Fructose is a monosaccharide commonly found in fruits and as a sweetener. Fructose is found either as a monosaccharide or as a part of the disaccharide sucrose molecule. The average daily consumption in diet is 11–54g [6]. The normal human fructose absorption capacity is limited—up to 25g. It’s usually dependent on other absorbed nutrients and other yet unknown factors [15, 16]. Fructose absorption along the small bowel is in a passive diffusion, facilitated by glucose transport protein 5 (GLUT5, Slc2a5) which is the main apical fructose transporter, while GLUT2 (Slc2a2) plays a facilitative and inducible role. The gene encoding for GLUT5 has been isolated on the short arm of chromosome 1 [17]. In contrast to lactose, malabsorption of fructose decreases with age. In human adults, small intestinal tissue GLUT5 expression is greater than in fetal tissue [18]. Glucose stimulates fructose uptake in a dose-dependent manner. The greatest effect was seen when equivalent amounts of fructose and glucose were used. The absorption capacity of fructose was much higher when given as sucrose [19].

GLUT5 is responsible for the majority of luminal fructose uptake, with GLUT2 becoming relevant only when high doses of fructose are ingested [20, 21]. GLUT2 expression may be susceptible to stress as well as to corticosteroids, a factor that is relevant in IBS patients. In fact, most people consume less than 8gr of fructose as fruits or soft drinks. Only few types of chocolates, caramel, and pralines contain up to 40 g per 100 g of food. So, the 25–50 g fructose test, which is supra-physiologic dose, may not reflect a true intolerance. As most people complaining of fructose intolerance do not have defect of the gene that encodes the luminal fructose transporter (GLUT5), other mechanisms such as the coexistence of IBS or abnormal colonic bacterial activity should be considered [22, 23]. Fructose and glucose content of different foods is given in Table 32.2.

Sorbitol is a sugar alcohol that is found in fruits and is also used as an artificial sweetener. Sorbitol is not completely absorbed in the small bowel. Positive breath test can be reached in dose as low as 5gr, mild symptoms in 10gr, and severe symptoms in 20gr (abdominal pain and diarrhea). Fructose absorption may be impeded when given together with sorbitol. Worsening of IBS symptoms after giving a combination of fructose-sorbitol is still controversial [8, 24].

The normal human gut microflora is a very complex ecosystem, comprising at least 400 different species. As the small intestine is the major organ for digesting and absorbing food, it should be devoid of bacteria, potentially competing on these nutrients and potentially penetrating the permeable small bowel mucosa. The definition of SIBO depends on the concentration of bacteria in certain anatomical locations along the small bowel. The most accepted definition is >10⁵ colony forming units (CFU) in the jejunum; however, other reports are in favor of concentrations >10³ CFU [25]. Mucosal injury induced by bacteria or their toxins could bring a brush border enzyme loss, injury to epithelium leading to increase mucosal permeability and inflammatory response leading to cytokine secretion. Intraluminal bacteria may compete over nutrients and potentially cause malnutrition and vitamin deficiencies. Bacterial metabolism could cause liver injury, creation of toxic metabolites, and symptoms compatible with functional gastrointestinal disorders (such as bloating, distension, flatulence, and diarrhea).

The most important defensive factors against the development of SIBO are gastric acid and intestinal motor activity. Gastric acid destroys most of the bacteria entering the stomach, thus preventing the development of SIBO. Small intestinal motor activity, especially phase III of the inter-digestive migrating motor complex (MMC III, “house keeper”), limit the colonizing ability of bacteria [26]. Other protective factors are the integrity of the intestinal mucosa, including its protective mucus layer and intrinsic antibacterial mechanisms (e.g., defensins, immunoglobulins); the enzymatic activities and bacteriostatic properties of intestinal, pancreatic, and biliary secretions; the protective effects of the commensal flora; and the mechanical and physiologic properties of the ileocecal valve [27].

