REVIEW URRENT C OPINION
Small intestinal bacterial overgrowth: what it is and what it is not Eamonn M.M. Quigley
Purpose of review To critically review recent literature on small intestinal bacterial overgrowth (SIBO). Recent findings When originally described, SIBO was added to the list of causes of the malabsorption syndrome and the pathophysiology of its consequences for the digestion and absorption of various nutrients was gradually revealed. More recently, SIBO was incriminated as a cause of diarrhea, especially in the elderly. However, the suggestion that SIBO may be a causative factor in irritable bowel syndrome and of its constituent symptoms has sparked debate and controversy on the very definition of SIBO. This debate revolves around the tests employed and the diagnostic cut-off values (for bacterial numbers) used to diagnose SIBO in clinical practice. Summary A fundamental problem with SIBO, and one that allows controversy to simmer, is the lack of a universally accepted and applied gold standard for the diagnosis of SIBO. Hopefully, the application of molecular microbiological methods to the characterization of the small intestinal microbiome will tell us, once and for all, what is normal and when ‘abnormality’ is truly responsible for symptoms and disease. Meanwhile, therapy remains, for the most part, empirical and is based on the correction, wherever possible, of any underlying cause, attention to nutritional deficiencies, and the use of antibiotics. Keywords diarrhea, hydrogen breath test, jejunal culture, malabsorption, small intestinal bacterial overgrowth
INTRODUCTION When originally described in a series of classical clinical and pathophysiological studies performed toward the middle of the last century, small intestinal bacterial overgrowth (SIBO) could be succinctly defined as ‘clinical and/or laboratory evidence of maldigestion/malabsorption related to qualitative and/or quantitative alterations in the small intestinal microbiota’. In these elegant studies, the consequences of SIBO in terms of B12 absorption, bile salt deconjugation, protein, carbohydrate and fat assimilation, and intestinal injury were delineated and a number of underlying disorders (e.g., achlorhydria, dysmotility, fistulae, and strictures) revealed [1]. Diagnosis rested largely on the aspiration and quantitative culture of jejunal contents and therapy was based on the empiric use of broad-spectrum antibiotics. Much has changed since then. First, breath tests and the analysis of duodenal fluid obtained through an endoscope replaced jejunal aspirates. Second, the clinical context wherein the diagnosis of SIBO is
entertained shifted dramatically from those aforementioned situations in which a plausible basis for the development of SIBO was evident and its clinical consequences (steatorrhea, B12 deficiency, proteinlosing enteropathy) visible, to a situation in which SIBO is incriminated as the cause of a broad spectrum of intestinal and extraintestinal ills. A good example of this seismic shift in our concept of SIBO is the much publicized proposal that SIBO is associated with irritable bowel syndrome (IBS), a suggestion that has generated considerable controversy and thrown the definition of SIBO into sharp relief [2]. In these instances, SIBO is linked to symptoms or Division of Gastroenterology and Hepatology, Houston Methodist Hospital, Houston, Texas, USA Correspondence to Eamonn M. M. Quigley, MD, FRCP, FACP, FACG, FRCPI, Chief, Division of Gastroenterology, Houston Methodist Hospital, 6550 Fannin St, Smith Tower 401, Houston, TX 77030, USA. E-mail: [email protected] Curr Opin Gastroenterol 2014, 30:141–146 DOI:10.1097/MOG.0000000000000040
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KEY POINTS SIBO is a well recognized cause of maldigestion and malabsorption. Until the clinical definition of SIBO is more precise, its role in other clinical contexts will remain controversial. There is currently no gold standard for the definition of SIBO. Treatment of SIBO remains largely empirical.
clinical entities in the absence of evidence of maldigestion/malabsorption and in a context in which the pathophysiological relationship with SIBO is far from clearly defined. Consequently, and critically, these associations then become totally reliant on two factors: the definition of SIBO and the performance characteristics of the test used to define it and, specifically, on the ability of that test to distinguish health from disease. Typically, correlations between original test results and the clinical responses to SIBO eradication have not been reported or, if they have, their interpretation remains rather murky. Absent such evidence and lacking biochemical and/or pathological findings that can be plausibly linked to SIBO, it has often been unclear in these situations whether SIBO is a cause, a consequence, or an epiphenomenon in relation to the other supposedly associated disorder.
