucose stools was obtained with norfloxacin (90%) and amoxi- breath test normalization) in terms of SIBO eradication cillin-clavulanic acid (60%), and none with S. boulardii . with respect to doses of 600 mg/day (16.7% of glucose A study by Castiglione et al. [15] found a good therapeu- breath test normalization) and 800 mg/day (26.7% of glu- tic efficacy of both metronidazole and ciprofloxacin in cose breath test normalization). Similarly, Cuoco et al. terms of SIBO eradication in patients affected by Crohn’s [18] assessed the efficacy of rifaximin (1,200 mg/day), disease. Ciprofloxacin showed a small, but not statisti- followed by a 20-day course of probiotics, in the treat- cally significant gain in terms of efficacy and tolerability ment of SIBO. The eradication rate of this schedule compared to metronidazole. Some authors evaluated the achieved 83% with a significant improvement of gastro-therapeutic efficacy of non-absorbable antibiotics such as rifaximin and neomycin in order to minimize the poten- Neomycin, a non-absorbable aminoglycoside, was tial side effects of systemic antibiotics.
shown to be of little efficacy when used alone in SIBO. In Data on rifaximin, a rifamycin derivative with anti- a recent study by Pimentel et al. [19] on 111 IBS patients, bacterial activity caused by inhibition of bacterial syn- treatment with neomycin achieved the normalization of thesis of RNA, show a bactericidal action against both lactulose breath test in 20% of patients with SIBO with aerobes and anaerobes, such as bacterioides, lactobacilli respect to 2% in the placebo group. No relevant side ef-and clostridia [16] . Less than 0.1% of the oral dose of ri- fects were observed during the study and no dropouts faximin is absorbed, therefore it exhibits less toxicity occurred. Given these data, there is no conclusive infor-than other antibiotics. In a double-blind controlled trial, mation regarding the most effective therapy that should Di Stefano et al. [12] compared the efficacy of rifaximin be used in the treatment of SIBO. Treatment decisions (1,200 mg/day) with respect to chlortetracycline in the should be individualized and consider risks of long-term short-term treatment of SIBO. The glucose breath test antibiotic therapy (diarrhea, Clostridium difficile infec-normalized in 70% of patients treated with rifaximin tion, intolerance, bacterial resistance, costs) and the pos-versus 27% of patients treated with chlortetracycline. No sibility of SIBO recurrence.
1 Luckey TD: Introduction to intestinal mi- 6 Wanitschke R, Ammon HV: Effects of dihy- 10 Corazza GR, Menozzi MG, Strocchi A, Ra- croecology. Am J Clin Nutr 1972;25:1292– droxy bile acids and hydroxy fatty acids on sciti L, Vaira D, Lecchini R, Avanzini P, the absorption of oleic acid in the human je- Chez zi C, Gasbarrini G: The diagnosis of 2 Hooper LV, Midtvedt T, Gordon JI: How small bowel bacterial overgrowth. Gastroen- host-microbial interactions shape the nutri- Sepe T, Golner B, Perrone G, Russell RM: 11 Romagnuolo J, Schiller D, Bailey RJ: Using Bacterial overgrowth without clinical mal- breath tests wisely in a gastroenterology 3 Donaldson RM Jr: Normal bacterial popula- absorption in elderly hypochlorhydric sub- practice: an evidence-based review of indi- tion of the intestine and their relation to in- jects. Gastroenterology 1994;106:615–623. cations and pitfalls in interpretation. Am J testinal function. N Engl J Med 1964;270: 8 Lin EC: Small intestinal bacterial over- growth, a framework for understanding ir- 12 Di Stefano M, Malservisi S, Veneto G, Ferri- 4 Nucera G, Gabrielli M, Lupascu A, Laurita- eri A, Corazza GR: Rifaximin versus chlor- tetracycline in the short-term treatment of marota G, Tondi P, Pola P, Gasbarrini G, 9 Lupascu A, Gabrielli M, Lauritano EC, Scar- small intestinal bacterial overgrowth. Ali- Gasbarrini A: Abnormal breath tests to lac- tose, fructose and sorbitol in irritable bowel Flore R, Tondi P, Pola P, Gasbarrini G, Gas- 13 Di Stefano M, Miceli E, Missanelli A, Maz- syndrome may be explained by small intesti- barrini A: Hydrogen glucose breath test to zochi S, Corazza GR: Absorbable vs. non-ab- nal bacterial overgrowth. Aliment Pharma- detect small intestinal bacterial overgrowth: sorbable antibiotics in the treatment of small prevalence case-control study in irritable intestine bacterial overgrowth in patients 5 Varcoe R, Haliday D, Tavill AS: Utilization of urea nitrogen for albumin synthesis in the stagnant loop syndrome: Gut 1974;15:898– 14 Attar A, Flourie B, Rambaud JC, Franchis- 16 Scarpignato C, Pelosini I: Experimental and 18 Cuoco L, Salvagnini M: Small intestine bac- seur C, Ruszniewski P, Bouhnik Y: Antibi- clinical pharmacology of rifaximin, a gas- terial overgrowth in irritable bowel syn- otic efficacy in small intestinal bacterial trointestinal selective antibiotic. Digestion drome: a retrospective study with rifaximin. overgrowth related chronic diarrhea: a cross- Minerva Gastroenterol Dietol 2006;52:89– over, randomized trial. Gastroenterology 17 Lauritano EC, Gabrielli M, Lupascu A, San- toliquido A, Nucera G, Scarpellini E, Vin- 19 Pimentel M, Chow EJ, Lin HC: Normaliza- 15 Castiglione F, Rispo A, Di Girolamo E, Coz- tion of lactulose breath testing correlates zolino A, Manguso F, Grassia R, Mazzacca G: Antibiotic treatment of small bowel bac- dose-finding study for the treatment of small terial overgrowth in patients with Crohn’s intestinal bacterial overgrowth. Aliment ized, placebo-controlled study. Am J Gastro- Gasbarrini/Lauritano/Gabrielli/Scarpellini/Lupascu/Ojetti/Gasbarrini

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