Bacteria are present across the length of the gastrointestinal tract with the highest concentration noted in colon (10^10-11/ml)^1,2. The concentration is lower in stomach and jejunum (<10³/ml) compared to ileum (10^4-6/ml). Normally, colon has more  anaerobes (e.g., Bacteroidetes, Clostridium) and gram negative bacteria (e.g., Escherichia, Klebsiella, Enterobacter, Proteus, Acinetobacter, etc.) compared to the small intestine^3-7. In the small intestine, gram positive organisms (Streptococcus, Staphylococcus, Lactobacillus, Enterococcus, etc.) are frequent and gram negative coliforms are less common⁴.  

The North American consensus defines SIBO as bacterial load greater than 10³ colony forming unit(CFU)/ml which is the generally accepted criteria currently^9,10. Some define SIBO based on presence of excess number of coliforms (>10³ CFU/ml) while others have kept a higher cut-off (>10⁵ CFU/ml) of bacterial population to define SIBO^11,5. In clinical practice, breath tests are done more commonly than culture to diagnose SIBO. According to the North American consensus, a >20 part per million (PPM) increase of hydrogen from baseline or a >10PPM increase of methane from baseline after lactulose administration is considered positive for diagnosis of SIBO¹⁰. These definitions are based on studies usually done on small populations and may not be generalizable for different geographical locations owing to the variations in lifestyle and dietary habits. There are interindividual variations in the type and density of bacterial population in proximal small intestine. Also, the organisms increased in abundance may differ depending on the cause of SIBO, with obstruction and dysmotility favoring growth of gram negative organism and reduced acid secretion in stomach favoring gram positive organisms^5,12. 

A number of factors influence the concentration and composition of bacteria in intestine¹³. The acidic secretion from stomach and other intestinal secretions, gastrointestinal motility, local immune response, intact ileocaecal valve, etc. keeps the small intestinal bacterial population in check. Alterations in these defense mechanisms predispose to SIBO, although in some conditions such as functional gastrointestinal disorders, the exact reason is not well known. Table 1 shows the various conditions associated with SIBO and Figure 1 shows the prevalence of SIBO in few selected conditions.Although the disorders are placed in separate categories for simplicity, in several of them, multiple factors may be responsible for causing SIBO. It is also important to note that the studies on prevalence of SIBO are affected by non-standardization of the definition and variability in the diagnostic methods chosen.

i)  Subjects without organic disorders and FGIDs: SIBO has been noted in 2% to 20% of healthy individuals with higher prevalence in older age^6,14,15. Dysbiosis is emerging as one of the contributory factors in several FGIDs (Functional gastrointestinal disorders or disorders of gut brain interaction)16. Among FGIDs, SIBO has been extensively studied in patients with irritable bowel syndrome (IBS). A meta-analysis of 50 studies on IBS, showed a pooled prevalence of SIBOto be  38% (95% CI, 32-44)¹⁷. Notably, the prevalence was higher (40%) when the diagnosis was made by breath test compared to culture (19%). The risk of SIBO is more in patients with IBS-diarrhoea subtype, women, those with symptoms of bloating and in older age subjects^17,18,19. Three studies from India have found the frequency of SIBO in IBS to be 8.5%, 11% and 46%^19-21. Another FGID where SIBO is commoners than control is dyspepsia.  A meta-analysis of seven studies showed a higher risk of SIBO with functional dyspepsia compared to controls²². The odds ratio of SIBO in functional dyspepsia was 4.3 (95% CI, 1.1-17.5) although the quality of data was low.

ii) Altered gastrointestinal secretion: Gastric acid and pancreatic enzymes make the micro-environment less suitable for bacterial growth^23,7. Most of the bacteria cannot survive in the stomach because of its highly acidic pH. Pancreatic enzymes degrade the proteins required for bacterial growth and digests the nutrients leading to absorption, thereby reducing stasis of nutrients²⁴. Bile acids, with their detergent action on bacterial cell membrane and anti-microbial properties prevent bacterial overgrowth in proximal small intestine^25,26,23,7. Conjugated Bile acids have an indirect protective action in the distal small bowel by activating Farsenoid X receptor  pathway. This pathway upregulates the genes involved in producing antimicrobial substances and strengthening epithelial integrity²⁶. Accordingly reduced gastric acid secretion, pancreatic enzyme insufficiency and chronic liver disease have all been associated with SIBO.

iii) Gastrointestinal dysmotility: The peristaltic waves of small intestine prevent stasis of chyme and growth of bacterial colonies in normal individuals³. Decreased activity of  migratory motor complexes (MMC) has been associated with SIBO40. Dysmotility results from abnormal  muscle and/or nerve function and can be transient (e.g. prolonged hospitalised states, medications, etc.) or chronic. Examples of condition  where SIBO is associated with altered motility includes gastroparesis, chronic intestinal pseudo-obstruction, diabetes mellitus, hypothyroidism, scleroderma, amyloidosis, chronic kidney disease, dyselectrolytemias, ileus and drugs^41,42. 

