Small intestinal bacterial and fungal overgrowth

Chapter 24

Small intestinal bacterial and fungal overgrowth Jigar Bhagatwalaa, Satish S.C. Raob a

Division of Gastroenterology/Hepatology, Medical College of Georgia, Augusta University, Augusta, GA, United States, bDigestive Health Clinical Research Center, Augusta University, Augusta, GA, United States

Key Points ●

● ●

●

Small Intestinal Bacterial (SIBO) and Fungal overgrowth (SIFO) are common gastrointestinal problems that present with unexplained gas, bloating, abdominal discomfort, constipation or diarrhea and are poorly recognized. When routine endoscopy, stool and imaging tests are negative a diagnosis of SIBO and/or SIFO should be considered. Glucose and Lactulose breath tests have been widely used for diagnosis and are helpful. It is important to assess for both hydrogen and methane gas in breath samples. Duodenal aspirate/culture is the gold standard with a cutoff of 103cfu/mL. If possible predisposing factors should be identified and eliminated. Treatment involves broad spectrum antibiotics or antifungals and are usually effective.

Small intestinal bacterial overgrowth Introduction, definition and epidemiology Over a century ago, Faber described the first report on the consequences of bacterial overgrowth in the human intestine from a patient with small bowel strictures. [1] Since then our knowledge of microbial dysbiosis has exploded. In the last few decades, both advances in diagnosis and improved understanding of gut microbiota and host-bacteria interactions have significantly contributed further to this new knowledge. Small intestinal bacterial overgrowth (SIBO) is defined as the presence of abnormally high amounts of bacteria in the small intestine together with a variety of symptoms including but not limited to bloating, flatulence, abdominal pain, nausea, dyspepsia, fatigue, diarrhea, and constipation [2, 3]. Unexplained abdominal pain, diarrhea, fullness, bloating, nausea, vomiting, heartburn and dyspepsia are reported by up to 40% of patients seen in primary care and in gastroenterology clinics [4–6]. The prevalence of SIBO in the general population is unknown because it requires diagnostic testing, but in patients presenting with GI symptoms, it can be up to 40%. [7, 8] Because symptoms are non-diagnostic, and routine diagnostic and imaging studies are normal, physicians should routinely consider a diagnosis of SIBO in the differential diagnosis of unexplained gastrointestinal symptoms.

Etiopathophysiology of SIBO and related conditions (Table 1) The GI tract harbors the largest microbial population in the human body, with over 35 trillion bacteria [45, 46]. The largest of this colonization is believed to be in the colon with relative absence of bacteria in the upper GI tract of healthy individuals. Stomach, due to its high acidic environment has virtually no bacteria, whereas the active motility and secretions in the small intestine and rapid transit of chyme through its 19 ft prevent overgrowth in this segment. However, there are small numbers of bacteria whose concentration increases progressively within the small intestine [9, 10]. The ileocolonic valve acts as a mechanical barrier preventing retrograde translocation of the bacteria from colon [11, 12]. Several studies have elucidated association between potential underlying etiology with development of SIBO including but not limited to the abnormalities in anatomy, motility, pH, medications and immune function. However, often there is overlap of more than one etiology that could predispose an individual to the development of SIBO.

Clinical and Basic Neurogastroenterology and Motility. https://doi.org/10.1016/B978-0-12-813037-7.00024-8 © 2020 Elsevier Inc. All rights reserved.

343

344  SECTION | B  Clinical approaches to neurogastroenterology

TABLE 1  Risk factors and conditions related to SIBO [9–44] Gut anatomy

Post-surgical changes - Roux En Y surgery - Ileocecal valve resection - Biliopancreatic bypass or duodenal switch Intra-abdominal adhesions Chronic pseudo obstruction Post-operative or radiation strictures Duodenal or jejunal diverticulosis Fistula formation

Gut dysmotility

Delayed small bowel transit Parkinson's disease Diabetes Systemic sclerosis and scleroderma Hypothyroidism Amyloidosis Advanced age

Reduction in luminal pH

Partial gastrectomy Achlorhydria Autoimmune gastritis Atrophic gastritis

Immune and inflammatory diseases

Celiac disease IgA deficiency Acquired immune deficiency syndromes Crohn’s disease Radiation enteritis

Medications

Proton-pump inhibitors Anti-diarrheals Anti-cholinergic Narcotics Calcium channel blockers

Miscellaneous

Irritable bowel syndrome Obesity Female gender Chronic renal failure Chronic pancreatitis Cirrhosis Alcoholism Cystic fibrosis Fibromyalgia Multiple sclerosis Autism spectrum diseases Excess probiotic use

Gut anatomy and motility Small bowel has inherent cleansing function with recurring antegrade peristalsis and migratory motor complexes organized into three phases of which the phase III MMC is an intense phasic and tonic contractile event that begins in the stomach or proximal bowel and sweeps through towards the colon, propelling chime, and secretions and bacteria and offering a natural protection against SIBO [13, 14]. This organized bio-protective mechanism may be disturbed by disorders of dysmotility including neuropathy or myopathy (example scleroderma, diabetes) or from medications such as opioids, anti-diarrheals or anticholinergics can reduce propulsive movements favoring overgrowth of organisms. Likewise, post-surgical changes such as gastrojejunostomy with a blind loop, injury to vagus nerve, strictures or adhesions causing partial or fixed obstruction and stagnation of the digestive content in the small bowel, may each provide an opportunity for bacterial overgrowth. Colectomy either partial or complete, and especially with a loss of ileocecal valve will allow retrograde movement of ­colonic contents resulting in small bowel colonization of bacteria [15]. Studies in patients with anatomical risk factors



Small intestinal bacterial and fungal overgrowth Chapter | 24  345

from intrinsic causes such as small bowel diverticulosis or fistula formation or iatrogenic consequences such as post Rouxen-Y, ileocolonic anastomosis or post-radiation stricture/adhesion formation have all shown a higher prevalence of SIBO. [7, 15–21] Advanced age and female gender are associated with higher likelihood of developing SIBO perhaps due to delays in gut transit [22, 23]. Other systemic diseases known to alter motility are associated with SIBO which includes Parkinson's disease, chronic renal failure, amyloidosis, systemic sclerosis, hypothyroidism, and diabetes mellitus [24–28].

Gastric acidity and proton pump inhibitors Gastric acidity plays an important role as gatekeeper to prevent overgrowth of bacterial organisms in the upper GI tract. Patients with hypo- or achlorhydria, secondary to autoimmune gastritis, partial or total gastrectomy are at increased risk for SIBO. [31–33] Proton pump inhibitors (PPIs) are one of the commonest used medications in patients suffering from unexplained GI symptoms. Spiegel and colleagues first described the association between PPI use and SIBO. [32] With few exceptions, majority of studies, including ours have shown a higher risk for PPI users to develop SIBO. [21, 33–36] For example, a retrospective study that included data from 1263 duodenal aspirates noted that PPI use had significantly greater prevalence of patients with positive duodenal culture results compared with negative cultures (52.6% vs 30.2%) [33]. Similarly, a meta-analysis of 19 studies in over 7000 subjects confirmed up to threefold higher risk of SIBO with PPI use [36]. In a study by Compare and colleagues, 42 patients with non-erosive esophagitis were given 8 weeks of PPI therapy. All patient had negative glucose hydrogen breath test prior to PPI use. On follow up, 26% of the patients tested positive for SIBO with breath test and reported significantly higher bloating, flatulence, abdominal pain and diarrhea. [37].

Immune function and inflammation Evidence supports association between SIBO and various immunodeficiency syndromes, such as IgA deficiency and common variable immunodeficiency [38–41]. Patients with celiac disease [42, 43], and inflammatory bowel disease also have approximately 20% prevalence of SIBO compared 1–2% in healthy controls [44].

Other conditions Several other conditions have been associated with SIBO such as cirrhosis and spontaneous bacterial peritonitis [47], chronic pancreatitis [48], cystic fibrosis [49], irritable bowel syndrome (IBS) [50], fibromyalgia [51], alcoholism [52], multiple sclerosis [53] and autism spectrum diseases [54], but the potential mechanism(s) underlying this relationship remains unclear.

