Small bowel bacterial overgrowth (SBBO) is a condition characterized by an increased number of endogenous symbiotic bacteria in the small bowel, which can present with a wide clinical spectrum, ranging from an asymptomatic illness or mild and nonspecific intestinal symptoms to a severe malabsorptive syndrome (1). Children with SBBO may experience nutritional deficiencies, weight loss, and growth stunting. As a result of the development of noninvasive and widely available breath tests (BTs), a renewed interest in investigating SBBO has been observed. An increasing number of publications show that this condition is more prevalent than previously believed and that it may be an underrecognized cause of pediatric morbidity (2–6). Studies show that SBBO is not limited to children with structural gut abnormalities or functional and motility gastrointestinal (GI) disorders, but that it also affects those living in unsanitary conditions or treated with proton pump inhibitors (PPIs) (2–6).
This article provides a general overview of the pathogenesis, available diagnostic procedures and their limitations as well as prevalence of SBBO, with particular emphasis on identifying risk factors in the pediatric population. We will discuss clinical manifestations, consequences of SBBO, and the controversy surrounding available treatment options in children.
A comprehensive literature search was performed in March 2015, using MEDLINE, PubMed, and Web of Science databases. The search was limited to abstracts and articles published in English with no date restrictions. Primary search terms included “small bowel bacterial overgrowth,” “small intestinal bacterial overgrowth,” and “bacterial overgrowth” and were combined with secondary search terms such as “children,” “prevalence,” “incidence,” “epidemiology,” “populations at risk,” “risk factors,” “symptoms,” “diarrhea,” “abdominal pain,” “functional GI disorders,” “definition,” “pathogenesis,” “intestinal microbiota,” “gut microbiota,” “diagnostic tests,” “hydrogen breath tests,” “glucose/lactulose breath tests,” “duodenal/jejunal aspirates,” “treatment,” “probiotics,” “antibiotics,” “rifaximin,” “metronidazol,” “proton pump inhibitors,” “hypochlorydia,” “malnutrition,” “complications,” “motility disorders,” “irritable bowel syndrome,” “celiac disease,” “intestinal failure,” “short bowel syndrome,” “Giardia lamblia,” “intestinal immunity,” “immunodeficiency,” and “malabsorption.” All relevant pediatric articles were included in this review. Furthermore, all systematic reviews and meta-analyses of adult studies were also included. We also make mention of specific adult studies whenever pertinent literature for pediatrics is missing or scarce. The reference lists of publications were searched for additional relevant studies.
PATHOGENESIS AND DEFINITION
The human intestinal microbiota is a complex and dynamic ecosystem comprising >500 different bacterial species and as many as 1014 bacterial cells, a number that is 10 times higher than that of all eukaryotic cells in the human body (7). Under physiological conditions, <103 colony forming units (CFU) per milliliter of bacteria are found in the stomach and upper small intestine, most of which are lactobacilli, enterococci, oral streptococci, and other gram-positive aerobic or facultative anaerobes reflecting the bacterial microbiota of the oropharynx (1,7). Bacterial quantity and diversity increase in a caudal direction reaching 109 CFU/mL in the ileum, consisting mainly of gram-negative organisms and anaerobes, and up to 1012 CFU/mL in the colon, with a predominance of anaerobes such as Bacteroides, Porphyromonas, Bifidobacterium, Lactobacillus, and Clostridium (1,7). The stability of the bowel microbiota is maintained by several factors listed in Table 1.
The mechanisms restricting bacterial colonization in the small bowel can become disturbed and lead to an imbalance leading to SBBO for a variety of reasons such as congenital or acquired anatomical abnormalities, diminished gastric acid secretion, alteration of intestinal motility as a result of small bowel diseases or other chronic disorders, and primary or acquired immunodeficiency (1).
There is no consensus regarding the definition of SBBO. The definition, however, most frequently used describes it as the microbiological presence of 105 or more CFU per milliliter of bacteria grown from a small intestinal aspirate (1). This definition has limited clinical value, as symptoms of SBBO depend on the qualitative microbiological composition of the contaminating microbiota. An excessive number of gram-positive bacteria from the upper respiratory tract is a frequent finding in the small bowel of healthy aged people and usually does not cause any clinical symptoms (8). SBBO, however, caused by growth of colonic bacteria that may occur in patients with altered GI motility or with abnormal communications between the large and the small bowel, is associated with symptoms. Therefore, a definition of SBBO as presence of 105 or more of colonic-type microbiota grown from a small intestine aspirate seems to be more suitable for clinical practitioners.
DIAGNOSTIC CHALLENGES IN PEDIATRIC SBBO
Diagnostic procedures used for the detection of SBBO are divided into invasive, direct tests (requiring aspiration, usually during endoscopy, and culture of enteric contents) and noninvasive, indirect tests (measuring the concentration of gaseous products of bacterial fermentation in expired air or metabolic products of fermentation in the blood) (9–12). Tests vary in sensitivity and specificity and both may give false-positive and false-negative results.
Aspirate and Culture of Jejunal Contents
Direct jejunal aspirate culture has been considered by many authors as the criterion standard for the diagnosis of SBBO (1,11,12). There are several limitations and difficulties associated with this method. Endoscopy is an expensive and invasive procedure, often requiring the use of conscious sedation or general anesthesia in children. Therefore, it is not an appropriate test for patients with mild nonspecific symptoms or who need repeated testing and is too invasive for research purposes. There are also other technical hurdles connected with culture of jejunal aspirates. Many microbes do not grow on routine media for bacterial culture and require special growth conditions or longer incubation times (1,10). Indeed, the traditional quantitative culture may underestimate the real number of bacteria in the small bowel. Moreover, samples of jejunal aspirates represent only a single site of the gut and SBBO may be patchy (1,10). This could result in false-negative outcomes and poor reproducibility of this method, which is reported to be as low as 38% (1). False-positive results can be obtained as a consequence of contamination of the jejunal aspirate by oropharyngeal bacteria during intubation. Finally, there is a lack of standardization of the protocol for jejunal aspirates culture and clarity on the cutoff values for positive culture results. For all of these reasons, direct aspiration of small bowel contents is far from an ideal diagnostic method for the detection of SBBO, especially in the pediatric population.
Breath Hydrogen Test
The basis of this test is the detection in breath of H2 gas, a byproduct of the fermentation of a carbohydrate substrate by luminal bacteria, especially anaerobic, colonizing the small bowel in the case of SBBO (9,13). H2 is absorbed through intestinal mucosa into the bloodstream and transported to the lungs, where it is exhaled. As humans do not produce H2 when fasting or at rest, it is assumed that H2 in the expired air derives from the anaerobic microbial metabolism of carbohydrates in the intestinal lumen (10). High fasting H2 concentration, exceeding 10 ppm in exhaled air, may occur in SBBO. Elevated fasting BH is, however, more often associated with slow intestinal transit time or residual carbohydrate arriving in the colon from failure to follow a low fermentable diet on the day before the test (10). The substrate for detection of SBBO is usually a metabolizable carbohydrate such as glucose, lactulose, sucrose, or xylose. At present, the glucose breath hydrogen test (GBHT) and the lactulose breath hydrogen test (LBHT) are the most frequently used for SBBO detection and our review focuses on these 2 tests.
Glucose is a monosaccharide that is rapidly and completely absorbed in the small bowel and, under physiological circumstances, does not reach the colon. Therefore, following glucose administration as part of a GBHT, BH should remain at baseline levels. Whenever excessive number of bacteria contaminate the small bowel, BH will, however, increase soon after glucose is administered presenting an “early” peak of H2 excretion (9).
Lactulose is a disaccharide that is poorly absorbed in the small bowel and reaches the cecum. Under normal circumstances, following the ingestion of lactulose, H2 will not be detected in breath until the load reaches the colon (usually 45 minutes or more). In patients with SBBO, the LBHT may show 2 distinct peaks of H2 excretion: an “early” peak resulting from the activity of the small intestinal microbiota on the carbohydrate and a second, a “late” peak, the result of colonic bacterial metabolism of lactulose (9). Sometimes there is an early peak that just persists overtime. In young children, the orogastric time may be so fast that it may be difficult to determine whether the H2 elevation represents a small bowel or a colonic peak.
