Small Intestinal Bacterial Overgrowth—Pathophysiology and Its Implications for Definition and Management

The concept of small intestinal bacterial overgrowth (SIBO) arose in the context of maldigestion and malabsorption among patients with obvious risk factors that permitted the small bowel to be colonized by potentially injurious colonic microbiota. Such colonization resulted in clinical signs, symptoms, and laboratory abnormalities that were explicable within a coherent pathophysiological framework. Coincident with advances in medical science, diagnostic testing evolved from small bowel culture to breath tests and on to next-generation, culture-independent microbial analytics. The advent and ready availability of breath tests generated a dramatic expansion in both the rate of diagnosis of SIBO and the range of associated gastrointestinal and nongastrointestinal clinical scenarios. However, issues with the specificity of these same breath tests have clouded their interpretation and aroused some skepticism regarding the role of SIBO in this expanded clinical repertoire. Furthermore, the pathophysiological plausibility that underpins SIBO as a cause of maldigestion/malabsorption is lacking in regard to its purported role in irritable bowel syndrome, for example. One hopes that the application of an ever-expanding armamentarium of modern molecular microbiology to the human small intestinal microbiome in both health and disease will ultimately resolve this impasse and provide an objective basis for the diagnosis of SIBO. The concept of small intestinal bacterial overgrowth (SIBO) arose in the context of maldigestion and malabsorption among patients with obvious risk factors that permitted the small bowel to be colonized by potentially injurious colonic microbiota. Such colonization resulted in clinical signs, symptoms, and laboratory abnormalities that were explicable within a coherent pathophysiological framework. Coincident with advances in medical science, diagnostic testing evolved from small bowel culture to breath tests and on to next-generation, culture-independent microbial analytics. The advent and ready availability of breath tests generated a dramatic expansion in both the rate of diagnosis of SIBO and the range of associated gastrointestinal and nongastrointestinal clinical scenarios. However, issues with the specificity of these same breath tests have clouded their interpretation and aroused some skepticism regarding the role of SIBO in this expanded clinical repertoire. Furthermore, the pathophysiological plausibility that underpins SIBO as a cause of maldigestion/malabsorption is lacking in regard to its purported role in irritable bowel syndrome, for example. One hopes that the application of an ever-expanding armamentarium of modern molecular microbiology to the human small intestinal microbiome in both health and disease will ultimately resolve this impasse and provide an objective basis for the diagnosis of SIBO. Any discussion of small intestinal bacterial overgrowth (SIBO) should surely begin with a definition based on objective and measurable parameters. This is where our difficulty with SIBO begins and leads to an impasse that has been further exacerbated in recent years. For example, recent reviews define SIBO as “a clinical disorder in which symptoms, clinical signs, and/or laboratory abnormalities are attributed to changes in the numbers of bacteria or in the bacterial composition in the small intestine”1Quigley E.M.M. Murray J.A. Pimentel M. AGA clinical practice update on small intestinal bacterial overgrowth: expert review.Gastroenterology. 2020; 159: 1526-1532Abstract Full Text Full Text PDF PubMed Scopus (35) Google Scholar or as “a disease in which the small bowel is abnormally colonized by an increased number and abnormal types of microorganisms,”2Bushyhead D. Quigley E.M.M. Small intestinal bacterial overgrowth.Gastroenterol Clin N Am. 2021; 50: 463-474Abstract Full Text Full Text PDF PubMed Google Scholar or as “characterized by the presence of an abnormal amount of bacteria in the small intestine together with a constellation of GI symptoms.”3Rao S.S.C. Bhagatwala J. Small intestinal bacterial overgrowth: clinical features and therapeutic management.Clin Transl Gastroenterol. 