Consequences of SIBO Bacterial overgrowth in the small intestine has significant consequences including multiple gastrointestinal symptoms, malabsorption, vitamin deficiencies and rarely brain fogginess and d-lactic acidosis. Typically, colonic type aerobic and anerobic organisms [55], mainly Escherichia coli, Enterococcus spp., Klebsiella pneumonia, Proteus mirabilis, and Staphylococcus sp., Clostridia sp., Neisseria sp. and Streptococcus sp. are usually found, however others such as Diphtherioids, Lactobacilli, Bacterioids, Prevotella sp., Rothia sp. are also found [21, 56] These bacteria now in the wrong place have the ability to prematurely ferment carbohydrates consumed in diet and in turn produce short-chain organic acids and gas as well as increase osmolarity of the intestinal fluid. These events cause gas, bloating and diarrhea. Furthermore, these byproducts can damage the intestinal brush border and reduce the disaccharidases, causing malabsorption of commonly consumed carbohydrates and further worsen osmosis [57]. SIBO also leads to fat malabsorption and diarrhea by deconjugation of bile salts from free bile acids which in turn impairs micelle formation and leads to impaired fat absorption, ultimately leading to secretory diarrhea and steatorrhea. The free bile acids formed in this reaction leads to toxic injury to mucosa [58]. Fat malabsorption due to SIBO could lead to deficiencies in fat soluble vitamins of A, D and E with relative sparing of vitamin K which is produced by the bacterial metabolism. Another more severe down-stream effects of SIBO is Vitamin B12 deficiency. Gram-negative bacteria compete to utilize B12 and make it unavailable to host for absorption. Several bacteria generate B12 but is retained within the bacteria cells and not freely available for absorption. Thus, a large quantity of B12 is available in the lumen but not absorbed in the gut [59]. On the other hand, folate is generated by bacterial metabolism and is absorbed in abundance by the host. A high folate to B12 ratio is seen in patients with SIBO. A methane producing Archaea increases gut methane production and reduces gut transit [60, 61] which can further increase stasis and promote SIBO. Recently, d-lactic acid production from bacterial metabolism in the human gut has been associated with metabolic changes and brain fogginess, especially in patients taking probiotics. In a study by Rao and colleagues, patients who presented with brain fogginess, abdominal pain, gas and bloating demonstrated high prevalence of SIBO, probiotic use and d-lactic acidosis [62].

346  SECTION | B  Clinical approaches to neurogastroenterology

Clinical manifestations of SIBO Abdominal pain, bloating, gas, distension, flatulence, and diarrhea are the most common symptoms described in patients with SIBO, and prevalent in over 2/3rds of patients [21, 63, 64]. In severe cases, nutritional deficiencies including vitamin B12, vitamin D, and iron can occur, although in most it is more subtle and may not be detectable. Some patients may also manifest fatigue, poor concentration and brain-fog. However, no single symptom can be specifically attributed to SIBO and symptoms often masquerade as other diagnoses such as IBS or functional dyspepsia or bloating. This in part is due to varied presentation of patients with SIBO and the underlying risk factors leading to development of SIBO. For example, in patient with chronic pancreatitis, it is difficult to assess whether diarrhea is from exocrine insufficiency or from co-existent SIBO and to what degree symptoms can be related to SIBO versus chronic pancreatitis. Similarly, in patients with Crohn’s disease needing ileocecal valve resection, symptoms of abdominal pain, boating and diarrhea could be from SIBO or from active inflammation, bile acid malabsorption or post-operative strictures. Indeed, several studies have attempted to assess this in systematic manner. Jacobs et al. compared 38 subjects with SIBO to 74 subjects without SIBO based on aerobic and anerobic small bowel aspiration and culture (one of the diagnostic tests discussed below) and reported no difference in the intensity, frequency, and duration of abdominal pain, bloating, fullness, belching, indigestion, nausea, vomiting diarrhea, and gas [21]. Therefore, close attention to patient’s symptom profile, risk factors for SIBO, and history of prior attempts at treating other underlying condition should be evaluated to help understand possibility of untreated SIBO in patient presenting with unexplained abdominal pain, gas, bloating, and diarrhea or malabsorptive symptoms.

Diagnostic tests for SIBO (Table 2) Presumptive diagnosis and empiric antibiotic treatment Due to a broad differential diagnosis, and lack of a gold standard, definitive pretest probability of making a clinical diagnosis of SIBO is very low to. As discussed, symptoms are poor predictor for diagnosis of SIBO and therefore, diagnostic testing is essential to identify SIBO. Some may argue for the use of empirical broad-spectrum antibiotics for the treatment of SIBO. However, such an approach carries significant disadvantages. First, antibiotics may not target causative organism and thereby fail and cause frustration to both patients and clinicians. Second, costs related to some antibiotics are prohibitive. Third, side effects from antibiotics including resistance, rash and diarrhea should all count against blind anti-microbial stewardship. And finally, and most importantly, untargeted repeated antibiotic use can further worsen dysbiosis in the gut and could lead to dreaded Clostridium difficile infection or fungal overgrowth. A recent study showed that antibiotics significantly disrupt normal intestinal microbiome and that probiotics generally felt to be useful in aiding rapid restoration of microbiota may in fact impair flora recovery [69]. Therefore, it seems prudent to perform appropriate diagnostic work-up before embarking on presumptive treatment for SIBO.

Small bowel aspirates and cultures This method is considered the gold standard for the diagnosis of SIBO. Standardized methods for aseptic collection of small bowel aspirate samples are lacking, because methods differ regarding the placement of the device for sample aspiration and amount collected, as well as for sample handling and subsequent culture. In general, during an upper endoscopy, a deep duodenal intubation can be achieved while minimizing suction during the insertion of the scope via mouth and stomach and to prevent cross contamination of secretions from outside the duodenum as described. [21, 64] A 2 mm Liguory catheter (COOK Medical, Bloomington, IN, USA) (Fig. 1) with multiple side holes is passed through the biopsy channel of an upper endoscope into the 3rd and 4th portions of the duodenum. Using gentle suction, approximately 3–5 mL of duodenal fluid is aspirated, and the specimen is sent to microbiology for aerobic/anaerobic culture. [21, 64] By wearing sterile gloves both by the endoscopist and assistant and during assembling the catheter, collecting samples and placing a sterile cap on the syringe are all key components for proper specimen collection and handling. Finally, the specimen should be promptly transferred to the microbiology laboratory that should be either fore warned or a relationship established such that these specimens are rapidly processed for aerobic, anaerobic and fungal cultures. It is important to communicate with the laboratory personnel regarding use of appropriate media and not to report results as positive or negative but to describe the growth of organism as a precise colony count in colony forming units (cfu)/mL. A typical example of microbiology report for SIBO including antibiotic sensitivity is shown in Fig. 2. This is important as a lower count is regarded as adequate for diagnosis of SIBO unlike traditional urine and blood culture data. Thus, a strong relationship with the microbiology team is essential component

Small intestinal bacterial and fungal overgrowth Chapter | 24  347



TABLE 2  Diagnostic tests for SIBO Diagnostic test

Substrate and characteristic

Testing protocol

Test interpretation

Diagnostic performance

Limitations

Breath tests • Glucose [8, 65, 66]

• Monosaccharide • Absorbed in proximal small intestine

• 75g of glucose in 250mL of water • Breath samples collected at baseline and every 15min for 90–120min and measured for hydrogen and methane

• Rise in hydrogen ≥20ppm from baseline Or • Rise in methane ≥10ppm from baseline Or • Rise in hydrogen and methane combined ≥15ppm from baseline

• Sensitivity: 20%–93% • Specificity: 30%–86%

• A negative test excludes proximal SIBO, but not distal SIBO • Not suitable for patient with diabetes

• Lactulose [32, 57, 65]

• Disaccharide • Nonabsorbable • Reaches colon • Used to measure oro-cecal transit in some cases

• 10g of lactulose • Breath samples are collected at baseline and every 15min for 180–240min for hydrogen

• Interpretation of test results requires reliable differentiation of colonic peak from small intestine peak • Positive test: increase from baseline ≥20ppm H2 by 90min

• Sensitivity: 31%–68% • Specificity: 44%–100%

• May accelerate gut transit, giving false negative results • May cause bloating • Interpretation difficult if only one peak in hydrogen concentration

• Fructose [65, 67]

• Monosaccharide • Absorbed in proximal small intestine • Suitable for patients with diabetes

• 25g of fructose in 250mL of water • Breath samples collected at baseline and every 15min for 180min and measured for hydrogen and methane

• Rise in hydrogen ≥20ppm above baseline Or • Rise in methane ≥10ppm above baseline Or • Rise in hydrogen and methane combined ≥15ppm from baseline

• Sensitivity: 25%- 71% • Specificity: 42% - 92%

• Observation based on single study • Cannot differentiate between SIBO and fructose intolerance in patients with diabetes

Small bowel aspirates and culture • Duodenal [64, 65]

Upper endoscopy performed to obtain samples from third or fourth portion of duodenum

• 3–5mL duodenal liquid aspirated using aseptic technique (eg, sterile gloves) • Samples sent to laboratory immediately after collection

• Positive test: ≥103cfu/ mL • 65.5% agreement between glucose breath test and duodenal aspirate/ culture

• Currently the gold standard test for SIBO

• Testing is invasive, time intensive, and expensive

• Jejunal [65, 68]

Upper endoscopy performed to obtain samples from proximal jejunum

• ≥2mL jejunal liquid aspirated • Samples sent to laboratory in sterile fashion and sent to lab immediately

• Positive test: ≥103cfu/ mL

• Currently the gold standard test for SIBO

• Testing is invasive, time intensive, and expensive • May be more difficult than accessing duodenum

348  SECTION | B  Clinical approaches to neurogastroenterology

FIG. 1  An endoscopic image of the distal duodenum that shows a Liguory catheter in place for aspirating duodenal juice under aseptic precautions for aerobic, anerobic and fungal cultures.

