Quantifiable definitions of small bowel bacterial overgrowth (SBBO) have been proposed with the definition being based on increased numbers of bacteria in addition to specific types of bacteria, generally coliform bacteria . Proposed numbers of bacteria range from greater than 10³–10⁵ colony-forming units of bacteria per milliliter of luminal fluid of colonic-type bacteria present in the proximal bowel. There are however many GI conditions and symptoms which have been reported at lower levels of bacteria [15, 16]. Previous culture techniques have not identified the true diversity of the intestinal contents that are now being discovered with current molecular DNA processes. Therefore, basing the definition on types of bacteria may not be completely accurate. In a more pathophysiological view, a definition of bacterial overgrowth should include not only the numbers and types of microorganisms present but also evidence that these two factors create pathological signs or symptoms.

The true prevalence of bacterial overgrowth is not known due to the lack of a uniform definition and imprecise diagnostic testing. Studies in the general population are lacking, and in those GI symptoms the likelihood is that prevalence would be overestimated if based on noninvasive methods such as breath testing . Estimates have ranged from 0 to 20 % of the general population who have SBBO when based on the actual numbers of bacteria [17]. SBBO may exist with greater prevalence in certain acquired conditions, for example, it occurs with intestinal dilatation in patients with short bowel syndrome (SBS) . The prevalence of bacterial overgrowth due to unusual intestinal colonization during the first year of life, however, is likely much lower.

Other factors predisposing to SBBO include achlorhydria and old age. Drug-induced hypochlorhydria may result in higher bacterial duodenal counts, especially in the elderly following long-term use [18]. In both adults and children, acid suppression may contribute to the presence of bacterial overgrowth [19–21] although this finding is not consistently seen and may be dependent upon the diagnostic method [22]. It has been estimated that proton pump inhibitors can increase the gastric pH to the point of significantly increasing the colonization of the stomach with gram-positive bacteria and potentially increasing colonization with Helicobacter pylori if present [23]. Diabetics more commonly have overgrowth, especially in adulthood [24]. Chronically immunosuppressed patients or patients with HIV may also have an increased incidence of SBBO [25]. Bacterial overgrowth has been reported in children with immunoglobulin A (IgA) deficiency [16, 26]. Patients with small bowel inflammatory diseases such as celiac disease may also have elevated bacterial counts as may patients with pancreatic insufficiency [27, 28]. Autoimmune diseases including scleroderma and rheumatoid arthritis have been associated with increased overgrowth [29].

A primary association with SBBO is a failure of small-bowel clearance due to various motility disorders. Patients with pseudo-obstruction syndrome, muscular dystrophy, diabetic neuropathy, and other disorders affecting gut motility typically experience symptoms due to increased small bowel bacterial counts particularly with coliform bacteria [15, 24]. Likewise, stricture formation with chronic dilatation is usually associated with overgrowth. This may be seen in Crohn’s disease, radiation enteritis, or children with congenital anomalies such as intestinal atresia who have postoperative strictures with some degree of dysmotility [30, 31].

Patients with SBS are characteristically troubled with bacterial overgrowth in the small intestine. Here, the reasons are multifactorial. Patients with SBS often have compensatory dilatation of the small intestine with poor motility. As peristalsis normally rids the small bowel of excessive bacteria, small-bowel dilatation with its associated impairment of normal antegrade peristalsis is a perfect setup for overgrowth. The presence of postoperative strictures may also play a role. Finally, the absence of the ileocecal valve, which functions to prevent reflux of colonic bacteria into the small intestine, further exacerbates the problem. Because of poor gastric emptying and reflux, patients with SBS are also frequently on chronic acid suppression which in many situations promote overgrowth [19, 32]. Table 42.1 lists commonly associated conditions which have been attributed to bacterial overgrowth.

In the stomach, gastric acidity and normal emptying tend to limit microbial growth. Once in the duodenum, the bile salts provide an unfavorable environment for microorganism proliferation. A prominent gut immunoglobulin, IgA typically can recognize and bind with microbes preventing mucosal penetration, it enhances clearance via peristalsis [33] and may have a more specific role in managing the overall amount and types of microbes in the upper small intestine [34]. The body’s natural production of antimicrobial compounds such as defensins has varying abilities to limit or alter the intestinal milieu. The large intestine has a much more favorable environment for microorganisms due to its higher pH, lower level of bile salts, and slower peristalsis. The substantially higher numbers of microbes in the large intestine provide short-chain fatty acids through the fermentation of any dietary components that are not utilized in the small intestine. These short-chain fatty acids, particularly butyrate, provide the primary fuel for the enterocytes in the large intestine. There are small numbers of protozoans and fungi also present in the large intestine [34]. Predominant bacterial populations also act as hosts to a variety of viruses which have an unidentified role in intestinal function [35].