iv) Anatomical factors: Anatomical alterations in small bowel (post-operative, disease related, etc.) can lead to bacterial overgrowth by promoting stasis of luminal contents. Examples include blind loops, diverticula, adhesions and strictures. Ileocaecal (IC) valve is an important anatomical barrier between ileum and colon and protects proximal reflux of colonic contents and bacteria^46,47. Diseases like Crohn’s disease(CD) and tuberculosis might effect IC valve and impair its natural barrier function, thereby promoting retrograde migration of bacteria. A study from North India found SIBO to be more common in patients with CD (18.6% vs 1.5%) but not in ulcerative colitis (4.4%) compared to healthy controls⁴⁸. Obesity surgeries like roux-en-Y gastric bypass increase the risk of SIBO by affecting protective gastric factors (acid content)  along with altered motility. Prevalence of SIBO in these patients was found to be around 40%^49,50. However, obesity itself has been associated with higher risk of SIBO⁵¹. 

v) Immune dysfunction: GI tract is protected from bacterial pathogens by integrity of mucosal surface and innate and adaptive immune system. Disruption of gut barrier function and impaired immune response (e.g., IgA secretion) may predispose to SIBO.Patients with disorders like IgA deficiency, common variable immune deficiency, T cell defects, acquired immune deficiency syndrome, etc.  are prone to develop SIBO⁵².

vi) Other conditions: The risk of SIBO has been noted to be high in several other conditions (Table 1). The underlying reason  may be a combination of factors such as dysmotility, impaired gastrointestinal secretion, abnormal gut permeability, etc. Growth stunting and intestinal inflammation (environmental enteropathy) have been noted to be frequent in children in low and middle income countries and SIBO has been proposed as one of the contributing factor^13,53. In a study from Bangladesh, SIBO was noted in 16.7% children and was associated with elevated intestinal inflammatory marker⁵⁴. There is increased risk of SIBO in celiac disease. In a meta-analysis, the pooled prevalence of SIBO in celiac disease was 20% (95% CI, 10-30) and was higher in patients with persistent symptoms after gluten free diet compared to those without symptoms (28% vs 10%)⁵⁵. Gut microflora has been noted to be altered in NASH and the risk of SIBO is increased. A meta-analysis showed the pooled prevalence of SIBO to be 0.41(95% CI, 0.22-0.63) in patient with NASH⁵⁶. 

Patients with SIBO can have a wide spectrum of clinical manifestations, from being asymptomatic to having a variable number and severity of symptoms. Some of these symptoms may be related to the underlying risk factor/disease and it may be difficult to attribute  the symptoms to SIBO with certainty. A thorough history including the presence of risk factors for SIBO and good clinical examination is essential. The severity of symptoms, features of underlying disease and nutritional status should be assessed. 

Diagnosis of SIBO requires demonstration of an increase in the number of bacteria or increase in their metabolic byproduct⁶³. Elevated serum folate levels and low vitamin B12 levels, although non-specific, may support a diagnosis of SIBO^11,63.

Quantitative culture of small bowel aspirate: Quantitative small bowel aspirate culture is considered the gold standard test for diagnosing SIBO¹¹. This entails collection of duodenal or jejunal content during endoscopy by using a sterile catheter which are then cultured by a serial dilution technique¹². A custom double lumen protected catheter which prevents the risk of oropharyngeal contamination while passing the catheter through the scope may be preferred to obtain samples^63,64. The small bowel bacterial load in healthy individuals, is generally < 10² CFU/ml⁶⁵. As the duodenal lumen is more acidic than  jejunum, the bacterial load is even lower than that of the jejunum. A recent North American consensus recommended  a colony count of  greater than 10³ CFU/ml for diagnosing SIBO¹⁰.  