The 1st Rome H2-Breath Testing Consensus Conference Working Group (2009) recommended the glucose over the lactulose BHT for the diagnosis of SBBO on the basis of several studies in which the GBHT had better diagnostic accuracy than the LBHT (9). The sensitivity and specificity of the GBHT in detecting SBBO is approximately 44 % and 80%, respectively, compared with 31% and 86% of the LBHT (14). False-negative results may occur in patients who produce little or no H2, or instead produce large amounts of methane (CH4) (13,15,16). It is estimated that approximately 15% to 44% of people have intestinal microbiota that contains Methanobrevibacter smithii, which use H2 to form CH4(13,15,16). “Nonhydrogen producers” may not excrete quantifiable amounts of H2 in spite of increased number of bacteria in the small bowel. In such subjects, measurement of H2 alone will underestimate the presence of SBBO.
To minimize basal H2 excretion, patients are asked to ingest a low-carbohydrate diet the day before the test and fast for 10 to 12 hours (9,13). On the day of the test, subjects brush their teeth and rinse with a mouthwash with antiseptic. Subsequently, patients ingest >5 minutes a glucose solution (2 g/kg body weight, maximum 50 g dissolved in 250 mL of water) or lactulose (maximum 10 g dissolved in 250 mL of water). End-alveolar breath samples are collected in a bag or syringes before intake of the carbohydrate solution and then every 15 minutes for 1.5 to 4 hours. Patients should avoid any food or drink, cigarette smoking and physical exercise during the test. H2 (and CH4) concentrations in expired air are measured immediately after samples are obtained using a special gas chromatograph. Samples can also be stored in special vacuum tubes for later analysis.
Interpretation of BHT Results
The BHT is an easy procedure to perform; however, its results are not always easy to interpret as there are still no firmly established criteria for a positive H2 test. The 1st Rome H2-Breath Testing Consensus Conference Working Group (2009) agreed that a GBHT result is compatible with the diagnosis of SBBO if there is a H2 increase of 10 to 12 ppm or greater over the baseline value (9). The authors suggest that higher cutoff values reduce the sensitivity of the GBHT. The original definition of a positive LBHT compatible with SBBO is a detection of an early H2 peak (20 ppm over baseline levels), which occurs at least 15 minutes before the second longer H2 peak (17). Some authors use less restrictive criteria for a positive LBHT in adults, such as an increase of H2 within the first 90 minutes of the test (18,19). This definition is, however, controversial, as it assumes that the orocecal transit time is always longer than 90 minutes so that a H2 peak within 90 minutes after lactulose intake must be caused by SBBO. Therefore, using these criteria there is a high risk of obtaining false-positive results in healthy subjects with rapid transit time. Orocecal transit time in young children may be much faster than 90 minutes.
Recommendations related to conducting and interpreting BHT are based on the studies on adults and direct application to young children is not valid. Furthermore, special populations of pediatric patients (eg, those with intestinal failure, short bowel syndrome [SBS], pulmonary diseases, or patients with fast intestinal transit time) may require different standards what additionally complicates the interpretation of the H2 test.
Carbon Labeled BTs
Another available diagnostic method for determining SBBO is the 13C-labeled xylose BT, in which the breath concentration of labeled CO2 is measured. 13C labeled compounds are nonradioactive and therefore can be used safely in pregnant women and children. It seems to be a useful diagnostic tool particularly for patients who do not produce H2. It was found to be 67% specific and 100% sensitive for the diagnosis of SBBO when tested in a small group of children (20). Nevertheless, in spite of promising results, the 13C-labeled xylose BT is still rarely used because of difficult access to the analytical equipment needed.
D-Lactate and Urine Indican Concentration
In patients with SBS chronic carbohydrate malabsorption can lead to the overdevelopment of microbiota capable of producing large amounts of D-lactate (21–23). It has been suggested that serum determination of D-lactate could be used as a diagnostic tool for SBBO (23). It is not clear, however, whether D-lactatic acid producing bacteria develop in the small bowel or in the colon but in any case they are likely to coexist with SBBO. D-Lactate serum concentration in excess of 1 mmol/L is suggestive of SBBO (23). Although simple and noninvasive, this method is rarely used in clinical practice as it is only useful in patients at risk for developing D-lactic acidosis such as those with SBS with carbohydrate malabsorption, colonic microbiota capable of producing D-lactic acid, combination of ingestion of a large amount of carbohydrate and diminished colonic motility, allowing time for nutrients in the colon to undergo bacterial fermentation, and impaired D-lactate metabolism (22). Furthermore, determination of phenol and indican in a 24-hour urine sample has been described as a method for selecting patients with signs of abnormal bacterial colonization in the small intestine; however, it is rarely used in children because 24-hour urine collections are not easy to obtain, particularly in not-toilet-trained female patients (23,24).
PREVALENCE AND RISK FACTORS OF SBBO IN CHILDREN
The extensive literature search did not reveal any study that evaluated the incidence of SBBO in healthy children. Only limited data from studies, which used a control group, report its incidence in healthy children being between 0% and 35% (2,3,5,25–27). The prevalence of SBBO in various disease states, in children living in unsanitary conditions and treated with PPIs, is reviewed in the following sections and in Table 2(28–42).
Irritable Bowel Syndrome and Other Functional GI Disorders
Most of the studies evaluating the prevalence of SBBO in children are on patients with irritable bowel syndrome (IBS) and other functional GI disorders. Because IBS symptoms are nonspecific and may mimic symptoms of SBBO, it can be difficult to assess whether SBBO is the cause for the GI symptoms or whether it is only a comorbid condition. Furthermore, the role of SBBO in functional disorders remains controversial because of discordant results of the studies. In early studies conducted among infants and young children with chronic diarrhea and abdominal pain, bacterial contamination of the small intestine was diagnosed in most of the patients (28,43,44). de Boissieu et al (27) assessed the incidence of SBBO, diagnosed by a GBHT, in children with chronic diarrhea, abdominal pain, or both. Eighteen of 53 patients (34%) tested positive for SBBO versus none of 15 control healthy subjects.
A high prevalence of SBBO among pediatric patients with chronic abdominal pain was reported by Collins and Lin (25). They noted that 68 of 75 (91%) patients with chronic abdominal pain and 14 of 40 (35%) healthy controls had an abnormal LBHT. Similarly, Scarpellini et al (26) reported relatively high incidence of SBBO in children with IBS (65%) compared with healthy subjects (7%). An abnormal LBHT and rise of H2 during the first 40 minutes after lactulose ingestion was found in 39% of children with functional symptoms and not in healthy controls (45). Hutyra et al (29) showed high prevalence of SBBO in a pediatric population with constipation-predominant IBS (54.55%). Most patients with diarrhea-predominant, however, did not have evidence of SBBO. These findings are in contrast with previous studies, which show a strong link between diarrhea and SBBO (28,43,44). There are other studies that report much lower prevalence of SBBO in functional GI disorders in children (30,31). Jones et al (30) indicated that only 13.6% (39/287) of pediatric patients with GI symptoms were diagnosed as having SBBO as detected by LBHT. The most recent study in the topic shows a similar incidence of SBBO (14.3%) among children with abdominal pain related functional GI disorders (31).
Conflicting results of studies investigating the frequency of SBBO in patients with IBS were also found in adults. One study reported that SBBO incidence, assessed by culture of small bowel aspirate, reached not more than 4% in both, patients with IBS and healthy subjects (46). Others, however, showed that SBBO was present in 65% to 84% of patients with IBS, as diagnosed by LBHT (19,47). A systematic review and meta-analysis of 12 studies investigating the prevalence of SBBO among patients with IBS found that there is insufficient evidence to justify the role of routine testing for SBBO (48). In another systematic review and meta-analysis of 11 case-control studies in patients with IBS with abnormal breath testing, the authors concluded that BHT findings in patients with IBS do not necessarily imply presence of SBBO but rather that an abnormal pattern of carbohydrate fermentation demonstrated by these tests support a role for abnormal intestinal bacterial distribution in IBS (49).
Owing to widely discordant results of the different studies in children and in adults, a relation between SBBO and functional GI disorders remains controversial. The disparity may presumably be caused by the use of different research methodologies and study designs including varying diagnostic tests and lack of an established criterion for the diagnosis of SBBO.
Proton Pump Inhibitors
Gastric acid is one of the main factors preventing from excessive proliferation of bacteria in the upper GI tract. Thus, it is not surprising that prolonged use of PPI may alter the intestinal microbiota and lead to SBBO. In recent years a growing interest in assessing the influence of PPI treatment on SBBO development has been observed.