2019; 10e00078Crossref Scopus (39) Google Scholar The vagueness of each of these efforts cannot but fail to impress; the clinician is scarcely helped and is left with several questions that continue to bedevil this contentious entity:•What clinical disorders or diseases are truly linked to SIBO?•What symptoms, clinical signs, and/or laboratory abnormalities can be attributed to SIBO?•What is the normal composition of the small intestinal microbiome?•What is the upper limit of normal for bacterial numbers in any given part of the small intestine? As we will see for some of these, we have partial answers, for others and for the latter 2, in particular, we currently fall well short. This is most unfortunate as the answers to these 2 questions should furnish the most objective definition of SIBO. It should also be noted that the second of these definitions2Bushyhead D. Quigley E.M.M. Small intestinal bacterial overgrowth.Gastroenterol Clin N Am. 2021; 50: 463-474Abstract Full Text Full Text PDF PubMed Google Scholar refers to “micro-organisms,” thus leaving the door open to a role for fungi, protozoa, and viruses, a concept that has already been floated in the context of small intestinal fungal overgrowth.4Jacob C. Coss Adame E. Attaluri A. Valestin J. Rao S.S.C. Dysmotility and PPI use are independent risk factors for small intestinal and/or fungal overgrowth.Aliment Pharmocol Ther. 2013; 37: 1103-1111Crossref PubMed Scopus (96) Google Scholar Our concept of SIBO has evolved considerably over time and a review of this history is vital toward an understanding of where we are today. Then referred to as “the blind loop syndrome,” SIBO was recognized as representing the consequences of bacterial overgrowth in, or “contamination” of, the small intestine leading to a malabsorption syndrome. In discussing current approaches to the diagnosis of SIBO it is vital to remember that this is the context in which many of our currently used diagnostic tests were developed–they were used in the evaluation of a maldigestion/malabsorption syndrome and not a functional gastrointestinal (GI) disorder. In other words, our forebears began with an objectively defined clinical entity and then studied how bacteria might play a role. Now, we attempt the very opposite, shoehorning clinical presentations into SIBO defined on the basis of poorly validated clinical tests. Some of the earliest reports of what was most likely SIBO date back to the mid to late 19th and early 20th centuries and refer to the development of megaloblastic anemia among individuals with small intestinal disease, including strictures5White W.H. On the pathology and prognosis of pernicious anemia.Guy’s Hosp Rep. 1890; 47: 149Google Scholar,6Barker W.H. Hummel L.E. Macrocytic anemia in association with intestinal strictures and anastomoses: review of literature and report of 2 new cases.Bull Johns Hopkins Hosp. 1939; 64: 215-256Google Scholar; how it came to be recognized that bacterial overgrowth was the common denominator to “a number of apparently diverse intestinal conditions, such as massive diverticulosis and intestinal stricture that present with a similar clinical picture of malnutrition, anemia, steatorrhea etc.” was nicely summarized by Card in 1959.7Card W.I. Blind loop syndrome.Proc R Soc Med. 1959; 52: 28-31PubMed Google Scholar One year later, at a meeting of the Section of Surgery of the Royal Society of Medicine, John Badenoch, a respected Oxford internist and gastroenterologist, described the clinical spectrum of SIBO as it was envisaged at that time and distinguished between 2 clinical presentations: a “surgical group” who had undergone an intestinal resection or bypass operation and a “medical group” in whom megaloblastic anemia, diarrhea, and/or steatorrhea were the presenting symptoms.8Badenoch J. The blind loop syndrome.Proc Roy Soc Med. 1960; 53: 657-658Crossref PubMed Scopus (0) Google Scholar While going on to describe the many clinical consequences that could result (hemorrhage from vitamin K deficiency, tetany and osteomalacia from vitamin D deficiency, as well as edema, muscle weakness from electrolyte and protein losses, and a dimorphic blood picture consequent on vitamin B12 and iron