Breath tests: Breath tests are frequently used to diagnose SIBO due to their non-invasive nature ^70,71. These tests are based on the production of hydrogen, methane and/or hydrogen sulfide gas  by the gut flora (bacteria and archaea) from substrates like glucose and lactulose⁷². Human cells do not produce hydrogen or methane from carbohydrates. Breath hydrogen and methane levels are recorded every 10 to 15 minutes for 2-4 hours, after ingestion of either 75-100 g of glucose in 20 ml of water (Glucose hydrogen breath test – GHBT)  or 10 g  of lactulose in a 15 ml solution (Lactulose hydrogen breath test – LHBT)^7,71. Up to 30% of general population may not release enough hydrogen in breath due to its utilization by bacteria to produce methane⁷³. Hence simultaneous methane assessment improves the  sensitivity of the test. Prior to the breath tests, the patient should not be on antibiotic, probiotic, motility affecting drugs and laxatives. They should avoid smoking, taking complex carbohydrate and dairy products before the test^3,70,74. Glucose may be less accurate in detecting distal small bowel bacterial overgrowth as it may be absorbed in the proximal bowel while lactulose may affect gut motility and can influence the result of the test³. In diabetics, glucose may cause hyperglycemia and lactulose may be preferred as a substrate for the test⁷⁵. Conventionally, a double peak in breath hydrogen after lactulose administration has been described in SIBO. The first peak is due to the production of hydrogen by the excessive small intestinal bacteria and the second by the resident colonic flora and an abnormal first peak is noted in SIBO. There are variations in cut-offs which have been used to diagnose SIBO. The North American consensus defines a positive breath test  when there is a>20 part per million (PPM) increase of hydrogen from baseline and a > 10 PPM increase of methane from baseline, within 90 minutes after administration of lactulose (Figure 2)¹⁰. The interval after which the level of gas rises depends on the orocaecal transit time which may vary among individuals. A Technetium scintigraphy along with LHBT can be used to identify the entry of the substrate ingested into the caecum to improve the accuracy of this test. 

The overall sensitivity of breath tests to diagnose SIBO is not very good and varies based on the substrate and the cut-offs used^36,76-87 (Table 2). A recent systematic review and meta-analysis of breath tests for the diagnosis of SIBO showed a pooled sensitivity and specificity of 54.5% and 83.2% and 42% and 70.6% respectively for GHBT and LHBT⁷⁶. The  sensitivity increased to 61.7% and specificity increased to 86% when a cut off of > 12 PPM  rise in H2 was used to diagnose SIBO. Accordingly the Asian Pacific consensus advocates a cut off of > 12 PPM rise in H2 after glucose administration for the diagnosis of SIBO¹¹. Breath tests are simple, non-invasive, less expensive and the results are available quickly. More recently capsule based devices have become available which have sensors for directly measuring the level of gases (hydrogen, methane, carbon dioxide, oxygen) in the small bowel⁸⁸. On comparing results with breath tests, a 3000 times higher concentration of hydrogen was measured by the capsule device. Additionally, the transit times can be estimated based on changes in the concentration of gases. As the performance of breath test is not very accurate, more than one test may be used if clinical suspicion is high⁷⁵. There are also suggestions for empirical antibiotic therapy if pre-test probability for diagnosis of  SIBO is high⁸⁹.

Treatment of SIBO is aimed at correcting the overgrowth of bacterial population in small bowel^9,11,63. In addition, the factor predisposing to SIBO should be corrected if feasible and the nutritional deficiencies should be replenished^9,11,63. Other coexisting conditions contributing to symptoms such as IBS, celiac disease, food intolerance, etc.also need to be recognized and managed.

Antimicrobial therapy: The microorganisms responsible for SIBO include  both anaerobic and aerobic organisms and gram positive and negative organisms. Many of them are difficult to grow in culture and hence culture/sensitivity guided therapy is not feasible⁸. Therefore, broad spectrum antimicrobials are used empirically for therapy. Antibiotics are the mainstay of therapy for SIBO. These include – rifaximin, metronidazole, ciprofloxacin, norfloxacin, doxycycline, tetracycline,  neomycin, amoxicillin/clavulanate, trimethoprim-sulfamethoxazole, etc. (Figure 3)⁸. Antibiotics are given for 7 to 10 days and lead to improvement of symptoms in 46-90% cases and normalization of HBT in 20-75%⁶³. 

Probiotics: Apart from antibiotics, probiotics have also been used, both as a standalone treatment or as add on therapy to antibiotic. A systematic review and meta-analysis evaluated the role of probiotic in preventing and treating SIBO (diagnosed by HBT)¹⁰⁵. There was no significant benefit of  probiotic  compared to no probiotic in reducing the incidence of SIBO (four studies). For treating SIBO, when probiotic was used alone the eradication rate was only 53.2% (40.1-65.9). Probiotics were more effective for pain relief but had a lesser impact on the frequency of stool. When probiotics were added to antibiotics (two studies) the eradication rate was 85.8%. The studies on probiotics have limitations in methodology and current guidelines do not recommend probiotics as a standard therapy for SIBO^9,11,63. In addition, there are reports of risk of D lactic acidosis with probiotics^74,106,107.