To the best of our knowledge, only 3 studies have investigated the risk of developing SBBO during PPI treatment in children (4–6). Hegar et al (4) performed a GBHT after 1 month of 20 mg omeprazole therapy among 70 Indonesian children. Positive test results were found in 30% of patients, 62% of whom were symptomatic. Another study by Rosen et al (5) confirmed, by performing gastric aspirates, that acid suppression in children results in gastric bacterial overgrowth. They reported that 46% of patients taking acid-suppressing medication had gastric bacterial growth compared with 18% of untreated patients. Staphylococcus and Streptococcus were found more commonly in gastric fluid of PPI-treated patients. The question is whether SBBO caused mainly by these genera of bacteria could be diagnosed by GBHT. Results of our recently published study also confirm that omeprazole treatment significantly increases the risk of developing SBBO in children (6). We reported that SBBO was diagnosed in 22.5% of 40 children treated for 3 months with a PPI. Only 2.5% of them (1 patient) had the evidence of SBBO before PPI treatment. Compared with those without SBBO, children with SBBO had a higher frequency of abdominal pain, bloating, eructation, and flatulence. Publications in adults show that the incidence of SBBO increases with the duration of PPI treatment and is rather an adverse effect of long-term therapy (50,51). Thus, results of the few studies conducted in the pediatric population may suggest that children are prone to SBBO development even after short-term PPI treatment.
Results from studies in adults are more contradictory. The latest meta-analysis on the association of PPI use and risk for SBOO included 11 studies and showed that there is a statistical association but only when the diagnosis was made by duodenal or jejunal aspirate (52). Discordant results, similarly to those of studies assessing the risk of SBBO in patients with IBS, are probably associated with different research methodologies, varying diagnostic tests, and not precise criteria for diagnosis of SBBO.
Alteration of Intestinal Motility
Alteration of intestinal motility can lead to SBBO, as bacteria may not be effectively swept from the small bowel distally into the colon, leading to food and bacterial stasis in the upper GI tract. Some studies show that abnormalities in the migrating motor complex may increase the risk of SBBO (53–55). There is, however, no available literature on the topic in the pediatric population.
A considerable number of studies conducted in adults show that SBBO may occur in various conditions connected with improper GI motility, that is, stomach and small bowel (eg, Crohn disease, gastroparesis), neurological (eg, muscular dystrophy), endocrine (eg, diabetes mellitus, hypothyroidism), iatrogenic (eg, postoperative blind loop, radiation enteritis), cirrhosis and portal hypertension, chronic renal failure, and some connective tissue diseases (eg, scleroderma) (56–64). Little has been published on SBBO in children with GI motility disorders. A few studies investigated the prevalence of SBBO children with intestinal failure, a condition characterized by loss of gut mucosal absorptive area, most often a result of surgical resection (SBS) or functional abnormality (enterocyte or intestinal dysmotility). Impaired motility or anatomical abnormalities in these patients result in stasis of food and proliferation of bacteria in the upper GI tract that predispose to the development of SBBO. Kaufman et al (32) assessed the impact of late complications of SBS, including SBBO, on the duration of parenteral nutrition. They showed that SBBO occurred in 7 of 7 parenteral nutrition–dependent children and in 55% (23/42) of children who eventually were weaned from it. The association between SBBO and prolonged parenteral nutrition may indicate that this group of children has altered intestinal motility predisposing them to SBBO. A pilot study, conducted among 10 infants with SBS who were parenteral nutrition dependent, showed that SBBO, as diagnosed by GBHT, occurred in 50% (33). The risk of bloodstream infection was 7 times higher in children with SBS and SBBO compared with those without SBBO. Furthermore, a recent study using a new technique (16S rRNA gene sequencing) reported that intestinal dysbiosis in children with SBS is associated with prolonged parenteral nutrition dependency (65). Another study by Gutierrez et al (34) also confirmed high prevalence of SBBO in children with intestinal failure. Seventy percent of 57 of these children (with such underlying diagnosis as motility disorders, necrotizing enterocolitis, intestinal atresia, gastroschisis, and Hirschsprung disease) had SBBO diagnosed by duodenal aspirate cultures. Patients receiving parenteral nutrition were more likely to develop SBBO compared with those without it (70% vs 35%). SBBO was, however, not related to increased risk of catheter-related bloodstream infection as shown in a previous study (33). All 3 studies indicate that SBBO is found in a wide variety of pediatric diseases associated with intestinal failure with a significant need of prolonged parenteral nutrition and, probably, increased risk of bloodstream infections.
Impaired motility may also cause SBBO in children with cystic fibrosis (35–38). Fridge et al (35) reported that SBBO, diagnosed by GBHT, was present in 56% (14/25) of the cystic fibrosis study group compared with 20% (5/25) in the control group. Two other studies confirmed high prevalence of SBBO in this population (36,37). Lisowska et al (38) showed similar SBBO incidence rates in both, children and adults (40% vs 37%) with cystic fibrosis. Poor motility is probably not the only reason for increased risk of SBBO in this group of patients and several other factors may predispose them to develop SBBO such as frequent use of PPI and H2 blockers, exocrine pancreatic insufficiency, mucosal damage or atrophy, postinflammatory narrowing of the intestinal lumen and abnormal accumulation of surface mucus in the intestinal lumen (35–38).
GI dysmotility may also occur in certain neurological disorders. The literature search revealed only 1 study in children on this topic. Ojetti et al (66) assessed the prevalence of SBBO in children affected by myelomeningocele and constipation. The authors reported that 7 of 18 patients (39%) presented SBBO diagnosed by LBHT. The pathogenesis of SBBO in these patients is probably the result of injured sensory and motor function of the perianal region leading to delayed colonic motility and stasis that in turn promotes excess bacterial proliferation in the upper GI tract.
There is a single report regarding incidence of SBBO in children with encopresis (39). The authors reported that SBBO, diagnosed by LBHT, was observed in 42% (21/50) patients with encopresis and 23% (9/39) of control subjects without constipation or encopresis.
Although there are some studies conducted among adults concerning the incidence of SBBO in other disorders which presumably can injure the enteric nervous system leading to disturbed GI motility such as Crohn disease, endocrine diseases (eg, diabetes), gastroparesis, chronic renal failure, cirrhosis and portal hypertension, and connective tissue diseases (eg, scleroderma), we found no such studies in the pediatric population.
Structural Abnormalities of the GI Tract
Congenital anatomical disorders or acquired abnormalities may increase the risk of SBBO development as they usually provide an ideal environment for bacterial colonization because of impaired motility, fecal stasis, and ineffective clearance of the small bowel. There are several studies in adults that show that surgical treatments that create a blind loop (such as total gastrectomy and Roux-en-Y reconstruction) predispose to SBBO, whereas others indicate that Crohn disease with strictures and fistulas in the small intestine and previous surgical intervention, especially resection of the ileocecal valve, are more prone to SBBO development than patients without structural abnormalities (67–69). Results of a study in children who underwent bowel surgery in the neonatal period indicate a greater risk of developing SBBO postoperatively (70). Loss of the ileocecal valve, however, appeared not to increase the risk for SBBO (70). Most of the studies that investigate the prevalence of SBBO among children with structural abnormalities of the GI tract refer to SBS and were reviewed in the previous section.
Children Living in Impoverished Conditions
Our review identified only 3 studies that investigated the prevalence of SBBO among children living in impoverished conditions (2,3,40). The first of such studies was performed in 1991 among 430 Burmese village children ages 1 to 59 months (40). The prevalence of SBBO, diagnosed by LBHT, was 12.5% in the first year of life, 27.8% in the second, 33.3% in the third, and remained in the range of 20% to 30% up to the age of 5 years. The authors underline that SBBO exhibited an age-prevalence pattern similar to that of acute childhood diarrhea in this region. dos Reis et al (2) evaluated the incidence of SBBO among 50 school-age children living in an urban slum in Brazil and 50 children who attended a private health clinic in the same town. Two BHT, 1 with lactulose, and 1 with glucose, on 2 different days were performed. The prevalence of SBBO among children living in a slum was 37.5% compared with only 2.1% in the control group, as assessed by LBHT, whereas it was 4.2% in both groups when assessed by GBHT. It must be, however, underlined that authors used cutoff values of ≥20 ppm of H2 in expired air above fasting levels as being compatible with SBBO for LBHT and GBHT. Similar results were obtained by Mello et al (3), who also compared the prevalence of SBBO among 85 children from the slum in Osasco, Brazil, and 43 children form a private school, all aged between 6 and 10 years. SBBO, diagnosed by LBHT, was found in 30.9% of the subjects from the slum group and in 2.4% among those from the private school group. The authors also reported a high incidence of CH4 production among children from the slum (63.1%). Results of these 3 studies strongly suggest that there is a relation between SBBO, low socioeconomic status and poor sanitation. Donowitz and Petri (71), in their review article on SBBO in children living in low-income countries, hypothesized that high incidence of SBBO associated with unsanitary living conditions is a consequence of repeated exposure to high levels of lipopolysaccharide via contaminated soil or drinking water. Lipopolysaccharide abrogates the migrating motor complex leading to impaired motility and luminal stasis that promotes excess bacteria proliferation in the upper GI tract. Different publications confirm that exposure to gram-negative bacillus-derived lipopolysaccharide may suppress the motor complex and lead to luminal stasis during fasting, which increases the risk of SBBO (72–74). Therefore, the hypothesis that high incidence of SBBO associated with unsanitary living conditions is a consequence of repeated exposure to abnormal levels LPS seems to be convincing.