deficiency), Badenoch conceded that while diarrhea was “almost universal” and anemia common, steatorrhea occurred in only 20%. An early hint of trouble to come was the extension of the spectrum of SIBO beyond maldigestion and malabsorption. Along the way, the definition of SIBO both influenced and was influenced by a nascent understanding of the “normal” bacteria that reside in the human intestines.9Hewetson J.T. The bacteriology of certain parts of the human alimentary canal and of the inflammatory processes arising therefrom.Br Med J. 1904; 2: 1457-1460Crossref PubMed Google Scholar, 10Donaldson Jr., R.M. Normal bacterial populations of the intestine and their relation to intestinal function.N Engl J Med. 1964; 30: 938-945Crossref Scopus (115) Google Scholar, 11Donaldson Jr., R.M. Normal bacterial populations of the intestine and their relation to intestinal function.N Engl J Med. 1964; 270: 994-1001Crossref PubMed Google Scholar, 12Donaldson Jr., R.M. Normal bacterial populations of the intestine and their relation to intestinal function.N Engl J Med. 1964; 270: 1050-1056Crossref PubMed Google Scholar, 13Finegold S.M. Intestinal bacteria. The role that they play in normal physiology, pathologic physiology and infection.Calif Med. 1969; 110: 455-459PubMed Google Scholar In healthy hosts, micro-organism counts were shown to increase distally along the GI tract, with the proximal small bowel containing up to 103Rao S.S.C. Bhagatwala J. Small intestinal bacterial overgrowth: clinical features and therapeutic management.Clin Transl Gastroenterol. 2019; 10e00078Crossref Scopus (39) Google Scholar, 4Jacob C. Coss Adame E. Attaluri A. Valestin J. Rao S.S.C. Dysmotility and PPI use are independent risk factors for small intestinal and/or fungal overgrowth.Aliment Pharmocol Ther. 2013; 37: 1103-1111Crossref PubMed Scopus (96) Google Scholar, 5White W.H. On the pathology and prognosis of pernicious anemia.Guy’s Hosp Rep. 1890; 47: 149Google Scholar colony-forming units of bacteria per milliliter (CFU/mL), whereas the colon could harbor up to 1011 CFU/mL.14Sender R. Fuchs S. Milo R. Revised estimates for the number of human and bacteria cells in the body.PLoS Biol. 2016; 14e1002533Crossref PubMed Scopus (2020) Google Scholar Bacteria found in proximal small bowel cultures were typically gram-positive aerobic or facultative anaerobic bacteria such as Enterococcus and Streptococcus. Such low bacterial counts ensure that the small bowel did not face competition for nutrients after food ingestion. The more densely populated colon harbors coliforms such as the anaerobic Bacteroides, Lactobacillus, and Clostridia.15Eckburg P.B. Bik E.M. Bernstein C.N. et al.Microbiology: diversity of the human intestinal microbial flora.Science. 2005; 308: 1635-1638Crossref PubMed Scopus (5273) Google Scholar,16Bouhnik Y. Alain S. Attar A. et al.Bacterial populations contaminating the upper gut in patients with small intestinal bacterial overgrowth syndrome.Am J Gastroenterol. 1999; 94: 1327Crossref PubMed Scopus (158) Google Scholar The colon uses these bacteria to accomplish tasks such as bile acid deconjugation17Molinero N. Ruiz L. Sanchez B. et al.Intestinal bacteria interplay with bile and cholesterol metabolism: implications on host physiology.Front Physiol. 2019; 10: 185Crossref PubMed Scopus (103) Google Scholar and production of short-chain fatty acids, an important substrate for the colonic mucosa and formed from otherwise unabsorbed carbohydrates.18Wong J.M. de Souza R. Kendall C.W. et al.Colonic health: fermentation and short chain fatty acids.J Clin Gastroenterol. 2006; 40: 235-243Crossref PubMed Scopus (1729) Google Scholar The healthy small bowel uses several different protective mechanisms to avoid colonization and maintain relatively low bacterial numbers (Figure 1). Gastric acid, bile, and pancreatic secretions inhibit the proliferation of both ingested and oropharyngeal bacteria that may migrate distally. Small bowel antegrade motor patterns, including peristalsis and phase III of the interdigestive or migrating motor complex, reduce stasis and bacterial growth.19Vantrappen 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: 1158-1166Crossref PubMed Google Scholar The intestinal mucosa includes a mucus layer and intrinsic antibacterial mechanisms, such as defensins and immunoglobulins. Commensal small bowel microbiota inhibit colonization by potentially injurious or even pathogenic organisms. Finally, the ileocecal valve limits retrograde movement of anaerobic colonic bacteria.20Griffen Jr., W.O. Richardson J.D. Medley E.S. Prevention of small bowel contamination by ileocecal valve South.Med J. 1971; 64: 1056-1058Google Scholar, 21Miller L.S. Vegesna A.K. Sampath A.M. et al.Ileocecal valve dysfunction in small intestinal bacterial overgrowth: a pilot study.World J Gastroenterol. 