FIG. 2  An example of culture/sensitivity result from small bowel aspirate from a 43 year-old female with suspected SIBO/SIFO. The results show significant growth of both bacteria and fungal organisms from duodenal aspirate.

of accurate diagnosis of SIBO. Historically, a growth of ≥105cfu/mL has been used for identifying any bacterial infection including a diagnosis of SIBO. However, when considering SIBO, this cutoff seems too stringent and lacks validation. [50] Healthy controls have <103cfu/mL in their small bowel and concentrations above 105cfu are mostly seen in patients with gastrectomy. [8] Therefore, a culture growth of ≥103cfu/mL is generally considered diagnostic of SIBO and has been recommended by the North American Consensus [19]. Diagnosis of SIBO using small bowel aspiration and culture is time consuming, expensive, and invasive procedure which requires sedation and carries the

Small intestinal bacterial and fungal overgrowth Chapter | 24  349



usual risk factors of endoscopy, but is technically simple, and can be widely performed outside of specialized referral centers or research environment. In one study [64] the diagnostic agreement of small bowel aspirates with breath testing was ~65% indicating that one testing method may not definitively diagnose SIBO, and additional testing may be necessary, particularly in patients with persistent symptoms and high suspicion for SIBO.

Breath testing

180 160 140 120 100 80 60 40 20 0 0

15

30

45

60

75

90

105

(C)

40

30

20

10

0

120

(B)

Time (min)

Hydrogen and methane levels (ppm)

(A)

50

Hydrogen and methane levels (ppm)

Hydrogen and methane levels (ppm)

Quantitative measurement of breath hydrogen (H2) and/or methane (CH4) is a relatively inexpensive, non-invasive, easy and widely available test. Newer mail-in kits are available for home testing for patients not able to travel or in remote locations. The premise of these tests is that human cells are incapable of producing H2 and CH4 gases [70]. Consequently, if these gases can be detected in breath samples it must signify another source such as the fermentation of carbohydrate residues in the gut, and subsequent absorption, and expiration through lungs [50]. This principle has led to the development of several carbohydrate substrate based breath tests. Here, after ingestion of a carbohydrate load, and its exposure to bacteria particularly anaerobes, the sugar is rapidly fermented to produce hydrogen and methane gas along with short chain fatty acids. A rise in the concentrations of these gases in breath samples facilitates a diagnosis of SIBO (Fig. 3A–C). The carbohydrates commonly used as substrates for detecting SIBO are glucose or lactulose or fructose, and each has unique characteristics (Table 2). Historically, breath testing used a radiolabeled substrate (e.g., xylose), which could be detected in breath exhalant if bacteria were present [71]. However, this technique is no longer used because of safety concerns with radiolabeled substrates [8]. A recent North American Consensus paper provides some guidelines for standardized method of performing and interpreting test results [65].

0

15

30

45

60

75

90

105

120

Time (min)

50

40

30

20

10

0 0

15

30

45

60

75

90

105

120

Time (min)

FIG. 3  A graphical representation of hydrogen (red) and methane (black) plots from a patient with a positive breath test showing a rise in hydrogen of ≥20ppm (A), and another patient with a positive test showing a rise in methane of ≥10ppm without a significant change in hydrogen (B), and a negative breath test with no change in hydrogen or methane (C) after glucose load. The time is shown on the horizontal axis and the breath hydrogen/methane concentration in PPM on the Y axis.

350  SECTION | B  Clinical approaches to neurogastroenterology

Before breath testing, it is recommended that patients avoid treatment with antibiotics for 4 weeks, promotility agents and laxatives for at least 1 week. The day before breath test, fermentable foods (e.g., complex carbohydrates) should be avoided and patients should fast for 8–12 h. In addition, during the breath test patients should avoid smoking and minimize physical exertion. The North American consensus recommends administering 75 g glucose or 10 g lactulose, either taken with or followed by 1 cup of water (~250 mL). The breath samples should be measured for H2 and CH4. An increase in H2 concentrations of ≥20 ppm from baseline within 90 [65] to 120 [72] minutes and an increase from baseline in CH4 concentrations of ≥10 ppm within 2 h, are recommended to be diagnostic of SIBO (Fig. 3A and B). A change in concentration of either of these gases, below these levels should be considered a negative test (Fig. 3C). When using lactulose as a substrate, an initial peak from bacterial overgrowth in the small intestine followed by a second peak from colonic bacterial fermentation has been described. However, as per the new consensus statement, a second peak is not required but the first peak must occur within 90min of substrate administration for the test to be considered positive. According to a systemic review by Khoshini and colleagues, the sensitivity of lactulose has ranged from 31% to 68% and specificity has ranged from 44% to 100% whereas the sensitivity of glucose breath testing has varied from 20% to 93% and specificity from 30% to 86% when compared to cultures of aspirates from the small bowel. [8] Recently, role of fructose as a monosaccharide substrate for diabetics with suspected SIBO has been evaluated, because a 75 g glucose load can cause acute hyperglycemia and gut dysmotility, causing symptoms and possibly impacting the breath test results. In this study, when compared to duodenal aspirates, the use of fructose solution as substrate in diabetics yielded similar sensitivity, specificity and diagnostic accuracy (48%, 71% and 58%, respectively) to diagnose SIBO to that of glucose solution in non-diabetics [67]. In addition to H2 and CH4, hydrogen sulfide (H2S) is another gas produced by gut bacteria, but a commercial system is not available. A recent study evaluated the role of H2S in patients with SIBO [73]. However, a cutoff value for diagnosis of SIBO using H2S gas needs to be validated and its utility determined.

Newer techniques It is recognized that the current breath tests have low sensitivity and specificity and need additional validation studies for standardization [74]. Lactulose breath test is criticized for high false positive values due the arrival in cecum, and the glucose for being absorbed in proximal duodenum and therefore, having low sensitivity for detecting distal SIBO in other words missing overgrowth in distal small bowel. [8, 65, 66] A novel and “hybrid” approach was reported in a study wherein the glucose load was administered via endoscope rather than ingested orally, resulting in a higher yield for diagnosis of SIBO for patients who had previously tested negative [75]. A unique orally ingested capsule technology is also under development that can measure in vivo hydrogen and carbon dioxide after ingestion of a carbohydrate meal and may provide a better alternative to current breath hydrogen measurement techniques [76].

Treatment of SIBO The treatment of SIBO carries similar dilemma as the diagnosis of SIBO due to lack of standardization on selection of treatment and inability to accurately quantify treatment response. General principles of treating SIBO should focus on (1) achieving eradication of the bacterial overgrowth; (2) improving symptoms; (3) preventing recurrence by eliminating or limiting modifiable risk factors such as unindicated PPI use, diet, post-surgical adhesions, improving motility, etc.; and (4) maintaining nutrition. In general, the approach depicted in Fig. 4 provides the most comprehensive framework for the effective treatment of SIBO [77].