There are several studies that evaluate the association between celiac disease and SBBO in adults; however, results are contradictory (75–77). Our literature search did not reveal any publication that addresses the prevalence of SBBO among pediatric celiac patients. Nevertheless, we found several studies that report that the microbiota of celiac children presents a different composition in duodenal biopsy and feces compared with that of healthy children. In celiac disease, the microbiota is characterized by an increase in the number of gram-negative and a decrease of gram-positive microbes (78–83). Nadal et al (78) compared bacteriological analyses of duodenal biopsy specimens, assessed by fluorescent in situ hybridization coupled with flow cytometry, of celiac children with active disease, symptom-free patients on a gluten-free diet and healthy controls. The authors reported that the higher incidence of gram-negative and potentially proinflammatory bacteria in the duodenal microbiota of celiac children was linked to the symptomatic presentation of the disease. Collado et al (79) showed that Bacteroides and Clostridium leptum groups were more abundant in feces and biopsies of celiacs than in controls regardless of the stage of the disease. Furthermore, Escherichia coli and staphylococcus counts were higher in feces and biopsies of nontreated celiacs patients than in those of controls. The results of a recent study on duodenal-mucosal bacteria in celiac children also showed that it is associated with overgrowth of possible pathobionts that exclude symbionts or commensals that are characteristic of the healthy small intestinal microbiota (80). Several other studies confirmed that imbalances in the composition of duodenal and fecal microbiota are common in celiac children (81–83). We suppose that such dysregulated microbiota may predispose children with celiac disease to SBBO development; however, this hypothesis needs to be confirmed by further studies.
The reason of potentially increased risk of SBBO associated with celiac disease is not known. Some authors suggest that long-standing celiac disease, especially in untreated patients, can impair gut motility (84). Riordan et al (85) showed that elevated immunoglobulin A (IgA)-antigliadin antibody levels are found in the proximal small bowel luminal secretions of >35% of subjects with SBBO. Furthermore, they demonstrated that luminal concentrations of IgA-antigliadin antibodies in subjects with SBBO were similar to those found in active celiacs and became undetectable after eradication of SBBO. Results of another study concerning the role of intestinal bacteria in gliadin-induced changes in intestinal mucosa also show the relation between bacterial overgrowth and increased gliadin-induced changes in the intestinal mucosa (86). Indeed, the link between SBBO and celiac disease is probably multifactorial and cannot be explained on the basis of the available literature.
Few publications evaluate the relation between Giardia lamblia infection and SBBO. In a study from 1977 by Tandon et al (87) SBBO, as diagnosed by bacterial culture and qualitative analysis of bile salt in jejunal fluid, was noted in 8 of 17 cases (48%) with giardia and steatorrhea and in none of patients with IBS or giardia infection who did not have malabsorption. A more recent study does not confirm an association between SBBO and giardia infection (88). There is only 1 publication addressing this problem in the pediatric population. Moya-Camarena et al (41) evaluated the incidence of SBBO by LBHT in 7 well-nourished children with asymptomatic giardiasis compared to 6 noninfected subjects from Mexico. The authors reported that no children presented SBBO as defined by the cutoff criteria. It must be emphasized that the study group was small and consisted of asymptomatic children.
It would be logical to assume that patients with immunodeficiency could be prone to develop SBBO. A literature search, however, revealed only 2 publications that address this problem in the pediatric population. In an Italian study from 1990, 12 pediatric patients with immunodeficiency syndromes (selective IgA deficiency, panhypogammaglobulinemia, and selective T-cell deficiency) were evaluated for SBBO (42). Five children were diagnosed as having SBBO by jejunal aspirate culture, 4 of whom had abnormal BHT. SBBO was not related to the nature of the immunological abnormality because it was present in all types of immunodeficiency included in the study, which leads to the conclusion that SBBO should be considered in all children with immunodeficiencies. Lagos et al (89) investigated the effect of SBBO on the immunogenicity of single-dose live oral cholera vaccine CVD 103-HgR. The investigators performed an LBHT among 202 school children from Santiago, Chile, ages 5 to 9 years the day before oral administration of CVD 103-HgR. In children with SBBO (10/178 analyzable children), vibriocidal seroconversion differed little from other children (60% vs 67%), but the geometric mean titer was significantly lower (160 vs 368), which also suggests that there is a relation between SBBO and impaired immune system.
In contrast to the pediatric population, adult patients with failure of cellular immunity or selective IgA deficiency do not appear to be predisposed to SBBO development (90,91). Results of the studies investigating the relation of SBBO and intestinal mucosal immunity are not consistent either (92–94).
CLINICAL MANIFESTATIONS AND COMPLICATIONS OF SBBO IN CHILDREN
SBBO symptoms in children vary widely among individuals and may include mild, nonspecific signs such as abdominal pain, diarrhea, bloating or flatulence, and more severe complications such as malnutrition and growth stunting (4,6,27,28,31,43,44,66,95). The precise prevalence of SBBO-related symptoms in children is, however, difficult to ascertain, because different, usually not validated, symptom questionnaires are used. Furthermore, most investigators do not assess the incidence of all possible symptoms that may occur in SBBO.
Most of the studies evaluating the prevalence of SBBO-related clinical signs in the pediatric population focus on IBS-like symptoms such as diarrhea, abdominal pain, bloating, and flatulence. Many authors notice a high incidence of diarrhea among children with SBBO (27,43,44), whereas some others do not confirm these results (4,6,30). Most of the studies, however, consistently show that abdominal pain is a common clinical symptom of SBBO in children (6,25–28,31,43,44,66,95). Flatulence and bloating are also frequent manifestations (4,6,66,95). Numerous publications in adults confirm that IBS-like symptoms are common in patients with SBBO (18,50,75). Clinical manifestations associated with SBBO are presented in Table 3.
Malnutrition, Growth Stunting, Nutritional and Metabolic Consequences
A literature search revealed only 2 studies that show a relation between SBBO and malnutrition or growth stunting in children (96,97). Omoike et al (96) assessed the prevalence of SBBO among 52 Nigerian children and reported that its incidence is higher in subjects with malnutrition compared with well-nourished controls. In another study of 256 children living in a Burmese village, it was found that children with SBBO had a high relative risk (10.7) of being rice malabsorbers, a common staple, and an associated high relative risk (59.7) of having faltered growth (97).
The nutritional consequences associated with SBBO are the result of nutrient malabsorption and maldigestion in the gut lumen. Carbohydrate malabsorption is a consequence of sugar use by bacteria contaminating the small bowel and/or loss of absorptive surface associated with disruption of intestinal brush border enzymes. Diminished carbohydrate absorption leads to diarrhea and increases the osmolarity of the intestinal fluid. Protein malabsorption can also be caused by protein digestion by bacteria or may be related to mucosal damage and loss of absorptive surface of the small bowel. Deconjugation of bile acids by luminal bacteria leads to fat malabsorption including deficiencies in fat-soluble vitamins (A, D, and E) and steatorrhea. SBBO is usually not associated with decreased levels of vitamin K because of bacterial synthesis of menaquinone (98). Megaloblastic, macrocytic anemia may occur in patients with SBBO as a result of use of vitamin B12 by luminal bacteria (99). Deficiencies of vitamins B2, B6, and folic acid have also been reported in adult patients (100). Another mechanism that can be associated with malnutrition and growth stunting in children with SBBO is an increased GI permeability. Tight junction dysfunction has been reported in adults with SBBO (101,102). Increased GI permeability may lead to systemic endotoxemia and systemic inflammation that may be responsible for growth retardation. A study conducted among 73 rural Gambian children has shown that increased GI permeability is associated with high antiendotoxin antibody levels and lower height- and weight-for-age scores (103). Two other studies among village Gambian and Bangladeshi infants also indicated a relation between tight junction dysfunction and growth stunting (104,105). Thus, the results of these studies strongly suggest that SBBO may be related to increased GI permeability and systemic inflammation that lead to malnutrition and growth stunting in children, although the molecular mechanism of this phenomenon has not been explained yet.