2012; 18: 6801-6808Crossref PubMed Scopus (14) Google Scholar, 22Roland B.C. Ciarleglio M.M. Clarke J.O. et al.Low ileocecal valve pressure is significantly associated with small intestinal bacterial overgrowth (SIBO).Dig Dis Sci. 2014; 59: 1269-1277Crossref PubMed Scopus (27) Google Scholar In discussing the epidemiology, etiology, and pathophysiology of SIBO we distinguish between 2 potential clinical manifestations of SIBO:1.SIBO as a cause of maldigestion/malabsorption; here the clinical presentation can be related to the effects of contaminating organisms on host morphology or function that, in turn, result in the clinical consequences typically associated with SIBO, such as steatorrhea, diarrhea, protein losing-enteropathy, and/or specific deficiency states.2.SIBO associated with symptoms or clinical entities in the absence of evidence of maldigestion/malabsorption (eg, SIBO in association with irritable bowel syndrome [IBS]) and where the pathophysiological linkage with SIBO is less clearly defined. In the absence of any community-based data, our only information on the prevalence of SIBO is mostly derived from retrospective surveys in symptomatic or at-risk cohorts. Table 1 presents several representative studies of SIBO prevalence in symptomatic and asymptomatic control populations,23McEvoy A. Dutton J. James O.F. Bacterial contamination of the small intestine is an important cause of occult malabsorption in the elderly.Br Med J. 1983; 287: 789-793Crossref PubMed Google Scholar, 24McMahon M. Lynch M. Mullins E. et al.Small intestinal bacterial overgrowth – an incidental finding?.J Am Geriatr Soc. 1994; 42: 146-149Crossref PubMed Scopus (25) Google Scholar, 25De Boissieu D. Chaussain M. Badoual J. et al.Small-bowel bacterial overgrowth in children with chronic diarrhea, abdominal pain or both.J Pediatr. 1996; 128: 203-207Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 26Riordan S.M. McIver C.J. Wakefield D. et al.Small intestinal bacterial overgrowth in the symptomatic elderly.Am J Gastroenterol. 1997; 92: 47-51PubMed Google Scholar, 27Parlesak A. Klein B. Schecher K. et al.Prevalence of small bowel bacterial overgrowth and its association with nutrition intake in nonhospitalized older adults.J Am Geriatr Soc. 2003; 51: 768-773Crossref PubMed Scopus (65) Google Scholar, 28Torres Lam R. Leon Barua R. Berendson Seminario R. et al.Small intestine bacterial overgrowth in patients with chronic diarrhea and normal control subjects.Rev Gastroenterol Peru. 2003; 23: 111-114PubMed Google Scholar, 29Teo M. Chung S. Chitti L. et al.Small bowel bacterial overgrowth is a common cause of chronic diarrhea.J Gastroenterol Hepatol. 2004; 19: 904-909Crossref PubMed Scopus (0) Google Scholar, 30Mitsui T. Shimaoka K. Goto Y. et al.Small bowel bacterial overgrowth is not seen in healthy adults but is in disabled older adults.Hepatogastroenterology. 2006; 53: 82-85PubMed Google Scholar whereas Table 2 presents common disorders that have been associated with SIBO. It can be readily observed that, whereas the likelihood of a positive test for SIBO varies according to the methodology used (culture vs breath test) and the geographic location of the study, SIBO is more common in the elderly among whom it appears to be a relatively common cause of diarrhea and malnutrition.Table 1Prevalence of SIBO in Selected Symptomatic and Asymptomatic Control SubjectsCountryNo. and type of subjectsDiagnostic test(s)% PositiveYear and reference no.England30, elderly malnutritionAspirate and culture31198323McEvoy A. Dutton J. James O.F. Bacterial contamination of the small intestine is an important cause of occult malabsorption in the elderly.Br Med J. 1983; 287: 789-793Crossref PubMed Google ScholarIreland30, elderly acutely illAspirate and culture66199424McMahon M. Lynch M. Mullins E. et al.Small intestinal bacterial overgrowth – an incidental finding?.J Am Geriatr Soc. 1994; 42: 146-149Crossref PubMed Scopus (25) Google ScholarFrance53, children age 2 mo to 12 y with diarrhea and/or abdominal painGlucose breath test34199625De Boissieu D. Chaussain M. Badoual J. et al.Small-bowel bacterial overgrowth in children with chronic diarrhea, abdominal pain or both.J Pediatr. 