The clinical manifestations of bacterial overgrowth are quite variable because validated symptom questionnaires do not exist. Symptoms range from very mild to severe. Most commonly, patients experience diarrhea, bloating, and abdominal pain as predominate features. Recently, it has been hypothesized that bacterial overgrowth may mimic the symptoms of irritable bowel syndrome [36, 37] . In these instances, abdominal distention, increased flatus, diarrhea, and even fecal urgency have responded to antibiotic therapy [38–40]. More severe symptoms consistent with malabsorption syndrome, such as weight loss, dehydration, and nutrient deficiencies, have also been reported. See Table 42.2.

Small-bowel bacterial overgrowth is associated with a combination of megaloblastic anemia due to vitamin B12 deficiency and fat-soluble vitamin deficiency due to fat malabsorption [15, 41]. Anaerobic bacteria use vitamin B12 to produce inactive compounds which may compete with vitamin B12 for ileal binding sites, decreasing absorption of the vitamin. Other vitamin deficiencies including thiamine have also been associated with SBBO [42]. Fat-soluble vitamin deficiencies including vitamins A, E, and D are commonly reported. These deficiencies are manifested in night blindness and osteopenia or osteoporosis as evidenced by decreased bone mineral density exist [43, 44]. Vitamin K deficiency is infrequent because of increased luminal production of vitamin K by bacteria. Deconjugation of bile salts by increased intestinal bacteria impairs bile acid reabsorption depleting the bile acid pool and decreasing the intraluminal conjugated bile acids further exacerbating fat and fat-soluble vitamin malabsorption. Bile acids are typically absorbed in the jejunum; however, if they reach that ileum and colon, they may also damage the intestinal mucosa leading to increased diarrhea and malabsorption [45].

Intestinal bacteria may deaminate dietary protein that is malabsorbed and create a situation in which dietary nitrogen is converted to urea and is unavailable for absorption [46]. Low levels of enterokinase may impair activation of pancreatic proteases and thereby reduce protein absorption [47]. Carbohydrate degradation by intestinal bacteria also increases malabsorption, and these malabsorbed carbohydrate by-products significantly contribute to the symptomatology of bloating, cramps, and diarrhea [48]. Neurological symptoms including central or peripheral neuropathy and symptoms of anemia including fatigue may predominate the clinical picture. There is some evidence to suggest that SBBO may be a contributory factor in nonalcoholic steatohepatitis (NASH) [49]. Endogenous ethanol production has also been reported with bacterial overgrowth in association with overgrowth of Candida albicans and Saccharomyces cerevisiae [50].

In children, abdominal pain , bloating, and diarrhea are more typical symptoms, especially when an underlying disorder is present. Anemia and evidence of gut inflammation including occult-blood-positive stools, and elevated fecal calprotectin levels may be seen in both adults and children [51, 52]. Systemic inflammatory changes including arthritis may occur. Poor weight gain and decreased appetite are not uncommon. In children, D-lactic acidosis may be a clinical presentation of SBBO [53]. Patients with this disorder develop higher levels of the lactate in the blood because some bacteria produce both D and L stereoisomers of lactate, but only the L form is metabolized well by the human liver. D-lactate accumulates in the blood stream resulting in a variety of neurological symptoms varying from poor school performance to coma. Elevated levels of serum D-lactate and rapid response to oral antibiotic therapy confirm the diagnosis. This disorder appears to be quite uncommon in adults.

Histologically, overgrowth is not uncommonly associated with inflammatory changes in the mucosa [54]. Consequently, reduced brush border disaccharidase levels may result in carbohydrate malabsorption , especially lactose malabsorption. Impaired protein absorption and protein-losing enteropathy may also result. A number of changes in the mucosa have been demonstrated not only by light microscopy but also by electron microscopy, which have identified numerous enterocyte abnormalities including microvillus injury [55].

The diagnosis of SBBO should be considered in patients with any of the symptoms and findings discussed above particularly when associated with an underlying disease process predisposing the patient to overgrowth. Small-bowel imaging may be helpful in the diagnosis of bacterial overgrowth by identifying areas of bowel dilatation and/or stricture formation which may be the causative factors. This is particularly indicated in conditions where there is a history of intestinal resection.

Aspiration of small intestinal fluid contents for quantitative culture was previously considered the gold standard for diagnosis [17, 56]. Normal values may vary significantly based upon the anatomic location of small bowel aspirate as well as the geographic location of the patient. Tropical patients may have normal values as high as 10⁷ microorganisms per milliliter of fluid, whereas 10⁴ may be normal in more temperate regions. Even within the same GI disease, such as ulcerative colitis, the intestinal bacteria differ depending on the geographic location of the patient [57].

Aspiration of duodenal versus jejunal fluid will result in different types and species of bacteria. Aspirates from above and below a stricture may also differ. Care must be taken to avoid contamination of the sample with oropharyngeal bacteria, and a number of different techniques have been described [58]. Likewise, appropriate handling of the specimen is very important. Culture of anaerobic bacteria is challenging. Prior to collecting the sample, it is a good idea to have a discussion with the culturing laboratory to make sure the specimen is handled appropriately. Regardless of the culturing techniques, it is estimated that a great majority of the intestinal microbiota is missed as compared with genomic or DNA sequence-based methods [34] .