D-Lactic acidosis is a rare neurologic syndrome that may occur in patients with SBS or following jeujnoileal bypass surgery as a result of an overgrowth of lactobacilli in the colon (21–23). Malabsorbed carbohydrates progress to the large intestine in which they are fermented to the D-isomer form of lactic acid. As humans cannot metabolize D-lactic acid, it is absorbed from the large intestine into the circulation, resulting in an elevated concentration of D-lactate in the blood. Neurological symptoms typically occur after intake of high-carbohydrate feedings and include altered mental status, confusion, cerebellar ataxia, slurred speech, loss of memory, with patients often appearing drunk. Nevertheless, most patients remain asymptomatic. D-Lactic acid–producing bacterial overgrowth is likely to occur in distal small bowel or colon.
Bacterial Translocation and Sepsis
Several studies show that increased GI permeability may promote translocation of enteric bacteria from the GI tract into the mesenteric lymph nodes and visceral organs (106,107). Thus, it can be hypothesized that SBBO, which may be associated with increased GI permeability, could lead to bacterial translocation and hence elevate the risk of gut-derived sepsis. Most studies, however, show that gut-derived bacteremia alone is of low proinflammatory potential and does not provoke an inflammation to a degree sufficient to cause sepsis, organ failure, and death (108,109). Whenever factors such as intestinal failure or anatomical abnormalities of GI tract exist, SBBO and bacterial translocation may increase the risk of systemic inflammation. A pilot study by Cole et al (33) including 9 infants with SBS who required parenteral nutrition showed that the odds of developing bloodstream infection in infants with SBS and SBBO was 7 times higher than in those without SBBO. In a prospective 5-year study by van Saene et al (110), 208 surgical infants <6 months of age were studied to determine the importance of SBBO with aerobic gram-negative bacilli in the pathogenesis of septic complications related to parenteral nutrition. The authors reported that 84% of septicemic infants carried such organisms, whereas 16% never did. Another study including 57 children with intestinal failure, however, did not report increased risk of bloodstream infection associated with SBBO (65). In conclusion, there is not enough evidence in the literature to prove that SBBO and bacterial translocation increase the risk of systemic inflammation and multiple organ failure; however, it can be hypothesized that an abnormal gut microbiota plays a role in the development of sepsis if other risk factors exist.
The main goals of SBBO treatment should be correction of the underlying disease or structural defect and elimination of the predisposing conditions whenever possible; replenishment of nutritional deficiencies, if present; and modification of the GI microbiota by oral antibiotics and probiotics.
Correction of the Underlying Cause of SBBO
Correction of the underlying cause of SBBO comprises surgical, dietary, and/or pharmacological treatment. Surgical management should be aimed at improving the digestive function and preventing stasis in the GI tract. For many patients, mainly after previous surgery, it is, however, simply not possible or too invasive to do it. Certain dietary restrictions may be beneficial to patients with celiac disease and SBBO caused by impaired GI motility (111,112,82). Pharmacological treatment with prokinetic agents should be considered whenever intestinal stasis and dysmotility is a prominent cause of SBBO, as is the case in chronic intestinal pseudoobstruction or gastroparesis.
Replenishment of nutritional deficiencies seems to be an important component of SBBO management, especially in children with weight loss, growth stunting, intestinal failure, or living in low-income countries. It probably should involve supplementation of fat-soluble vitamins, vitamin B12, and certain minerals; however, there have been no studies proving the effectiveness of nutritional support in SBBO and no guidelines exist for nutritional treatment of SBBO in adults or children yet.
Treatment of SBBO with antibiotics aims to modify and reduce, rather than eradicate, the GI microbiota. Owing to limitations associated with SBBO diagnostic procedures, antibiotic therapy remains primarily empiric and should involve a drug with activity against both, aerobic and anaerobic enteric bacteria. A variety of antibiotic regimens for SBBO treatment have been proposed (47,95,113–119). Several small observational studies and 1 crossover, randomized trial without control group show the effectiveness of antibiotics such as amoxicillin-clavulanic acid, cefoxitim, norfloxacin, or ciprofloxacin in SBBO treatment in adults. A pilot study comparing clinical efficacy of probiotic (Lactobacillus casei and plantarum, Streptococcus faecalis, and Bifidobacterium brevis) versus metronidazol in the treatment of patients with SBBO reported that the probiotic was more effective in terms of clinical improvement (115). One of the few studies concerning antibiotic efficacy of SBBO treatment in children found that a 14-day trimethoprim-sulfamethoxazole and metronidazole therapy was effective in treating 20 children with SBBO (116). In recent years, an increasing interest in the use of rifaximin, a nonabsorable antibiotic, for SBBO treatment has been observed. To the best of our knowledge, there are only 2 interventional studies assessing the efficacy of rifaximin in SBBO treatment in children (95,119). Collins and Lin (119) conducted a double-blind, placebo-controlled rifaximin treatment study of SBBO in 75 children with chronic abdominal pain. No significant difference in symptom improvement was found between subjects who were treated with 550 mg rifaximin for 10 days and those who received placebo. The authors also showed that only 20% of children treated with antibiotic normalized the LBHT. In contrast, Scarpellini et al (95) in a study of 50 children with IBS found that 200 mg 3 times a day of rifaximin was effective in SBBO treatment, as assessed by LBHT and symptom improvement. This trial, however, did not include a placebo group. Contradictory results of these 2 studies may be the consequence of different criteria used for the definition of positive LBHT, different characteristics of the studied groups and different mean age of the subjects. A systematic review and meta-analysis of 10 trials investigating the clinical effectiveness of antibiotic therapies in the treatment of patients with SBBO found that rifaximin was the most commonly studied antibiotic with overall BHT normalization rate of 49.5% compared with metronidazol with BHT normalization rate of 51.2% and ciprofloxacin with the highest rate of BHT normalization of 100% (120). For all antibiotic regimens combined, BHT normalization occurred in 51.1% compared with only 9.8% of placebo-treated subjects. Although there is some controversy regarding efficacy of proper dosage and duration of rifaximin therapy in SBBO treatment, it should be stressed that it showed low incidence of adverse effects in all studies.
In conclusion, there are no official recommendations and too little data is available concerning antibiotic treatment of SBBO in children. SBBO is usually a benign disorder; however, in some cases, especially when predisposing conditions persist, there may be a high recurrence rate so that prolonged or repeated courses of antibiotics are sometimes necessary. Although there are no interventional studies that assess the consequences of antibiotic treatment of SBBO in children, it can be hypothesized that recurrent antibiotic therapy may lead to disturbances in the ecological balance between the host and the normal microbiota, the intensity of which depends on the properties and frequency of the used drugs (121,122). Hence, decisions on management should be individualized and the physician should consider all significant problems associated with antibiotic treatment such as diarrhea, Clostridium difficile infection, toxic and allergic reactions, high cost, microbiota resistance, degree of systemic absorption of the antibiotic, and alterations of the protective microbiota (121,122). Taking into consideration the potential complications of antibiotic intake, a nonabsorbable product with a low incidence of adverse effects such as rifaximin seems to be best option for first-line treatment of SBBO, especially in the pediatric population. Probiotics could offer an alternative therapy (see below).
Studies of probiotics for treatment of SBBO are limited, especially in the pediatric population. To the best of our knowledge, there are no studies that evaluate the efficacy of probiotics in SBBO treatment and only 1 study that assesses the role of probiotics in the prevention of SBBO in children. Results of a double-blind placebo-controlled randomized trial with probiotics for prevention of SBBO in 70 children treated for 4 weeks with omeprazole show that Lactobacillus rhamnosus R0011 and Lactobacillus acidopillus R0052 did not decrease the risk of developing SBBO (4). Studies among adults show conflicting results. Del Piano et al (51) reported that a 10-day intake of 4 specific probiotic strains (Lactobacillus rhamnosus LR06, Lactobacillus pentosus LPS01, Lactobacillus plantarum LP01, and Lactobacillus delbrueckii subsp delbrueckii LDD01) with a marked antagonistic activity toward 5 E coli bacteria and an effective amount of N-acetylocysteine was able to significantly reduce SBBO in long-term PPI-treated subjects. Another study that confirms that probiotics could be effective in SBBO treatment demonstrate that GBHT normalization rate achieved after treatment of 40 patients with SBBO with Bacillus clausii for 1 month was 47% (19/40) what is comparable with that observed with many antibiotics (123). Soifer et al (115) reported that probiotics appeared to be even more effective than metronidazol in term of clinical improvement. Two other studies show that sequential probiotic supplementation on routine antibiotic therapy in SBBO significantly improved GI symptoms (124,125).