1996; 128: 203-207Abstract Full Text Full Text PDF PubMed Scopus (0) Google ScholarAustralia52, symptomaticDyspepsiaDiarrhea age <50Diarrhea age 50–74Diarrhea age ≥75Aspirate and culture001064199726Riordan S.M. McIver C.J. Wakefield D. et al.Small intestinal bacterial overgrowth in the symptomatic elderly.Am J Gastroenterol. 1997; 92: 47-51PubMed Google ScholarGermany294, age >6134, age 24–59All living in the communityGlucose breath test15.65.9200327Parlesak A. Klein B. Schecher K. et al.Prevalence of small bowel bacterial overgrowth and its association with nutrition intake in nonhospitalized older adults.J Am Geriatr Soc. 2003; 51: 768-773Crossref PubMed Scopus (65) Google ScholarPeru54, chronic diarrhea15, controlsLactulose breath test2412.5200328Torres Lam R. Leon Barua R. Berendson Seminario R. et al.Small intestine bacterial overgrowth in patients with chronic diarrhea and normal control subjects.Rev Gastroenterol Peru. 2003; 23: 111-114PubMed Google ScholarAustralia87, chronic diarrhea15, controlsAspirate and culture330200429Teo M. Chung S. Chitti L. et al.Small bowel bacterial overgrowth is a common cause of chronic diarrhea.J Gastroenterol Hepatol. 2004; 19: 904-909Crossref PubMed Scopus (0) Google ScholarJapan41, healthy elderly42, disabled elderlyGlucose breath test025.6200630Mitsui T. Shimaoka K. Goto Y. et al.Small bowel bacterial overgrowth is not seen in healthy adults but is in disabled older adults.Hepatogastroenterology. 2006; 53: 82-85PubMed Google Scholar Open table in a new tab Table 2Disorders Linked to SIBOAbnormal small intestinal motility Diabetic autonomic neuropathy Systemic sclerosis/scleroderma Amyloidosis Hypothyroidism Idiopathic intestinal pseudo-obstruction Acromegaly Gastroparesis Myotonic muscular dystrophy Chronic opiate use Long-standing use of motility-suppressing drugsAnatomic abnormalities Small intestinal diverticulosis Surgically induced alterations in anatomy (Billroth II gastrectomy, end-to-side anastomosis) Strictures (Crohn’s disease, radiation, surgery) Blind loops Gastrocolic or jejunocolic fistula Ileo-cecal valve resection HypochlorhydriaPostsurgicalLong-term acid suppressionImmune deficiency Inherited immune deficiencies Acquired immune deficiency (eg, AIDS, severe malnutrition)Multifactorial Chronic pancreatitis Celiac disease Tropical sprue Crohn’s disease Cystic fibrosis Intestinal failure Radiation enteropathy Liver disease End-stage renal disease Open table in a new tab Small bowel motor patterns, including the migrating motor complex, promote antegrade movement of intestinal contents and reduce stasis and, thereby, limit bacterial growth. Diabetic autonomic neuropathy and scleroderma are prominent examples of dysmotility-related SIBO. In a patient with diabetes and diarrhea and especially in the individual with long-standing type 1 diabetes,31Ojetti V. Pitocco D. Scarpellini E. et al.Small bowel bacterial overgrowth and type 1 diabetes.Eur Rev Med Pharmacol Sci. 2009; 13: 419-423PubMed Google Scholar SIBO should be sought as a potentially remediable cause. SIBO is common in scleroderma being documented in 43%–56% of patients in 2 studies.32Marie I. Ducrotté P. Denis P. et al.Small intestinal bacterial overgrowth in systemic sclerosis.Rheumatology. 2009; 48: 1314-1319Crossref PubMed Google Scholar,33Parodi A. Sessarego M. Greco A. et al.Small intestinal bacterial overgrowth in patients suffering from scleroderma: clinical effectiveness of its eradication.Am J Gastroenterol. 2008; 103: 1257-1262Crossref PubMed Scopus (64) Google Scholar Intestinal pseudo-obstruction and jejunal diverticulosis are 2 less common situations where SIBO develops on the basis of myogenic or neurogenic intestinal dysmotility.34Krishnamurthy S. Kelly M.M. Rohrmann C.A. Schuffler M.D. Jejunal diverticulosis: a heterogeneous disorder caused by a variety of abnormalities of smooth muscle or myenteric plexus.Gastroenterology. 