Antibiotic therapy Despite several randomized trials and meta-analyses of various therapies for SIBO worldwide, there is no medical agency, example FDA, approved treatment for SIBO. Hence, the treatment is either empirical or based on positive breath test or small bowel culture and sensitivity data. The presence of predominantly H2 versus CH4 producing bacteria, patient’s allergies, past use of a class of antibiotics, clinician’s preference, local resistance patterns, cost to the patient and insurance coverage are all factors that contribute to clinical decision making [15, 62]. There is lack of large, well-controlled, placebo controlled double blind randomized trials in treatment of SIBO that was emphasized in a comprehensive review that found 23 trials of antibiotics for SIBO. Of these, 17 had 20 or fewer subjects and many had poorly defined endpoints regarding symptom improvement [8]. These studies have used several antibiotics including clindamycin, metronidazole, neomycin, rifaximin, ampicillin, amoxicillin, chloramphenicol, ciprofloxacin, erythromycin, and trimethoprim/sulfamethoxazole, and for a variable duration ranging from 5 to 30 days. Nevertheless, data can be derived from the experience in IBS studies. In a 2003 double-blind randomized placebo-controlled trial [78], Pimentel and colleagues recruited 111 IBS patients, of which 84% had a positive



Small intestinal bacterial and fungal overgrowth Chapter | 24  351

FIG. 4  A summary of the approach to treatment of SIBO.

lactulose breath test (LBT). The participants were randomized to receive 10 days of neomycin 500 mg twice daily orally or placebo. Predefined study endpoint (at least 50% reduction in a composite score calculated from the three symptoms of abdominal pain, diarrhea, and constipation each on a scale of 0–5) was achieved in 46% of those with abnormal LBT in the neomycin arm compared to 15% in placebo (P<0.01). In an earlier uncontrolled open-label study by the same group, 157 patients with IBS and hydrogen predominant bacterial overgrowth received neomycin, ciprofloxacin, metronidazole, or doxycycline as per discretion of managing physicians [79]. A follow-up breath test after 7–10days of antibiotic therapy was obtained in 47 patients. A total of 22 (~47%) subjects who eradicated bacteria demonstrated significant improvement in symptoms of diarrhea and abdominal pain. In a 2013 meta-analysis, Shah and colleagues investigated 10 studies using a variety of antibiotics such as ciprofloxacin, metronidazole, neomycin, rifaximin, and tetracycline. Almost 51% of subjects on antibiotics normalized breath test when compared to 10% on placebo [80]. Of all the antibiotics studied for bacterial overgrowth, Rifaximin has unique characteristics: no systemic absorption, minimal side effect profile, rare o­ ccurrence of C. difficile infection, etc., However, its cost in USA is an issue and the drug is not approved for SIBO. TARGET 1, 2 and 3 trials in IBS patients elucidated the role of rifaximin in diarrhea and abdominal pain [81]. In these trials, however, inclusion criteria did not require breath test or other form of diagnosis to separate IBS patients with SIBO and therefore, the results can only be approximated and not definitively used for SIBO. Regardless, in TARGET 1 and 2, by week 4, ~40.7% patients in the treatment arm had achieved relief from global IBS symptoms as compared to 31.7% in placebo (P<0.001). Similarly, 40.2% in rifaximin compared to 30.3% in placebo had adequate relief in bloating. Rifaximin was comparable to placebo for adverse events and no cases of C. difficile were reported. However, the exact mechanism of rifaximin in IBS is not known but, given high prevalence of SIBO in IBS patients, rifaximin could be considered for SIBO treatment. Another important factor is targeting CH4 producing organisms causing SIBO such as Methanobrevibacter smithii that may require dual antibiotics such as rifaximin and neomycin. These patients may present with symptoms related to constipation secondary to the anti-motility effects of CH4 as discussed earlier. In two separate studies, neomycin with rifaximin was superior in reducing methane production and improving stool consistency, bloating and straining when compared to either drugs given as monotherapy [82, 83] Studies with statins that have the ability to block a key enzyme required for gut CH4 production are also underway.

Non-pharmacologic therapies Given the cost and side effects of antibiotic therapy, non-pharmacological treatments for SIBO have been tried. These include trial of elemental diet, FODMAPs diet, herbal preparations including herbal antibiotics, probiotics and others. Elemental diet consists of pre-digested nutrients that are selectively absorbed in the proximal small bowel. This approach

352  SECTION | B  Clinical approaches to neurogastroenterology

could potentially limit the delivery of nutrients to the bacteria residing in the distal portion of small bowel. However, it requires very high level of motivation given the poor palatability of these diets, and both compliance, taste and tolerability remain major hurdles [84]. One hundred and twenty four SIBO patients who were on elemental diet for at least 2 weeks were checked for normalization of breath test and if not, they continued diet for another week [83]. By day 15, 80% of subjects normalized their breath test. Of 19 subjects who did not normalize their breath test, only five had a normal breath test by day 22 for a cumulative response of 85%. A total of 14 patients could not tolerate the diet. At 2 weeks patients who normalized their breath test showed 66% improvement in symptoms as opposed to 12% who did not [85]. Low Fermentable oligo-, di-, mono-saccharides and polyols (FODMAPs) diet has been shown to be beneficial in IBS, possibly by depriving nutrition to bacteria, but evidence is lacking. Probiotics have garnered significant attention in recent years but their role in improving SIBO and related symptoms is controversial. Counter intuitively they can cause worsening dysbiosis and potential complications including d-lactic acidosis and brain-fogginess [77]. A combination of herbal remedies have been investigated for treating SIBO. One such uncontrolled trial enrolled 165 lactulose breath test (LBT) positive SIBO patients who received either 400mg rifaximin tablets three times daily or two capsules twice daily of the following commercial herbal preparations; Dysbiocide and FC Cidal (Biotics Research Laboratories, Rosenberg, Texas) or Candibactin-AR and Candibactin-BR (Metagenics, Inc., Aliso Viejo, California) for four consecutive weeks. Of these, 104 had a repeat LBT after treatment. Of the 37 patients who received herbal therapy, 17 (46%) had a negative follow-up LBT compared to 23/67 (34%) of rifaximin. Fourteen of the 44 (31.8%) rifaximin non-responders were offered herbal rescue therapy, with 8 of the 14 (57.1%) having a negative LBT after completing the rescue herbal therapy. A patient in rifaximin had anaphylaxis, two had hives, three had diarrhea of which one had C. difficile. On the other hand, only one case of diarrhea was reported in the herbal therapy [86]. Other options such as peppermint oil, parabiotic, symbiotic and turmeric are all potential candidates but lack rigorous clinical trials.

Prevention of recurrence It is estimated that ~44% of patient by 9 months will have recurrent symptoms and breath test positivity for SIBO after the initial treatment [87]. Therefore, it is important to identify underlying factors that predispose or increase the risk of recurrence and if so should be addressed. Some factors are reversible such as avoiding medication that delay gut transit (example opioids and anticholinergic drugs), trial of medicines to improve gut motility, reducing PPI use, better glycemic control, correction of thyroid function, dilation of accessible strictures, surgical removal of adhesions or correction of blind loops and fistula closure; whereas some are not such as radiation enteritis, surgical resection of ileocecal valve, etc., Prokinetic agents improve gut motility and could enhance antegrade clearance of bacteria in small intestine. One such approach is trial of prokinetic agents. Prucalopride, tegaserod and erythromycin are prokinetic agents that could improve small intestinal peristalsis and reduce SIBO and prevent recurrence. However, some of these agents are not universally available in different parts of the world and may have cardiac side effects [88, 89]. In an older study, five patients with scleroderma were given low doses of octreotide (50μg at bedtime for 3 weeks), a somatostatin analogue, to improve MMC III activity. Patients had normalization of breath test and reduction in bloating, nausea, abdominal pain and vomiting. Larger controlled trials are needed before they can be recommended for conditions such as scleroderma and intestinal pseudo obstruction [90].

Nutritional support Maintaining adequate nutrition and close monitoring of deficiencies should be given heavy importance. Mucosal damage from SIBO could take longer to reverse and maintaining goal directed vitamin and micronutrient supplement should occur alongside pharmacological or non-pharmacological treatment of SIBO. Lactose free diet, substitution with medium chain fatty triglycerides and parenteral administration of fat-soluble vitamins, minerals and iron should be considered.