There are also several studies, however, that do not confirm efficacy of probiotics in SBBO treatment (114,126,127). Contradictory results of studies investigating the role of probiotics in SBBO may be explained by different strains and dosage regimens of probiotics used in the trials, different characteristics of the studied population, different criteria and diagnostic procedures used for SBBO determination as well as small sample sizes. Until now, there has been no systematic-review and meta-analysis on this topic. Thus, further studies are needed to define the role of probiotic therapy in SBBO, especially in the pediatric population.
SBBO is a prevalent clinical problem, which is found in a wide variety of childhood diseases and conditions. It should be considered in children who experience abdominal pain, diarrhea, bloating, flatulence, malnutrition, or growth stunting and have risk factors for SBBO development. The few diagnostic procedures available have limitations and may be falsely positive or negative. Noninvasive tests such as GBHT seem to be the most appropriate diagnostic tool for SBBO determination in the pediatric population, especially for patients with mild symptoms or who need repeated testing. When a firm diagnosis cannot be made, but clinical symptoms strongly suggest SBBO, empirical antibiotic treatment could be considered. Nevertheless, there are still no established guidelines for the prevention and treatment of SBBO in children. The detailed literature review performed has shown that there is a lack of knowledge about SBBO in children and demonstrated a strong need for further studies assessing the prevalence of SBBO, establishing the criterion standard for its diagnosis and determining the role of antibiotics and prebiotics in SBBO treatment.
1. Quigley EM, Quera R. Small intestinal bacterial overgrowth: roles of antibiotics, prebiotics, and probiotics
2. dos Reis JC, de Morais MB, Oliva CA, et al. Breath hydrogen test in the diagnosis of environmental enteropathy in children living in an urban slum. Dig Dis Sci
3. Mello CS, Tahan S, Melli LC, et al. Methane production and small intestinal bacterial overgrowth in children living in a slum. World J Gastroenterol
4. Hegar B, Hutapea E, Advani N, et al. A double-blind placebo-controlled randomized trial on probiotics
in small bowel bacterial overgrowth in children treated with omeprazole. J Pediatr (Rio J)
5. Rosen R, Amirault J, Liu H, et al. Changes in gastric and lung micromicrobiota with acid suppression: acid suppression and bacterial growth. JAMA Pediatr
6. Sieczkowska A, Landowski P, Kaminska B, et al. Small bowel bacterial overgrowth associated with persistence of abdominal symptoms in children treated with proton pump inhibitors. J Pediatr
7. Sekirov I, Russell SL, Antunes LC, et al. Gut microbiota in health and disease. Physiol Rev
8. Husebye E, Skar V, Høverstad T, et al. Fasting hypochlorhydria with gram positive gastric microbiota is highly prevalent in healthy old people. Gut
9. Gasbarrini A, Corazza GR, Gasbarrini G, et al. Methodology and indications of H2-breath testing in GI diseases: the Rome Consensus Conference. 1st Rome H2-Breath Testing Consensus Conference Working Group. Aliment Pharmacol Ther
2009; 29 (suppl 1):1–49.
10. Malik BA, Xie YY, Wine E, et al. Diagnosis and pharmacological management of small intestinal bacterial overgrowth in children with intestinal failure. Can J Gastroenterol
11. Corazza GR, Menozzi MG, Strocchi A, et al. The diagnosis of small bowel bacterial overgrowth. Reliability of jejunal culture and inadequacy of breath hydrogen testing. Gastroenterology
12. Stotzer PO, Brandberg A, Kilander AF. Diagnosis of small intestinal bacterial overgrowth in clinical praxis: a comparison of the culture of small bowel aspirate, duodenal biopsies and gastric aspirate. Hepatogastroenterology
13. Ghoshal UC. How to interpret hydrogen breath tests. J Neurogastroenterol Motil
14. Ghoshal UC, Ghoshal U, Das K, et al. Utility of hydrogen breath tests in diagnosis of small intestinal bacterial overgrowth in malabsorption syndrome and its relationship with oro-cecal transit time. Indian J Gastroenterol
15. Levitt MD, Furne JK, Kuskowski M, et al. Stability of human methanogenic microbiota over 35 years and a review of insights obtained from breath methane measurements. Clin Gastroenterol Hepatol
16. Bjørneklett A, Jenssen E. Relationships between hydrogen (H2) and methane (CH4) production in man. Scand J Gastroenterol
17. Rhodes JM, Middleton P, Jewell DP. The lactulose hydrogen breath test as a diagnostic test for small-bowel bacterial overgrowth. Scand J Gastroenterol
18. Pimentel M, Chow EJ, Lin HC. Eradication of small intestinal bacterial overgrowth reduces symptoms of irritable bowel syndrome. Am J Gastroenterol
19. Nucera G, Gabrielli M, Lupascu A, et al. Abnormal breath tests to lactose, fructose and sorbitol in irritable bowel syndrome may be explained by small intestinal bacterial overgrowth. Aliment Pharmacol Ther
20. Dellert SF, Nowicki MJ, Farrell MK, et al. The 13C-xylose breath test for the diagnosis of small bowel bacterial overgrowth in children. J Pediatr Gastroenterol Nutr
21. Petersen C. D-Lactic acidosis. Nutr Clin Pract
22. Uribarri J, Oh MS, Carroll HJ. D-Lactic acidosis. A review of clinical presentation, biochemical features, and pathophysiologic mechanisms. Medicine (Baltimore)
23. Vanderhoof JA, Young RJ, Murray N, et al. Treatment strategies for small bowel bacterial overgrowth in short bowel syndrome. J Pediatr Gastroenterol Nutr
24. Aarbakke J, Schjonsby H. Value of urinary simple phenol and indican determinations in the diagnosis of the stagnant loop syndrome. Scand J Gastroenterol
25. Collins BS, Lin HC. Chronic abdominal pain in children is associated with high prevalence of abnormal microbial fermentation. Dig Dis Sci
26. Scarpellini E, Giorgio V, Gabrielli M, et al. Prevalence of small intestinal bacterial overgrowth in children with irritable bowel syndrome: a case-control study. J Pediatr
27. de Boissieu D, Chaussain M, Badoual J, et al. Small-bowel bacterial overgrowth in children with chronic diarrhea, abdominal pain, or both. J Pediatr
28. Dahlström KA, Danielsson L, Kalin M, et al. Chronic non-specific diarrhea of infancy successfully treated with trimethoprim-sulfamethoxazole. Scand J Gastroenterol
29. Hutyra T, Iwanczak B, Pytrus T, et al. Assessment of small intestinal bacterial overgrowth in functional disorders of the alimentary canal in children. Can J Gastroenterol
30. Jones HF, Davidson GP, Brooks DA, et al. Is small-bowel bacterial overgrowth an underdiagnosed disorder in children with GI symptoms? J Pediatr Gastroenterol Nutr
31. Korterink JJ, Benninga MA, van Wering HM, et al. Glucose hydrogen breath test for small intestinal bacterial overgrowth in children with abdominal pain-related functional GI disorders. J Pediatr Gastroenterol Nutr
32. Kaufman SS, Loseke CA, Lupo JV, et al. Influence of bacterial overgrowth and intestinal inflammation on duration of parenteral nutrition in children with short bowel syndrome. J Pediatr
33. Cole CR, Frem JC, Schmotzer B, et al. The rate of bloodstream infection is high in infants with short bowel syndrome: relationship with small bowel bacterial overgrowth, enteral feeding, and inflammatory and immune responses. J Pediatr
34. Gutierrez IM, Kang KH, Calvert CE, et al. Risk factors for small bowel bacterial overgrowth and diagnostic yield of duodenal aspirates in children with intestinal failure: a retrospective review. J Pediatr Surg
35. Fridge JL, Conrad C, Gerson L, et al. Risk factors for small bowel bacterial overgrowth in cystic fibrosis. J Pediatr Gastroenterol Nutr