Dietary therapy: Growth of bacteria requires appropriate nutrients, and one of the therapeutic options may be to limit the amount of fermentable nutrients available to the bacteria by dietary modification. In a study by Pimental et al.,  elemental diet led to the normalization of LBT in 85% of the 93 patients with SIBO by day 21. Normalization of LBT was associated with higher rate of symptom improvement¹⁰⁸. The benefit of elemental diet may be due to its predominant absorption in the proximal small bowel which leaves less nutrients for bacteria to grow¹⁰⁸. Elemental diets are less palatable and are expensive and more evidence is required on their efficacy before making firm recommendations. Diet with low FODMAP (Fermentable  oligosaccharides, disaccharides, monosaccharides and polyols) content have been shown to be effective in patients with IBS but adequate data on managing SIBO with this diet is awaited^11,95. In addition to specific interventions, general dietary measures may be helpful in some patients. For example, reducing intake of carbonated beverages and  non-absorbable sugars may help reduce symptoms of bloating and flatulence^9,95. Avoiding milk may minimize symptoms of lactose maldigestion (bloating, flatulence, diarrhea) in patients with lactase deficiency⁷. Vegan diet may also have a beneficial effect on microbial composition¹⁰⁹. 

Other therapies: A recent randomized placebo controlled study evaluated fecal microbiota transplantation (FMT, one capsule weekly for 4 weeks) for treating SIBO in 55 patients¹¹⁰. FMT was better than placebo in alleviating gastrointestinal symptoms. However more data is required. A small study found a three week course of  octreotide to be effective in treating SIBO in systemic sclerosis¹¹¹. Alternative treatments such as herbal therapies have also been tried in SIBO¹⁰⁶. A metanalysis on alternative treatments for SIBO found limited benefit of herbal therapy in SIBO¹¹². 

Recurrence of symptoms: Following initial successful therapy, about half of the patients have recurrence of symptoms within one year and hence they require close follow up and repeat treatment if required^8,113. Risk of recurrence is high in patients with persistent underlying cause, old age, those using long term PPI and in patients with history of appendectomy⁸. For recurrent symptoms, rifaximin may be used again if this was efficacious earlier^11,114. If symptoms recur frequently(>4 episodes per year), cyclical antibiotic has been suggested rather than the same antibiotic every month to reduce the risk of antimicrobial resistance^38,63. Cyclical antibiotics may be given for 7 to 10 days per month and can include two or three antibiotics (metronidazole, rifaximin, quinolone, etc.) with one of them being given each month⁶³. 

Management of nutritional deficiencies: Symptoms of SIBO often appear before nutritional deficiencies are apparent but they must be carefully looked for^3,9. The nutritional deficiencies should be identified by both clinical assessment and laboratory evaluation for both macronutrients and micronutrients³. There may be deficiency of vitamin B12, iron and fat soluble vitamins³. Deficient nutrients should be appropriately replaced.

Correction of predisposing factors: This is an important component of management of SIBO. Patients with anatomical abnormalities (e.g., blind loop, fistula, diverticula or obstruction) may need surgical intervention. Improving the motility of the intestine with prokinetics (e.g., domperidone, erythromycin, itopride, etc.) has been suggested in patients with dysmotility  although there is limited evidence for their efficacy^8,74,115. Another important consideration is to avoid medication associated with risk of SIBO (e.g., PPI, opioid, etc.). 

Identification of coexisting conditions causing symptoms: About one-third of patients with symptoms suggestive of SIBO may not respond to treatment⁷⁴. Apart from failure of antibiotics, the cause of symptoms  may be a coexisting condition like IBS, celiac disease, bile salt malabsorption, food(e.g. lactose) intolerance, drugs, etc. and this must be identified and managed accordingly⁷⁴.

Methane producing organisms are present in up to two thirds of individuals. These organisms belong to the domain archaea and are distinct from bacteria and hence the term intestinal methanogen overgrowth (IMO) has been proposed⁹. In IMO, there is overproduction of methane, mostly by the archaea Methanobrevibacter smithii^9,116. Methane  inhibits intestinal motility and has been associated with chronic constipation. In a meta-analysis, methane positive SIBO was more frequent in IBS-C compared to IBS-D (OR 3.1, 1.7-5.6)⁵⁹. Treatment with antibiotics has shown benefit in improving bowel movement^59,117,118. In a study from India on patients with chronic constipation, rifaximin improved symptoms of constipation by reducing methane production and improving colonic transit time¹¹⁷. Combination of rifaximin and neomycin may have better efficacy than rifaximin alone^118,119. Statins have also been found to reduce methane production by Methanobrevibacter but more data is required^118,120.

SIBO occurs in a variety of clinical settings and due to the non-specific nature of the symptoms, a high index of clinical suspicion is required for diagnosis. Figure 4 outlines the approach to a patient with suspected SIBO. Diagnosis can be made by quantitative culture of small bowel aspirate or breath tests. Treatment with short course of antibiotics is often effective in reducing overgrowth of bacteria but treatment of underlying cause is needed to prevent recurrence.