Conclusions SIBO is an important player in the causation of nonspecific and unexplained GI symptoms. Several conditions and risk factors have been identified, and its prevalence is increasing. There is no perfect test for diagnosis of SIBO. But, small bowel aspirates and culture using proper technique although invasive and expensive remains the gold-standard with a bacterial growth cutoff of ≥103cfu/mL for diagnosis of SIBO. Glucose, lactulose and fructose breath tests are non-invasive and less expensive and widely available and can be considered as alternative approaches. Sometimes when the suspicion is high, more than one test may be necessary to diagnose SIBO. The North American consensus statement for hydrogen and methane breath test provides the most current framework for diagnostic testing of SIBO. Routine use of empiric antibiotics is not ideal and ideally a formal diagnosis should be established before treatment. No standardized antibiotic regimen



Small intestinal bacterial and fungal overgrowth Chapter | 24  353

is available, but selection of an agent with adequate broad coverage and least side effects is preferred. Rifaximin has been widely used and considered safe and effective but has not been approved. Other antibiotics that have been used include amoxicillin, metronidazole, ciprofloxacin, levofloxacin and others. In patients with recurrent symptoms, identification and correction of underlying risk factors should be considered. Several non-pharmacological alternatives have been proposed but merit further robust trials.

Small intestinal fungal overgrowth Introduction Small intestinal fungal overgrowth (SIFO) is characterized by the presence of excessive amounts of fungi in small intestine together with unexplained gas, bloating, pain, constipation or diarrhea. The human alimentary canal harbors varying concentrations of fungi, often commensal flora with host immune adaptation. Any change in this balance could lead to fungal overgrowth at various locations. Such overgrowth in small intestine could lead to symptoms of abdominal pain, gas, bloating, flatulence, diarrhea and symptoms of malabsorption, but has only recently been fully recognized. Candida is the commonest fungal species found in the small bowel.

Pathophysiology and risk factors for SIFO The two orifices of human alimentary canal, mouth and anorectum have the highest population of fungi, whereas, the stomach and jejunum have the lowest amount of fungal colonization (0–102cfu/mL) [91, 92]. With appropriate culture technique, almost all human stool samples will grow Candida albicans [93]. Almost 4 decades ago, Cohen and colleagues cultured 86 specimens in 27 healthy adults (23 oropharyngeal, 26 jejunal, 20 ileal and 17 fecal samples). C. albicans was the most frequent fungus and concentrations of 102cfu/mL or greater, were encountered in the 43%, 50% of ileal and 59% of colon specimens [91]. However, significant colonization of the gut with yeast or fungus rarely develops unless the protective mechanisms have been breached. One such mechanism is the interplay between bacteria in the gut commensal flora and fungal overgrowth, as evidenced by studies in human and animal models [94, 95]. Bacteria such as Lactobacillus species can interact and inhibit growth of Candida species in the gut by producing hydrogen peroxide [96]. An intact innate, adaptive and cell-mediated gut immune function is key to prevent fungal overgrowth [97–99]. Gastric acidity is also protective against fungal overgrowth and pancreatic enzymes have fungistatic properties. Patients admitted to hospital, and those receiving oral or parenteral antibiotic therapy or chemotherapy, and those with underlying HIV infection are more susceptible to SIFO [91, 100–102]. The importance and clinical relevance of the level of fungal overgrowth on culture of fluid from the small intestine is unclear [63]. In two recent studies, higher prevalence of SIFO has been described in patients with PPI use and small bowel dysmotility and those who underwent colectomy in otherwise immunocompetent individuals without having recent antibiotic use [21]. In mice, an elegant experiment by Yang and colleagues reported that chronic ethanol administration resulted in intestinal fungal overgrowth. Also, effects of alcoholic liver injury could be reversed by administering systemic anti-fungal therapy [103].

Clinical manifestations of SIFO There are limited studies of symptom patterns caused by SIFO especially in a immunocompetent host. In one interesting experiment, a healthy volunteer and an author of a report drank a saline suspension containing 1012 cells of C. albicans. Two hours later, he developed signs and symptoms suggestive of septicemia, including chills, headache, and high fever. The administration of a cathartic and oral nystatin gave an almost immediate remission [104]. A high candida load clearly appears to cause a severe reaction but it underscores the point that high levels of fungi in the gut can cause symptoms and possibly systemic manifestations. There are several other case reports regarding the presence of fungi, especially C. albicans, in the small intestine of otherwise healthy subjects who have presented with abdominal pain or diarrhea and whose symptoms resolved after antifungal treatment [105, 106]. Jacobs reported that patients with SIFO report chronic abdominal pain, nausea, bloating, gas, fullness, diarrhea, indigestion and emesis, symptoms that were generally similar to those with SIBO [21]. Similar symptoms were reported in patients with IBS indicating that symptoms of SIFO are non-specific [107]. Another larger study of SIFO also showed similar symptom profiles, and all of these patients were diagnosed with SIFO based on duodenal culture [108]. Thus, SIFO related symptoms could range from nausea, bloating to vomiting and dyspepsia and mild flatulence to severe diarrhea. In more severe forms, colonic erosions and bloody diarrhea have been reported with Candida enterocolitis [102, 106].

354  SECTION | B  Clinical approaches to neurogastroenterology

Diagnosis of SIFO Clinical history and any of the above risk factors should raise suspicion for SIFO in patients with unexplained GI symptoms. As discussed earlier, none of the common GI symptoms can predict SIFO [21, 108]. Consequently, direct aspiration and culture of the small bowel juice during upper endoscopy for fungal organisms is the only method available for diagnosing SIFO. The technique for collecting sample, handling and culture on fungal media are similar to that described in “Diagnostic tests for SIBO” section and Fig. 1, and an example of overgrowth report is shown in Fig. 2. The usual organisms are C. albicans, Torulopsis glabrata and other Candida sp. SIFO is however different to the finding of candida overgrowth elsewhere such as oral or esophageal candidiasis, or isolation of Candida species in stool often at thresholds of 101–103 fungal cells per gram stool [92, 93]. In 120 stool samples collected from patients with chronic diarrhea in a hospital in India, 26% grew 105cfu/mL yeast followed by C. albicans, Candida tropicalis, Candida krusei, Candida famata and Candida parapsilosis [109]. This study shows that opportunistic yeast may cause symptoms like chronic diarrhea and possibly related to excess candida in colon or colonic fungal dysbiosis. However, the finding of candida in stool, which is a normal commensal, should not be inferred as SIFO. Also, the threshold cutoff for defining fungal overgrowth in small intestine and establishing a diagnosis of SIFO in immunocompetent and compromised hosts is unclear. In four studies, a cutoff of ≥103cfu/mL of fungal organisms was considered diagnostic of SIFO [63]. This threshold is similar to that recommended for SIBO by the North American consensus. Identification of fungi by culture-dependent methods is limited by the fact that the majority of fungal species cannot be cultured in vitro. In the future, new molecular tools and techniques may increase the speed and sensitivity of detecting SIFO and help understand antifungal sensitivity and resistance patterns [110].

Treatment of SIFO General principles of treatment as discussed in SIBO section apply to the treatment of SIFO also, such as elimination of risk factors (PPI and overuse of broad-spectrum antibiotics), steroids and immunosuppressants, correction of small bowel dysmotility and reestablishment of host immunity, and replacement of electrolyte and micronutrients. The mainstay of antifungal therapy is drugs and the most commonly used anti-fungals are azole derivatives. The primary effect of azoles is the inhibition of cytochrome P450-dependent enzyme lanosterol 14-alpha-demethylase. This group includes fluconazole, voriconazole, posaconazole, and itraconazole. Fluconazole is the treatment of choice due to oral route of administration, low cost, good bioavailability and safety profile. There is emergence of fluconazole resistance due to wide-spread preventive use in HIV and chemotherapy patients [111, 112]. In immunocompetent host, a daily dose of 100mg for 2–3 weeks would be a good approach to treat SIFO. Higher doses may be required in immunocompromised patients. Nystatin is mainly used for oral candidiasis and is used topically for mucosal and skin candidiasis. Because it is not absorbed from the GI tract and skin, toxicity is rare for nystatin. No studies are available in SIFO patients but nystatin is equal to placebo in treating fungal colonization in patients with immunodeficiency [113]. This may not be a good choice as first line regimen but can be considered in immunocompetent host, intolerant to azole agents. Echinocandins, fungal cell synthesis inhibitors such as micafungin, caspofungin, and anidulafungin can be considered, but are routinely used in invasive fungal infections in ICU setting and require intravenous route. Similarly, Amphotericin B is an intravenous agent with high risk for nephrotoxicity [113]. Use of this agent cannot be supported in SIFO patients given risky side-effect profile.