36. Lisowska A, Wójtowicz J, Walkowiak J. Small intestine bacterial overgrowth is frequent in cystic fibrosis: combined hydrogen and methane measurements are required for its detection. Acta Biochim Pol
37. Schneider AR, Klueber S, Posselt HG, et al. Application of the glucose hydrogen breath test for the detection of bacterial overgrowth in patients with cystic fibrosis—a reliable method? Dig Dis Sci
38. Lisowska A, Cofta S, Walkowiak J, et al. Small intestine bacterial overgrowth and fat digestion and absorption in cystic fibrosis patients. Acta Sci Pol Technol Aliment
39. Leiby A, Mehta D, Gopalareddy V, et al. Bacterial overgrowth and methane production in children with encopresis. J Pediatr
40. Pereira SP, Khin-Maung U, Bolin TD, et al. A pattern of breath hydrogen excretion suggesting small bowel bacterial overgrowth in Burmese village children. J Pediatr Gastroenterol Nutr
41. Moya-Camarena SY, Sotelo N, Valencia ME. Effects of asymptomatic Giardia intestinalis infection on carbohydrate absorption in well-nourished Mexican children. Am J Trop Med Hyg
42. Pignata C, Budillon G, Monaco G, et al. Jejunal bacterial overgrowth and intestinal permeability in children with immunodeficiency syndromes. Gut
43. Davidson GP, Robb TA, Kirubakaran CP. Bacterial contamination of the small intestine as an important cause of chronic diarrhea and abdominal pain: diagnosis by breath hydrogen test. Pediatrics
44. Hill ID, Mann MD, Moore L, et al. Duodenal micromicrobiota in infants with acute and persistent diarrhoea. Arch Dis Child
45. Landskron G, Klapp G, Reyes A, et al. Lactulose hydrogen breath test and functional symptoms in pediatric patients. Dig Dis Sci
46. Posserud I, Stotzer PO, Björnsson ES, et al. Small intestinal bacterial overgrowth in patients with irritable bowel syndrome. Gut
47. Pimentel M, Chow EJ, Lin HC. Normalization of lactulose breath testing correlates with symptom improvement in irritable bowel syndrome: a double-blind, randomized, placebo-controlled study. Am J Gastroenterol
48. Ford AC, Spiegel BM, Talley NJ, et al. Small intestinal bacterial overgrowth in irritable bowel syndrome: systematic review and meta-analysis. Clin Gastroenterol Hepatol
49. Shah ED, Basseri RJ, Chong K, et al. Abnormal breath testing in IBS: a meta-analysis. Dig Dis Sci
50. Lombardo L, Foti M, Ruggia O, et al. Increased incidence of small intestinal bacterial overgrowth during proton pump inhibitor therapy. Clin Gastroenterol Hepatol
51. Del Piano M, Anderloni A, Balzarini M, et al. The innovative potential of Lactobacillus rhamnosus
LR06, Lactobacillus pentosus
LPS01, Lactobacillus plantarum
LP01, and Lactobacillus delbrueckii
LDD01 to restore the “gastric barrier effect” in patients chronically treated with PPI: a pilot study. J Clin Gastroenterol
52. Lo WK, Chan WW. Proton pump inhibitor use and the risk of small intestinal bacterial overgrowth: a meta-analysis. Clin Gastroenterol Hepatol
53. Nieuwenhuijs VB, Verheem A, van Duijvenbode-Beumer H, et al. The role of interdigestive small bowel motility in the regulation of gut micromicrobiota, bacterial overgrowth, and bacterial translocation in rats. Ann Surg
54. Vantrappen G, Janssens J, Hellemans J, et al. The interdigestive motor complex of normal subjects and patients with bacterial overgrowth of the small intestine. J Clin Invest
55. Stotzer PO, Björnsson ES, Abrahamsson H. Interdigestive and postprandial motility in small-intestinal bacterial overgrowth. Scand J Gastroenterol
56. Strid H, Simrén M, Stotzer PO, et al. Patients with chronic renal failure have abnormal small intestinal motility and a high prevalence of small intestinal bacterial overgrowth. Digestion
57. Gunnarsdottir SA, Sadik R, Shev S, et al. Small intestinal motility disturbances and bacterial overgrowth in patients with liver cirrhosis and portal hypertension. Am J Gastroenterol
58. Kaye SA, Lim SG, Taylor M, et al. Small bowel bacterial overgrowth in systemic sclerosis: detection using direct and indirect methods and treatment outcome. Br J Rheumatol
59. Armbrecht U, Lundell L, Lindstedt G, et al. Causes of malabsorption after total gastrectomy with Roux-en-Y reconstruction. Acta Chir Scand
60. Rana SV, Sharma S, Malik A, et al. Small intestinal bacterial overgrowth and orocecal transit time in patients of inflammatory bowel disease. Dig Dis Sci
61. Ojetti V, Pitocco D, Scarpellini E, et al. Small bowel bacterial overgrowth and type 1 diabetes. Eur Rev Med Pharmacol Sci
62. Lauritano EC, Bilotta AL, Gabrielli M, et al. Association between hypothyroidism and small intestinal bacterial overgrowth. J Clin Endocrinol Metab
63. George NS, Sankineni A, Parkman HP. Small intestinal bacterial overgrowth in gastroparesis. Dig Dis Sci
64. Tarnopolsky MA, Pearce E, Matteliano A, et al. Bacterial overgrowth syndrome in myotonic muscular dystrophy is potentially treatable. Muscle Nerve
65. Engstrand Lilja H, Wefer H, Nyström N, et al. Intestinal dysbiosis in children with short bowel syndrome is associated with impaired outcome. Microbiome
66. Ojetti V, Bruno G, Paolucci V, et al. The prevalence of small intestinal bacterial overgrowth and methane production in patients with myelomeningocele and constipation. Spinal Cord
67. Iivonen MK, Ahola TO, Matikainen MJ. Bacterial overgrowth, intestinal transit, and nutrition after total gastrectomy. Comparison of a jejunal pouch with Roux-en-Y reconstruction in a prospective random study. Scand J Gastroenterol
68. Lakhani SV, Shah HN, Alexander K, et al. Small intestinal bacterial overgrowth and thiamine deficiency after Roux-en-Y gastric bypass surgery in obese patients. Nutr Res
69. Castiglione F, Del Vecchio Blanco G, Rispo A, et al. Orocecal transit time and bacterial overgrowth in patients with Crohn's disease. J Clin Gastroenterol
70. Maestri L, Fava G, Fontana M, et al. Small bowel overgrowth: a frequent complication after abdominal surgery in newborns. Pediatr Med Chir
71. Donowitz JR, Petri WA Jr. Pediatric small intestine bacterial overgrowth in low-income countries. Trends Mol Med
72. Cullen JJ, Caropreso DK, Ephgrave KS. Effect of endotoxin on canine GI motility and transit. J Surg Res
73. Husebye E, Hellström PM, Sundler F, et al. Influence of microbial species on small intestinal myoelectric activity and transit in germ-free rats. Am J Physiol Gastrointest Liver Physiol
74. Husebye E, Skar V, Høverstad T, et al. Abnormal intestinal motor patterns explain enteric colonization with gram-negative bacilli in late radiation enteropathy. Gastroenterology
75. Tursi A, Brandimarte G, Giorgetti G. High prevalence of small intestinal bacterial overgrowth in celiac patients with persistence of GI symptoms after gluten withdrawal. Am J Gastroenterol
76. Chang MS, Minaya MT, Cheng J, et al. Double-blind randomized controlled trial of rifaximin for persistent symptoms in patients with celiac disease. Dig Dis Sci
77. Rubio-Tapia A, Barton SH, Rosenblatt JE, et al. Prevalence of small intestine bacterial overgrowth diagnosed by quantitative culture of intestinal aspirate in celiac disease. J Clin Gastroenterol
78. Nadal I, Donat E, Ribes-Koninckx C, et al. Imbalance in the composition of the duodenal microbiota of children with coeliac disease. J Med Microbiol
79. Collado MC, Donat E, Ribes-Koninckx C, et al. Specific duodenal and faecal bacterial groups associated with paediatric coeliac disease. J Clin Pathol
80. Sánchez E, Donat E, Ribes-Koninckx C, et al. Duodenal-mucosal bacteria associated with celiac disease in children. Appl Environ Microbiol