Motility disorders are especially common in patients with type 1 diabetes (diabetic autonomic neuropathy) [28], scleroderma (52–73%) [29, 30], and intestinal pseudo-obstruction [31]. In old age patients, motility disorders are probably the major cause of development of SIBO [32]. Recent study found that prolonged small bowel transit time was more common in patients with typical complaints and positive lactulose breath test. This was demonstrated using the wireless motility capsule. In this study, colonic transit and whole gut transit were prolonged. However, gastric emptying was normal [33].

Anatomical defects include small intestinal diverticulosis (especially jejunal diverticula) [31]. Postoperative changes include gastrectomy [34, 35] which may cause hypochlorhydria or achlorhydria (pending on the extent of resection), secondary changes in motility, creation of blind loops and diverticula. Intestinal strictures, fistulae, and anastomosis may cause stagnation of intestinal content, thus enhancing bacterial flourishing. Hypochlorhydria has been associated with the extensive worldwide use of proton pump inhibitors (PPIs) [32]. A meta-analysis revealed a pooled odds ratio of 2.82 for SIBO among PPI users. This was proved only in studies using small intestinal aspirates and not breath tests [36]. This cause is still controversial as few reports failed to establish this association [37]. SIBO has been described in patient suffering from immunodeficiencies such as hypogammaglobulinemia as well as HIV [38]. SIBO has been linked to other conditions (e.g., Parkinson’s disease, esophagitis, rosacea, and obesity), however, the most controversial is it’s relation to IBS. Pimental et al. reported a 84% prevalence of SIBO among IBS patients using lactulose breath test in diagnosis [39, 40]. Other studies using lactulose report figures ranging between 34 and 84% [41, 42]. Studies using glucose breath test report a much lower percentage of 6–16% [43, 44].

A detailed medical history, dietary and lifestyle assessment, followed by clinical investigations in accordance with national guidelines should be committed. Investigations may include blood and fecal tests, endoscopy, and radiological imaging to rule out any organic disease. In the absence of organic disease, patients will often be diagnosed with a functional gastrointestinal disorder [45]. However, there are a few clinically useful tests in the identification of specific carbohydrate intolerance.

Exclusion diets to achieve symptom improvement followed by gradual food reintroduction to identify tolerance can be the first diagnostic modality for carbohydrate malabsorption. In patients suspected of having IBS , an exclusion diet avoiding several dietary components might be required. Low short chain fermentable carbohydrates (low FODMAP) diet is considered the most successful of the exclusion diets for IBS, with expected resolution of symptoms within 3–4 weeks of dietary change [45]. However, this is a very restrictive diet, difficult to follow for long periods of time.

Hydrogen and/or methane breath testing are useful, noninvasive measurements to assess carbohydrate malabsorption in the gastrointestinal tract. In these tests, a measured amount of lactose or fructose is given to the patient. The unabsorbed carbohydrate is metabolized by the gastrointestinal microbiota producing hydrogen or methane which is absorbed into the bloodstream and expired via the lungs.

Lactulose , a nonabsorbable synthetic disaccharide of fructose and galactose, is used for SIBO diagnosis, as this carbohydrate is metabolized solely by the microbiota, a high hydrogen/methane reading of the test is diagnostic for SIBO.

The test protocols vary highly; strict breath test protocols require 14-day abstinence from antibiotics, colonoscopy preparations, laxatives, or probiotics. A diet low in fermentable carbohydrates 48 hours prior to each breath test and an overnight fast prior to commencement of the test is advised. Some protocols require brushing the teeth and use of an antiseptic mouthwash prior to testing to ensure that oropharyngeal fermentation is not contributing to measurements.

The most common protocols for lactose / fructose / sorbitol entails drinking 25-100 g of the investigated carbohydrate, taking a baseline sample and thereafter exhaling into a tube every 15 min up to 3 h. A deviation of >20 ppm (part per million) over baseline reading is a marker of a positive test.