Conclusions SIFO is an emerging cause of unexplained GI symptoms and could be more common than hitherto recognized especially in patients with diabetes, gut dysmotility, PPI and steroid or antibiotic use, and those who are immunocompromised. Diagnosis is based on small bowel aspiration and culture. Treatment includes use of azole anti-fungal and eliminating risk factors. Clearly, more research is needed to understand symptom patterns, diagnostic criteria and effective treatment strategies based on RCTs.

Conflict of interest On behalf of all authors, the corresponding author states that there is no conflict of interest. All authors have approved the final version being submitted.



Small intestinal bacterial and fungal overgrowth Chapter | 24  355

References [1] Neale G, Gompertz D, Schonsby H, Tabaqchali S, Booth CC. The metabolic and nutritional consequences of bacterial overgrowth in the small intestine. Am J Clin Nutr 1972;25(12):1409–17. [2] Sachdev AH, Pimentel M. Gastrointestinal bacterial overgrowth: pathogenesis and clinical significance. Ther Adv Chronic Dis 2013;4(5):223–31. [3] Gutierrez IM, Kang KH, Calvert CE, Johnson VM, Zurakowski D, Kamin D, 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 2012;47(6):1150–4. [4] Russo  MW, Wei  JT, Thiny  MT, Gangarosa  LM, Brown  A, Ringel  Y, et  al. Digestive and liver diseases statistics, 2004. Gastroenterology 2004;126(5):1448–53. [5] Chang L. Review article: epidemiology and quality of life in functional gastrointestinal disorders. Aliment Pharmacol Ther 2004;20(Suppl 7):31–9. [6] Peery AF, Crockett SD, Barritt AS, Dellon ES, Eluri S, Gangarosa LM, et al. Burden of gastrointestinal, liver, and pancreatic diseases in the United States. Gastroenterology 2015;149(7):1731–3. [7] Kim DB, Paik CN, Kim YJ, Lee JM, Jun KH, Chung WC, et al. Positive glucose breath tests in patients with hysterectomy, gastrectomy, and cholecystectomy. Gut Liver 2017;11(2):237–42. [8] Khoshini  R, Dai  SC, Lezcano  S, Pimentel  M. A systematic review of diagnostic tests for small intestinal bacterial overgrowth. Dig Dis Sci 2008;53(6):1443–54. [9] Drasar BS, Shiner M, McLeod GM. Studies on the intestinal flora: I. The bacterial flora of the gastrointestinal tract in healthy and achlorhydric persons. Gastroenterology 1969;56(1):71–9. [10] Gorbach SL. Population control in the small bowel. Gut 1967;8(6):530–2. [11] Gazet RJ, Jarrett J. The Ileocaeco-colic sphincter. Studies in vitro in man, monkey, cat, and dog. Br J Surg 1964;51:368–70. [12] Roland BC, Ciarleglio MM, Clarke JO, Semler JR, Tomakin E, Mullin GE, et al. Low ileocecal valve pressure is significantly associated with small intestinal bacterial overgrowth (SIBO). Dig Dis Sci 2014;59(6):1269–77. [13] Code CF, Marlett JA. The interdigestive myo-electric complex of the stomach and small bowel of dogs. J Physiol 1975;246(2):289–309. [14] Vantrappen G, Janssens J, Hellemans J, Ghoos Y. The interdigestive motor complex of normal subjects and patients with bacterial overgrowth of the small intestine. J Clin Invest 1977;59(6):1158–66. [15] Rao SSC, Tan G, Abdulla H, Yu S, Larion S, Leelasinjaroen P. Does colectomy predispose to small intestinal bacterial (SIBO) and fungal overgrowth (SIFO)? Clin Transl Gastroenterol 2018;9(4):146. [16] Bures J, Cyrany J, Kohoutova D, Forstl M, Rejchrt S, Kvetina J, et al. Small intestinal bacterial overgrowth syndrome. World J Gastroenterol 2010;16(24):2978–90. [17] Petrone P, Sarkisyan G, Fernandez M, Coloma E, Akopian G, Ortega A, et al. Small intestinal bacterial overgrowth in patients with lower gastrointestinal symptoms and a history of previous abdominal surgery. Arch Surg 2011;146(4):444–7. [18] Yamini D, Pimentel M. Irritable bowel syndrome and small intestinal bacterial overgrowth. J Clin Gastroenterol 2010;44(10):672–5. [19] Pyleris E, Giamarellos-Bourboulis EJ, Tzivras D, Koussoulas V, Barbatzas C, Pimentel M. The prevalence of overgrowth by aerobic bacteria in the small intestine by small bowel culture: relationship with irritable bowel syndrome. Dig Dis Sci 2012;57(5):1321–9. [20] Husebye E, Skar V, Hoverstad T, Iversen T, Melby K. Abnormal intestinal motor patterns explain enteric colonization with gram-negative bacilli in late radiation enteropathy. Gastroenterology 1995;109(4):1078–89. [21] Jacobs C, Coss Adame E, Attaluri A, Valestin J, Rao SS. Dysmotility and proton pump inhibitor use are independent risk factors for small intestinal bacterial and/or fungal overgrowth. Aliment Pharmacol Ther 2013;37(11):1103–11. [22] Newberry  C, Tierney  A, Pickett-Blakely  O. Lactulose hydrogen breath test result is associated with age and gender. Biomed Res Int 2016;2016:1064029. [23] Choung RS, Ruff KC, Malhotra A, Herrick L, Locke 3rd GR, Harmsen WS, et al. Clinical predictors of small intestinal bacterial overgrowth by duodenal aspirate culture. Aliment Pharmacol Ther 2011;33(9):1059–67. [24] Barboza JL, Okun MS, Moshiree B. The treatment of gastroparesis, constipation and small intestinal bacterial overgrowth syndrome in patients with Parkinson’s disease. Expert Opin Pharmacother 2015;16(16):2449–64. [25] Lauritano EC, Bilotta AL, Gabrielli M, Scarpellini E, Lupascu A, Laginestra A, et al. Association between hypothyroidism and small intestinal bacterial overgrowth. J Clin Endocrinol Metab 2007;92(11):4180–4. [26] Mulak A, Bonaz B. Brain-gut-microbiota axis in Parkinson’s disease. World J Gastroenterol 2015;21(37):10609–20. [27] Strid H, Simren M, Stotzer PO, Ringstrom G, Abrahamsson H, Bjornsson ES. Patients with chronic renal failure have abnormal small intestinal motility and a high prevalence of small intestinal bacterial overgrowth. Digestion 2003;67(3):129–37. [28] Bhagatwala J, Erdogan A, Leelasinjaroen P, Sharma A, Mack A, Rao SS. Altered small bowel motility and small intestinal bacterial overgrowth: time to target the culprit? Gastroenterology 2016;150(4):97. [29] Saltzman JR, Kowdley KV, Pedrosa MC, Sepe T, Golner B, Perrone G, et al. Bacterial overgrowth without clinical malabsorption in elderly hypochlorhydric subjects. Gastroenterology 1994;106(3):615–23. [30] Husebye E, Skar V, Hoverstad T, Melby K. Fasting hypochlorhydria with gram positive gastric flora is highly prevalent in healthy old people. Gut 1992;33(10):1331–7. [31] Paik CN, Choi MG, Lim CH, Park JM, Chung WC, Lee KM, et al. The role of small intestinal bacterial overgrowth in postgastrectomy patients. Neurogastroenterol Motil 2011;23(5):e191–6.