81. Di Cagno R, De Angelis M, De Pasquale I, et al. Duodenal and faecal microbiota of celiac children: molecular, phenotype and metabolome characterization. BMC Microbiol
82. Schippa S, Iebba V, Barbato M, et al. A distinctive ’microbial signature’ in celiac pediatric patients. BMC Microbiol
83. Collado MC, Donat E, Ribes-Koninckx C, et al. Imbalances in faecal and duodenal Bifidobacterium species composition in active and non-active coeliac disease. BMC Microbiol
84. Bai JC, Mauriño E, Martínez C, et al. Abnormal colonic transit time in untreated celiac sprue. Acta Gastroenterol Latinoam
85. Riordan SM, McIver CJ, Wakefield D, et al. Luminal antigliadin antibodies in small intestinal bacterial overgrowth. Am J Gastroenterol
86. Cinova J, De Palma G, Stepankova R, et al. Role of intestinal bacteria in gliadin-induced changes in intestinal mucosa: study in germ-free rats. PLoS One
87. Tandon BN, Tandon RK, Satpathy BK, et al. Mechanism of malabsorption in giardiasis: a study of bacterial microbiota and bile salt deconjugation in upper jejunum. Gut
88. Morken MH, Nysaeter G, Strand EA, et al. Lactulose breath test results in patients with persistent abdominal symptoms following Giardia lamblia infection. Scand J Gastroenterol
89. Lagos R, Fasano A, Wasserman SS, et al. Effect of small bowel bacterial overgrowth on the immunogenicity of single-dose live oral cholera vaccine CVD 103-HgR. J Infect Dis
90. Wilcox CM, Waites KB, Smith PD. No relationship between gastric pH, small bowel bacterial colonisation, and diarrhoea in HIV-1 infected patients. Gut
91. McLoughlin GA, Hede JE, Temple JG, et al. The role of IgA in the prevention of bacterial colonization of the jejunum in the vagotomized subject. Br J Surg
92. Riordan SM, McIver CJ, Wakefield D, et al. Mucosal cytokine production in small-intestinal bacterial overgrowth. Scand J Gastroenterol
93. Riordan SM, McIver CJ, Wakefield D, et al. Serum immunoglobulin and soluble IL-2 receptor levels in small intestinal overgrowth with indigenous gut microbiota. Dig Dis Sci
94. Kett K, Baklien K, Bakken A, et al.. Intestinal B-cell isotype response in relation to local bacterial load: evidence for immunoglobulin A subclass adaptation. Gastroenterology
95. Scarpellini E, Giorgio V, Gabrielli M, et al. Rifaximin treatment for small intestinal bacterial overgrowth in children with irritable bowel syndrome. Eur Rev Med Pharmacol Sci
96. Omoike IU, Abiodun PO. Upper small intestinal micromicrobiota in diarrhea and malnutrition in Nigerian children. J Pediatr Gastroenterol Nutr
97. Khin-Maung U, Bolin TD, Duncombe VM, et al. Epidemiology of small bowel bacterial overgrowth and rice carbohydrate malabsorption in Burmese (Myanmar) village children. Am J Trop Med Hyg
98. Ramotar K, Conly JM, Chubb H, et al. Production of menaquinones by intestinal anaerobes. J Infect Dis
99. Brandt LJ, Bernstein LH, Wagle A. Production of vitamin B 12 analogues in patients with small-bowel bacterial overgrowth. Ann Intern Med
100. Parlesak A, Klein B, Schecher K, et al. Prevalence of small bowel bacterial overgrowth and its association with nutrition intake in nonhospitalized older adults. J Am Geriatr Soc
101. Riordan SM, McIver CJ, Thomas DH, et al. Luminal bacteria and small intestinal permeability. Scand J Gastroenterol
102. Miele L, Valenza V, La Torre G, et al. Increased intestinal permeability and tight junction alterations in nonalcoholic fatty liver disease. Hepatology
103. Campbell DI, Elia M, Lunn PG. Growth faltering in rural Gambian infants is associated with impaired small intestinal barrier function, leading to endotoxemia and systemic inflammation. J Nutr
104. Goto R, Mascie-Taylor CG, Lunn PG. Impact of intestinal permeability, inflammation status and parasitic infections on infant growth faltering in rural Bangladesh. Br J Nutr
105. Lunn PG, Northrop-Clewes CA, Downes RM. Intestinal permeability, mucosal injury, and growth faltering in Gambian infants. Lancet
106. Nieuwenhuijs VB, van Dijk JE, Gooszen HG, et al. Obstructive jaundice, bacterial translocation and interdigestive small-bowel motility in rats. Digestion
107. Reddy BS, MacFie J, Gatt M, et al. Commensal bacteria do translocate across the intestinal barrier in surgical patients. Clin Nutr
108. Laughlin RS, Musch MW, Hollbrook CJ, et al. The key role of Pseudomonas aeruginosa PA-I lectin on experimental gut-derived sepsis. Ann Surg
109. Alverdy J, Holbrook C, Rocha F, et al. Gut-derived sepsis occurs when the right pathogen with the right virulence genes meets the right host: evidence for in vivo virulence expression in Pseudomonas aeruginosa. Ann Surg
110. van Saene HK, Taylor N, Donnell SC, et al. Gut overgrowth with abnormal microbiota: the missing link in parenteral nutrition-related sepsis in surgical neonates. Eur J Clin Nutr
111. Tursi A. GI motility disturbances in celiac disease. J Clin Gastroenterol
112. Sadik R, Abrahamsson H, Kilander A, et al. Gut transit in celiac disease: delay of small bowel transit and acceleration after dietary treatment. Am J Gastroenterol
113. Bouhnik Y, Alain S, Attar A, et al. Bacterial populations contaminating the upper gut in patients with small intestinal bacterial overgrowth syndrome. Am J Gastroenterol
114. Attar A, Flourié B, Rambaud JC, et al. Antibiotic efficacy in small intestinal bacterial overgrowth-related chronic diarrhea: a crossover, randomized trial. Gastroenterology
115. Soifer LO, Peralta D, Dima G, et al. Comparative clinical efficacy of a probiotic vs. an antibiotic in the treatment of patients with intestinal bacterial overgrowth and chronic abdominal functional distension: a pilot study. Acta Gastroenterol Latinoam
116. Tahan S, Melli LC, Mello CS, et al. Effectiveness of trimethoprim-sulfamethoxazole and metronidazole in the treatment of small intestinal bacterial overgrowth in children living in a slum. J Pediatr Gastroenterol Nutr
117. Lauritano EC, Gabrielli M, Lupascu A, et al. .Rifaximin dose-finding study for the treatment of small intestinal bacterial overgrowth. Aliment Pharmacol Ther
118. Majewski M, Reddymasu SC, Sostarich S, et al. Efficacy of rifaximin, a nonabsorbed oral antibiotic, in the treatment of small intestinal bacterial overgrowth. Am J Med Sci
119. Collins BS, Lin HC. Double-blind, placebo-controlled antibiotic treatment study of small intestinal bacterial overgrowth in children with chronic abdominal pain. J Pediatr Gastroenterol Nutr
120. Shah SC, Day LW, Somsouk M, et al. Meta-analysis: antibiotic therapy for small intestinal bacterial overgrowth. Aliment Pharmacol Ther
121. Hawrelak JA, Myers SP. The causes of intestinal dysbiosis: a review. Altern Med Rev
122. Sullivan A, Edlund C, Nord CE. Effect of antimicrobial agents on the ecological balance of human micromicrobiota. Lancet Infect Dis
123. Gabrielli M, Lauritano EC, Scarpellini E, et al. Bacillus clausii
as a treatment of small intestinal bacterial overgrowth. Am J Gastroenterol
124. Khalighi AR, Khalighi MR, Behdani R, et al. Evaluating the efficacy of probiotic on treatment in patients with small intestinal bacterial overgrowth (SIBO)—a pilot study. Indian J Med Res
125. Rosania R, Giorgio F, Principi M, et al. Effect of probiotic or prebiotic supplementation on antibiotic therapy in the small intestinal bacterial overgrowth: a comparative evaluation. Curr Clin Pharmacol
126. Stotzer PO, Blomberg L, Conway PL, et al. Probiotic treatment of small intestinal bacterial overgrowth by Lactobacillus fermentum
KLD. Scand J Infect Dis
127. Gaon D, Garmendia C, Murrielo NO, et al. Effect of Lactobacillus
strains (L. casei
and L. acidophillus
Strains cerela) on bacterial overgrowth-related chronic diarrhea. Medicina (B Aires)