1983; 85: 538-547Abstract Full Text PDF PubMed Google Scholar Diverticula in the jejunum occur in 0.07%–2% of the population and tend to be large and multiple, whereas those in the ileum are small and single. These features explain the observation that symptoms and complications, such as SIBO, have been reported more frequently in association with jejunal than with ileal diverticula. Jejunal diverticula are twice as frequent in men and are observed predominantly among those older than 60 years of age. A variety of surgical procedures that alter GI anatomy have been associated with SIBO.35Lakhani S.V. Shah H.N. Alexander K. et al.Small intestinal bacterial overgrowth and thiamine deficiency after Roux-en-Y gastric bypass surgery in obese patients.Nutr Res. 2008; 28: 293-298Crossref PubMed Scopus (107) Google Scholar, 36Paik C.N. Choi M.G. Lim C.H. et al.The role of small intestinal bacterial overgrowth in post-gastrectomy patients.Neurogastroenterol Motil. 2011; 23: e191-e196Crossref PubMed Scopus (0) Google Scholar, 37Mo J. Gao L. Zhang N. et al.Structural and quantitative alterations of gut microbiota in experimental small bowel obstruction.PLoS One. 2021; 16 (e0255651.xw)Crossref Scopus (0) Google Scholar Indeed, much of the original work on SIBO was performed on postgastrectomy patients.38Neale G. Gompertz D. Schönsby H. et al.The metabolic and nutritional consequences of bacterial overgrowth in the small intestine.Am J Clin Nutr. 1972; 25: 1409-1417Crossref PubMed Google Scholar Here again a number of pathophysiological factors may be operative: hypochlorhydria, formation of blind loops (depending on the nature of the surgical procedure), lack of contact between chyme and bile and/or digestive enzymes, and disruption of intestinal motility. Stagnation and/or recirculation of intestinal contents resulting from strictures, fistulas, enterostomies, and anastomoses also predispose to SIBO, thus, explaining the frequent association of SIBO with Crohn’s disease, radiation enteropathy, and reconstructive surgery. Indeed, SIBO should be considered in the differential diagnosis of a symptomatic relapse of Crohn’s disease.39Klaus J. Spaniol U. Adler G. et al.Small intestinal bacterial overgrowth mimicking acute flare as a pitfall in patients with Crohn’s disease.BMC Gastroenterol. 2009; 9: 61Crossref PubMed Scopus (0) Google Scholar As previously mentioned, small bowel diverticulosis is also a risk factor for SIBO. Initially described in relation to surgical procedures that reduced gastric acid secretion, hypochlorhydria has, perhaps inevitably, been invoked in the development of SIBO among individuals on long-term treatment with proton-pump inhibitors (PPIs). Although some studies suggested that long-term PPI therapy was associated with SIBO,40Lombardo L. Foti M. Ruggia O. Chiecchio A. Increased incidence of small intestinal bacterial overgrowth during proton pump inhibitor therapy.Clin Gastroenterol Hepatol. 2010; 8: 504-508Abstract Full Text Full Text PDF PubMed Scopus (236) Google Scholar,41Lo W.K. Chan W.W. Proton pump inhibitor use and the risk of small intestinal bacterial overgrowth: a meta-analysis.Clin Gastroenterol Hepatol. 2013; 11: 483-490Abstract Full Text Full Text PDF PubMed Scopus (213) Google Scholar others have failed to confirm this.42Ratuapli S.K. Ellington T.G. O'Neill M.T. et al.Proton pump inhibitor therapy use does not predispose to small intestinal bacterial overgrowth.Am J Gastroenterol. 2012; 107: 730-735Crossref PubMed Scopus (83) Google Scholar Furthermore, although their meta-analysis revealed a pooled odds ratio of 2.82 for SIBO among PPI users vs nonusers, Lo and Chan41Lo W.K. Chan W.W. Proton pump inhibitor use and the risk of small intestinal bacterial overgrowth: a meta-analysis.Clin Gastroenterol Hepatol. 2013; 11: 483-490Abstract Full Text Full Text PDF PubMed Scopus (213) Google Scholar found that this association held true only for studies using intestinal culture rather than breath tests in making the diagnosis of SIBO. Similarly, Ratuapli et al,42Ratuapli S.K. Ellington T.G. O'Neill M.T. et al.Proton pump inhibitor therapy use does not predispose to small intestinal bacterial overgrowth.Am J Gastroenterol. 