Significant inflammatory changes may be seen both endoscopically and histologically in patients with severe overgrowth. Occasionally, such changes may be difficult to differentiate from Crohn’s disease unless granulomas are present. A typical example of such changes is pouchitis seen after resection for ulcerative colitis. Diffuse nonspecific inflammatory changes occasionally with ulceration can be visualized. Patients with SBS and significant bowel dilatation with poor motility will commonly have similar findings when overgrowth is present. Unfortunately, the chronic inflammatory changes seen histologically are nonspecific, and their use for diagnostic purposes must be considered in clinical context and with other associated laboratory findings.

A number of tests have been devised to predict SBBO noninvasively. Perhaps the most widely used due to the ease and lack of expense is breath hydrogen testing using either glucose of lactulose. These tests are based on the premise that small-bowel bacteria will metabolize the ingested carbohydrate into carbon dioxide and hydrogen or methane gas. Glucose is rapidly and completely absorbed in the small intestine; therefore, an early rise fasting breath hydrogen levels of more than 20 ppm above baseline following an oral load of glucose is considered consistent with the diagnosis of bacterial overgrowth [17, 56]. Glucose is an ideal substrate because it is rapidly absorbed in the small bowel and consequently is not subject to bacterial metabolism in the colon. It is less predictive of ileal bacterial overgrowth for this reason, and likewise can be falsely elevated in patients with SBS who have an extremely short bowel or rapid transit. Patients with chronic overgrowth may have elevated fasting breath hydrogen levels. Lactulose is primarily metabolized in the colon, typically 90 min after ingestion; however, in bacterial overgrowth, there will be an early peak of hydrogen production followed by a later peak when it reaches the colon .

If overgrowth is not associated with large numbers of hydrogen-producing organisms, the breath hydrogen test may not be valid. ¹⁴C-xylose- and ¹³C-xylose-labeled breath tests have also been utilized but are less commonly available. It has been estimated that approximately 10–20 % of humans do not have detectable hydrogen production from their GI flora. Some bacteria such as enterococci, Staphylococcus aureus, and Pseudomonas do not produce hydrogen when metabolized but do produce methane gas [59]. A combination of breath hydrogen and breath methane testing may offer considerable improvement in the diagnosis of bacterial overgrowth [60].

Other screening tests such as serum D-lactate levels may occasionally be helpful if they are elevated. However, care must be taken to make certain that the blood test is ordered correctly and the laboratory knows exactly what is desired, that is, doing a D-lactate level and not a lactic acid. Urine indican is an indicator of the intestinal overgrowth of anaerobic bacteria. Indican is an indole produced when bacteria in the intestine act on tryptophan. Most indoles are excreted in the feces. The remainder are absorbed, metabolized by the liver, and excreted in the urine. Consequently, excessive bacterial activity on protein in the small bowel will result in excessive indican excretion in the urine.

An empiric trial of antibiotics in patients with symptoms suggestive of bacterial overgrowth may be used diagnostically. Measurement of symptom response of course is hindered by a lack of a validated assessment tool as previously mentioned. However, given the lack of standardized diagnostic testing, short courses of broad-spectrum antibiotics may be the simplest and least expensive method to establish a diagnosis. Future diagnostic testing may include metabolic profiling of the metabolome, the use of electronic nose, and/or field asymmetric ion mobility spectrometry which detects volatile organic compounds from intestinal gases [17] .

If there is an identifiable structural or functional condition amenable to surgical treatment, then that should be corrected as the first option. Procedures to correct strictures or areas of small bowel dilatation are usually amenable to either endoscopic or surgical revision. Serial transverse tapering enteroplasty is a procedure which lengthens the dilated bowel by stapling it in a zigzag pattern and is particularly efficacious in children whose intestine dilates in the process of adaptation after a major resection [61, 62]. This procedure may add additional more functional intestinal surface as well. Motility disorders may be amenable to therapy with pro-motility agent such as an erythromycin, metoclopramide, cisapride, or domperidone.

Medical treatment of SBBO typically starts with antibiotic therapy [63]. A variety of strategies may be employed. Accurately obtained cultures may reveal a dominant organism and specific sensitivities may be helpful. However, due to the limitations of qualitative and quantitative sampling, empiric trials are typically used to direct therapy. Antibiotic choice generally involves therapy directed at both aerobic and anaerobic organisms. There is no agreement on a standard dosage or duration of treatment. Antibiotics may be given the first 5–7 days of each month, continued for 1 week every other week, or given continuously and rotated depending upon the clinical situation. It is important to remember that the intention is not to sterilize the gut, but simply reduce the enteric population enough to alleviate the symptoms and clear up any inflammatory process. Antibiotic therapy should be individualized and consideration should be given to the high prevalence of the development of bacterial resistance, the cost of treatment, and potential side effects from long-term usage. A list of antibiotics is shown in the Table 42.3.