356  SECTION | B  Clinical approaches to neurogastroenterology

[32] Spiegel BM, Chey WD, Chang L. Bacterial overgrowth and irritable bowel syndrome: unifying hypothesis or a spurious consequence of proton pump inhibitors? Am J Gastroenterol 2008;103(12):2972–6. [33] Franco DL, Disbrow MB, Kahn A, Koepke LM, Harris LA, Harrison ME, et al. Duodenal aspirates for small intestine bacterial overgrowth: yield, PPIs, and outcomes after treatment at a tertiary Academic Medical Center. Gastroenterol Res Pract 2015;2015:971582. [34] Lombardo L, Foti M, Ruggia O, Chiecchio A. Increased incidence of small intestinal bacterial overgrowth during proton pump inhibitor therapy. Clin Gastroenterol Hepatol 2010;8(6):504–8. [35] Ratuapli SK, Ellington TG, O'Neill MT, Umar SB, Harris LA, Foxx-Orenstein AE, et al. Proton pump inhibitor therapy use does not predispose to small intestinal bacterial overgrowth. Am J Gastroenterol 2012;107(5):730–5. [36] Su T, Lai S, Lee A, He X, Chen S. Meta-analysis: proton pump inhibitors moderately increase the risk of small intestinal bacterial overgrowth. J Gastroenterol 2018;53(1):27–36. [37] Compare D, Pica L, Rocco A, De Giorgi F, Cuomo R, Sarnelli G, et al. Effects of long-term PPI treatment on producing bowel symptoms and SIBO. Eur J Clin Invest 2011;41(4):380–6. [38] Riordan SM, McIver CJ, Wakefield D, Thomas MC, Duncombe VM, Bolin TD. Serum immunoglobulin and soluble IL-2 receptor levels in small intestinal overgrowth with indigenous gut flora. Dig Dis Sci 1999;44(5):939–44. [39] Kett K, Baklien K, Bakken A, Kral JG, Fausa O, Brandtzaeg P. Intestinal B-cell isotype response in relation to local bacterial load: evidence for immunoglobulin A subclass adaptation. Gastroenterology 1995;109(3):819–25. [40] Belitsos PC, Greenson JK, Yardley JH, Sisler JR, Bartlett JG. Association of gastric hypoacidity with opportunistic enteric infections in patients with AIDS. J Infect Dis 1992;166(2):277–84. [41] Pignata C, Budillon G, Monaco G, Nani E, Cuomo R, Parrilli G, et al. Jejunal bacterial overgrowth and intestinal permeability in children with immunodeficiency syndromes. Gut 1990;31(8):879–82. [42] Lasa JS, Zubiaurre I, Fanjul I, Olivera P, Soifer L. Small intestinal bacterial overgrowth prevalence in celiac disease patients is similar in healthy subjects and lower in irritable bowel syndrome patients. Rev Gastroenterol Mex 2015;80(2):171–4. [43] Rubio-Tapia A, Barton SH, Rosenblatt JE, Murray JA. Prevalence of small intestine bacterial overgrowth diagnosed by quantitative culture of intestinal aspirate in celiac disease. J Clin Gastroenterol 2009;43(2):157–61. [44] Sanchez-Montes C, Ortiz V, Bastida G, Rodriguez E, Yago M, Beltran B, et al. Small intestinal bacterial overgrowth in inactive Crohn’s disease: influence of thiopurine and biological treatment. World J Gastroenterol 2014;20(38):13999–4003. [45] D'Argenio V, Salvatore F. The role of the gut microbiome in the healthy adult status. Clin Chim Acta 2015;451(Pt A):97–102. [46] Sender R, Fuchs S, Milo R. Are we really vastly outnumbered? Revisiting the ratio of bacterial to host cells in humans. Cell 2016;164(3):337–40. [47] Bauer TM, Steinbruckner B, Brinkmann FE, Ditzen AK, Schwacha H, Aponte JJ, et al. Small intestinal bacterial overgrowth in patients with cirrhosis: prevalence and relation with spontaneous bacterial peritonitis. Am J Gastroenterol 2001;96(10):2962–7. [48] Therrien A, Bouchard S, Sidani S, Bouin M. Prevalence of small intestinal bacterial overgrowth among chronic pancreatitis patients: a case-control study. Can J Gastroenterol Hepatol 2016;2016:7424831. [49] Fridge JL, Conrad C, Gerson L, Castillo RO, Cox K. Risk factors for small bowel bacterial overgrowth in cystic fibrosis. J Pediatr Gastroenterol Nutr 2007;44(2):212–8. [50] Rezaie A, Nikfar S, Abdollahi M. The place of antibiotics in management of irritable bowel syndrome: a systematic review and meta-analysis. Arch Med Sci 2010;6(1):49–55. [51] Pimentel M, Wallace D, Hallegua D, Chow E, Kong Y, Park S, et al. A link between irritable bowel syndrome and fibromyalgia may be related to findings on lactulose breath testing. Ann Rheum Dis 2004;63(4):450–2. [52] Gabbard SL, Lacy BE, Levine GM, Crowell MD. The impact of alcohol consumption and cholecystectomy on small intestinal bacterial overgrowth. Dig Dis Sci 2014;59(3):638–44. [53] Zhang Y, Liu G, Duan Y, Han X, Dong H, Geng J. Prevalence of small intestinal bacterial overgrowth in multiple sclerosis: a case-control study from China. J Neuroimmunol 2016;301:83–7. [54] Wang L, Yu YM, Zhang YQ, Zhang J, Lu N, Liu N. Hydrogen breath test to detect small intestinal bacterial overgrowth: a prevalence case-control study in autism. Eur Child Adolesc Psychiatry 2018;27(2):233–40. [55] Sachdev AH, Pimentel M. Antibiotics for irritable bowel syndrome: rationale and current evidence. Curr Gastroenterol Rep 2012;14(5):439–45. [56] Frissora CL, Cash BD. Review article: the role of antibiotics vs. conventional pharmacotherapy in treating symptoms of irritable bowel syndrome. Aliment Pharmacol Ther 2007;25(11):1271–81. [57] Giannella  RA, Rout  WR, Toskes  PP. Jejunal brush border injury and impaired sugar and amino acid uptake in the blind loop syndrome. Gastroenterology 1974;67(5):965–74. [58] Wanitschke R, Ammon HV. Effects of dihydroxy bile acids and hydroxy fatty acids on the absorption of oleic acid in the human jejunum. J Clin Invest 1978;61(1):178–86. [59] Welkos SL, Toskes PP, Baer H. Importance of anaerobic bacteria in the cobalamin malabsorption of the experimental rat blind loop syndrome. Gastroenterology 1981;80(2):313–20. [60] Jahng J, Jung IS, Choi EJ, Conklin JL, Park H. The effects of methane and hydrogen gases produced by enteric bacteria on ileal motility and colonic transit time. Neurogastroenterol Motil 2012;24(2):185–90. e92. [61] Attaluri A, Jackson M, Valestin J, Rao SS. Methanogenic flora is associated with altered colonic transit but not stool characteristics in constipation without IBS. Am J Gastroenterol 2010;105(6):1407–11.