2012; 107: 730-735Crossref PubMed Scopus (83) Google Scholar who failed to identify a relationship between PPI use and SIBO, based their analysis on breath tests. Although gastric acid secretion and immune responses may decrease in later life, small intestinal dysmotility, rather than fasting hypochlorhydria or immunodeficiency, is probably the major contributor to the relatively high prevalence of SIBO that has been reported among the elderly. It is important to emphasize that hypochlorhydria may be an important cofactor in the development of SIBO when it coexists with other predisposing factors. SIBO has been described in association with hypogammaglobulinemia, both in inherited and acquired forms,43Ghoshal U.C. Goel A. Ghoshal U. et al.Chronic diarrhea and malabsorption due to hypogammaglobulinemia: a report of twelve patients.Indian J Gastroenterol. 2011; 30: 170-174Crossref PubMed Scopus (0) Google Scholar as well as with disorders of cellular immunity, such as human immunodeficiency virus infection. The cause of SIBO in chronic pancreatitis is multifactorial and includes the loss of pancreatic enzymes, a decrease in intestinal motility consequent upon the inflammatory process, the effects of narcotics on gut motility, and the presence, in some instances, of intestinal obstruction. SIBO has long been regarded as a potential complication of celiac disease and one of the causes of a failure to respond to gluten withdrawal44Ghoshal U.C. Ghoshal U. Misra A. Choudhuri G. Partially responsive celiac disease resulting from small intestinal bacterial overgrowth and lactose intolerance.BMC Gastroenterol. 2004; 4: 10Crossref PubMed Scopus (0) Google Scholar,45Tursi A. Brandimarte G. Giorgetti G. High prevalence of small intestinal bacterial overgrowth in celiac patients with persistence of gastrointestinal symptoms after gluten withdrawal.Am J Gastroenterol. 2003; 98: 839-843Crossref PubMed Scopus (154) Google Scholar; here, again, a number of factors may be operative: dysmotility and impaired defenses against bacterial colonization and pancreatic insufficiency, for example (Figure 1). Overall, SIBO may be responsible for 9%–10% of all instances of nonresponsive celiac disease.46Rubio-Tapia A. Barton S.H. Rosenblatt J.E. Murray J.A. Prevalence of small intestine bacterial overgrowth diagnosed by quantitative culture of intestinal aspirate in celiac disease.J Clin Gastroenterol. 2009; 43: 157-161Crossref PubMed Scopus (76) Google Scholar,47Dewar D.H. Donnelly S.C. McLaughlin S.D. et al.Celiac disease: management of persistent symptoms in patients on a gluten-free diet.World J Gastroenterol. 2012; 18: 1348-1356Crossref PubMed Scopus (78) Google Scholar Those with coexistent SIBO have evidence of more severe malabsorption. However, a more recent study failed to demonstrate any benefit from a course of rifaximin among a group of patients with nonresponsive celiac.48Chang M.S. Minaya M.T. Cheng J. et al.Double -blind randomized controlled trial of rifaximin for persistent symptoms in patients with celiac disease.Dig Dis Sci. 2011; 56: 2939-2946Crossref PubMed Scopus (0) Google Scholar It is likely that multiple factors contribute to the pathophysiology of instances of SIBO reported in association with cystic fibrosis,49Lisowska A. Pogorzelski A. Oracz G. Siunda K. et al.Oral antibiotic therapy improves fat absorption in cystic fibrosis patients with small intestine bacteraial overgrowth.J Cyst Fibros. 2011; 10: 418-421Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar,50Lisowska A. Wojtowicz J. Walkowiak J. Small intestinal bacterial overgrowth is frequent in cystic fibrosis: combined hydrogen and methane measurements are required for its detection.Acta Biochim Pol. 2009; 56: 631-634PubMed Google Scholar intestinal failure,51Malik B.A. Xie Y.Y. Wine E. Huynh H.Q. Diagnosis and pharmacological management of small intestinal bacterial overgrowth in children with intestinal failure.Can J Gastroenterol. 2011; 25: 41-45Crossref PubMed Google Scholar and liver disease.52Quigley E.M. Stanton C. Murphy E.F. The gut microbiota and the