Small intestinal bacterial and fungal overgrowth Chapter | 24  357

[62] Rao SSC, Rehman A, Yu S, Andino NM. Brain fogginess, gas and bloating: a link between SIBO, probiotics and metabolic acidosis. Clin Transl Gastroenterol 2018;9(6):162. [63] Erdogan A, Rao SS. Small intestinal fungal overgrowth. Curr Gastroenterol Rep 2015;17(4):16. [64] Erdogan A, Rao SS, Gulley D, Jacobs C, Lee YY, Badger C. Small intestinal bacterial overgrowth: duodenal aspiration vs glucose breath test. Neurogastroenterol Motil 2015;27(4):481–9. [65] Rezaie A, Buresi M, Lembo A, Lin H, McCallum R, Rao S, et al. Hydrogen and methane-based breath testing in gastrointestinal disorders: the north American consensus. Am J Gastroenterol 2017;112(5):775–84. [66] Romagnuolo J, Schiller D, Bailey R. Using breath tests wisely in a gastroenterology practice: an evidence-based review of indications and pitfalls in interpretation. Am J Gastroenterol 2002;96(5):1113–26. [67] Bhagatwala JSA, Leelasinjaroen P, Tetangco E, Martinez De Andino N, Rao S. Investigation of small intestinal bacterial overgrowth (SIBO) in diabetics using fructose breath test. Gastroenterology 2018;154(6):53–4. [68] Bohm M, Siwiec RM, Wo JM. Diagnosis and management of small intestinal bacterial overgrowth. Nutr Clin Pract 2013;28(3):289–99. [69] Zmora N, Zilberman-Schapira G, Suez J, Mor U, Dori-Bachash M, Bashiardes S, et al. Personalized gut mucosal colonization resistance to empiric probiotics is associated with unique host and microbiome features. Cell 2018;174(6):1388–405. e21. [70] Baker J, Eswaran S, Saad R, Menees S, Shifferd J, Erickson K, et al. Abdominal symptoms are common and benefit from biofeedback therapy in patients with dyssynergic defecation. Clin Transl Gastroenterol 2015;6:e105. [71] Newman A. Breath-analysis tests in gastroenterology. Gut 1974;15(4):308–23. [72] Erdogan ALY, Badger C, Hall P, O'Banion M, Rao S. What is the optimal threshold for an increase in hydrogen and methane levels with glucose breath test (GBT) for detection of small intestinal bacterial overgrowth (SIBO)? Gastroenterology 2014;146:. s-532. [73] Lin ECK, Pichetshote N, Rezaie A, Gupta K, Pimentel M. Measurement of hydrogen sulfide during breath testing correlates to patient symptoms. Gastroenterology 2017;152(1):205–6. [74] Erdogan A, Rao SS, Gulley D, Jacobs C, Lee YY, Badger C. Possible underestimation of SIBO in IBS patients: is lack of glucose breath test standardization responsible? Neurogastroenterol Motil 2015;27(8):1192–3. [75] Viswanathan LLS, Shaffer N, Sharma A, Rao SC. Endoscopically assisted glucose breath test (EAGBT): a novel diagnostic approach for distal SIBO. Gastroenterology 2017;152(5):413. [76] Kalantar-Zadeh K, Berean KJ, Ha N, Chrimes AF, Xu K, Grando D, et al. A human pilot trial of ingestible electronic capsules capable of sensing different gases in the gut. Nat Electron 2018;1(1):79–87. [77] Rezaie A, Pimentel M, Rao SS. How to test and treat small intestinal bacterial overgrowth: an evidence-based approach. Curr Gastroenterol Rep 2016;18(2):8. [78] 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 2003;98(2):412–9. [79] Pimentel  M, Chow  EJ, Lin  HC. Eradication of small intestinal bacterial overgrowth reduces symptoms of irritable bowel syndrome. Am J Gastroenterol 2000;95(12):3503–6. [80] Shah SC, Day LW, Somsouk M, Sewell JL. Meta-analysis: antibiotic therapy for small intestinal bacterial overgrowth. Aliment Pharmacol Ther 2013;38(8):925–34. [81] Pimentel M, Lembo A, Chey WD, Zakko S, Ringel Y, Yu J, et al. Rifaximin therapy for patients with irritable bowel syndrome without constipation. N Engl J Med 2011;364(1):22–32. [82] Pimentel M, Chang C, Chua KS, Mirocha J, DiBaise J, Rao S, et al. Antibiotic treatment of constipation-predominant irritable bowel syndrome. Dig Dis Sci 2014;59(6):1278–85. [83] Low K, Hwang L, Hua J, Zhu A, Morales W, Pimentel M. A combination of rifaximin and neomycin is most effective in treating irritable bowel syndrome patients with methane on lactulose breath test. J Clin Gastroenterol 2010;44(8):547–50. [84] Winitz M, Adams RF, Seedman DA, Davis PN, Jayko LG, Hamilton JA. Studies in metabolic nutrition employing chemically defined diets. II Effects on gut microflora populations. Am J Clin Nutr 1970;23(5):546–59. [85] Pimentel M, Constantino T, Kong Y, Bajwa M, Rezaei A, Park S. A 14-day elemental diet is highly effective in normalizing the lactulose breath test. Dig Dis Sci 2004;49(1):73–7. [86] Chedid V, Dhalla S, Clarke JO, Roland BC, Dunbar KB, Koh J, et al. Herbal therapy is equivalent to rifaximin for the treatment of small intestinal bacterial overgrowth. Glob Adv Health Med 2014;3(3):16–24. [87] Lauritano EC, Gabrielli M, Scarpellini E, Lupascu A, Novi M, Sottili S, et al. Small intestinal bacterial overgrowth recurrence after antibiotic therapy. Am J Gastroenterol 2008;103(8):2031–5. [88] Madrid AM, Hurtado C, Venegas M, Cumsille F, Defilippi C. Long-term treatment with cisapride and antibiotics in liver cirrhosis: effect on small intestinal motility, bacterial overgrowth, and liver function. Am J Gastroenterol 2001;96(4):1251–5. [89] Pimentel M, Morales W, Lezcano S, Sun-Chuan D, Low K, Yang J. Low-dose nocturnal tegaserod or erythromycin delays symptom recurrence after treatment of irritable bowel syndrome based on presumed bacterial overgrowth. Gastroenterol Hepatol 2009;5(6):435–42. [90] Soudah  HC, Hasler  WL, Owyang  C. Effect of octreotide on intestinal motility and bacterial overgrowth in scleroderma. N Engl J Med 1991;325(21):1461–7. [91] Stone HH, Geheber CE, Kolb LD, Kitchens WR. Alimentary tract colonization by Candida albicans. J Surg Res 1973;14(4):273–6. [92] Schulze J, Sonnenborn U. Yeasts in the gut: from commensals to infectious agents. Dtsch Arztebl Int 2009;106(51–52):837–42.

358  SECTION | B  Clinical approaches to neurogastroenterology

[93] Isenberg HD, Pisano MA, Carito SL, Berkman JI. Factors leading to overt monilial disease. I. Preliminary studies of the ecological relationship between Candida albicans and intestinal bacteria. Antibiot Chemother 1960;10:353–63. [94] Hummel RP, Oestreicher EJ, Maley MP, Macmillan BG. Inhibition of Candida albicans by Escherichia coli in vitro and in the germfree mouse. J Surg Res 1973;15(1):53–8. [95] Montgomery BE, Boor AK, Arnold L, Bergeim O. Destruction of yeast in the small and large intestines. Exp Biol Med 1931;28(6):589–90. [96] Fitzsimmons N, Berry DR. Inhibition of Candida albicans by Lactobacillus acidophilus: evidence for the involvement of a peroxidase system. Microbios 1994;80(323):125–33. [97] Netea MG, Brown GD, Kullberg BJ, Gow NA. An integrated model of the recognition of Candida albicans by the innate immune system. Nat Rev Microbiol 2008;6(1):67–78. [98] Blanco JL, Garcia ME. Immune response to fungal infections. Vet Immunol Immunopathol 2008;125(1–2):47–70. [99] Polonelli L, Casadevall A, Han Y, Bernardis F, Kirkland TN, Matthews RC, et al. The efficacy of acquired humoral and cellular immunity in the prevention and therapy of experimental fungal infections. Med Mycol 2000;38(Suppl 1):281–92. [100] Seelig MS. The role of antibiotics in the pathogenesis of Candidainfections. Am J Med 1966;40(6):887–917. [101] Seelig MS. Mechanisms by which antibiotics increase the incidence and severity of candidiasis and alter the immunological defenses. Bacteriol Rev 1966;30(2):442–59. [102] Gupta TP, Ehrinpreis MN. Candida-associated diarrhea in hospitalized patients. Gastroenterology 1990;98(3):780–5. [103] Yang AM, Inamine T, Hochrath K, Chen P, Wang L, Llorente C, et al. Intestinal fungi contribute to development of alcoholic liver disease. J Clin Invest 2017;127(7):2829–41. [104] Krause W, Matheis H, Wulf K. Fungaemia and funguria after oral administration of Candida albicans. Lancet 1969;1(7595):598–9. [105] Kane JG, Chretien JH, Garagusi VF. Diarrhoea caused by Candida. Lancet 1976;1(7955):335–6. [106] Friedman M, Ramsay DB, Borum ML. An unusual case report of small bowel Candida overgrowth as a cause of diarrhea and review of the literature. Dig Dis Sci 2007;52(3):679–80. [107] Middleton SJ, Coley A, Hunter JO. The role of faecal Candida albicans in the pathogenesis of food-intolerant irritable bowel syndrome. Postgrad Med J 1992;68(800):453–4. [108] Erdogan ALY, Sifuentes H, Rao SS. Small intestinal fungal overgrowth (SIFO): a cause of gastrointestinal symptoms. Gastroenterology 2014;146(5). [109] Banerjee P, Kaur R, Uppal B. Study of fungal isolates in patients with chronic diarrhea at a tertiary care hospital in North India. J Mycol Med 2013;23(1):21–6. [110] Zoll J, Snelders E, Verweij PE, Melchers WJ. Next-generation sequencing in the mycology lab. Curr Fungal Infect Rep 2016;10:37–42. [111] Rex JH, Rinaldi MG, Pfaller MA. Resistance of Candida species to fluconazole. Antimicrob Agents Chemother 1995;39(1):1–8. [112] Rex JH, Pappas PG, Karchmer AW, Sobel J, Edwards JE, Hadley S, et al. A randomized and blinded multicenter trial of high-dose fluconazole plus placebo versus fluconazole plus amphotericin B as therapy for candidemia and its consequences in nonneutropenic subjects. Clin Infect Dis 2003;36(10):1221–8. [113] Johansen HK, Gotzsche PC. Amphotericin B versus fluconazole for controlling fungal infections in neutropenic cancer patients. Cochrane Database Syst Rev 2014;4(9):CD000239.