THE NORMAL HUMAN MICROBIOME Although our understanding of the human microbiome, its various functions, and interactions with the host has increased at a very rapid pace, it must be remembered that most human studies of the gut microbiome have been based on fecal samples. In contrast, and due to its inaccessibility, relatively few studies have attempted to define the normal microbiological profile of the stomach, duodenum, jejunum, and ileum. If experience gained in studies of the colon is, as is very likely, reproduced in the small intestine, two important observations derived from studies on the microbiota of the large intestine need to be emphasized. First, it is likely that the majority of the strains that normally comprise the small intestinal microbiota have not been identified by conventional culture approaches and, second, it is very probable that luminal and juxtamucosal bacterial populations are not the same. We already know from time-honored culture-based studies that there is a very dramatic change in bacterial numbers and diversity as one moves longitudinally along the small intestine indicating that, when the complete 142
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small intestinal microbiome is finally revealed, regional differences will be even more evident. So what do we know of the composition of the small intestinal microbiome, the very starting point for considering the diagnostic validity of any test that purports to define SIBO? The complete characterization of the microbiota of the small intestine and the final resolution of current controversies regarding the diagnostic validity of various tests for SIBO will come from studies that not only define the complete microbiome of the duodenum, jejunum, and ileum, but also enumerate its functions, employing such techniques as metabolomics and metatranscriptome analysis [3]. In this manner, abnormal microbial populations can be identified and their metabolic and immunological functions linked to symptoms and disease. Although much has been learned regarding the fecal microbiome and, to a lesser extent, colonic bacterial populations, very few studies have sought to explore the bacterial populations of the small intestine employing modern sequencing approaches [4]. To date, there is limited information on the ileum, thanks to studies of ileostomy effluent [3,5–8,9 ] or terminal ileal biopsies [8,10], and duodenum, based on duodenal biopsies [11–21]. Many of the latter studies are related to explorations of relationships between the microbiota and celiac diseases, whether treated or untreated [11–20]. All of these studies involved relatively small numbers of normal controls. Furthermore, the validity of ileostomy effluent sampling has been questioned [5] and relationships between duodenal mucosal and luminal communities have scarcely been examined. Apart from one autopsy study involving just three participants [21], the distal duodenum, jejunum, and proximal ileum continue to represent terra incognita, as far as the full characterization of their microbiomes is concerned. Available data [21], as well as results from animal studies [22], indicate significant differences in microbial populations along the small intestine. Though relatively inaccessible, techniques for sampling the jejunum and ileum have been developed [10,23,24], so it is to be hoped that more data are imminent. So for now, old, far from gold standards must prevail [25]. So what of the old and sometimes trusted? &
RISK FACTORS The prevalence of SIBO in the general population is unknown; depending on the study population or the test employed, SIBO has been detected in anywhere from 0 to 20% of apparently healthy controls [26 ]. Wide variations in prevalence rates have also &&
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been reported for disorders apparently associated with SIBO; in IBS, for example, the prevalence of SIBO has ranged from 4 to 64%. These numbers underscore the dilemma that SIBO presents; not only is there no ‘gold’ standard for its definition or diagnosis, but the interpretation of widely employed tests such as breath tests also lacks consensus. Not surprisingly, the sensitivity and specificity of breath tests and of the lactulose breath hydrogen test (LBT), in particular, leave much to be desired. Rana et al. [27], for example, found that 34.3% of their IBS patients had a positive LBT; in contrast, only 6.2% were positive on a glucose breath test. In IBS and other disorders in which transit may be accelerated, lactulose will arrive prematurely in the cecum and provide a false-positive result for SIBO [28].
THE CLINICAL CONTEXT &&
In their comprehensive review, Grace et al. [26 ] evaluated relationships between SIBO and symptoms and other presenting features. Their first observation was that there was surprisingly little literature on the symptomatology of SIBO and, although a myriad of symptoms, clinical signs, and laboratory findings have been reported in relation to SIBO, only diarrhea, abdominal pain, and bloating had been linked with any degree of consistency. These three symptoms, of course, are not only common, but also nonspecific; no wonder that so many clinicians and clinical investigators have been attracted to the possibility that SIBO may be a causative factor in IBS [29–31], an association that has been hotly debated and disputed [32]. Can one identify risk factors that might help to raise suspicion for the presence of SIBO? A number of factors that predispose to SIBO were identified in the older literature and included the consequences of interventions that impaired acid secretion and/or altered intestinal anatomy as well as a number of disease states. Common to these situations were defects in the physiological functions that normally prevent colonization: gastric acid, gut motility (and the migrating motor complex, in particular [33]), and an intact mucosal immune system. Although the likelihood of a positive test for SIBO varies according to the methodology employed (culture vs. breath test) and the geographic location of the study, SIBO is, in general, more common in the elderly among whom it appears to be an important cause of unexplained diarrhea. The relative prevalence of the traditional risk factors for SIBO nowadays is provided by a large retrospective series of patients who had duodenal aspirates performed; here the main risk factors for SIBO were older age, steatorrhea, and the use of
narcotics and significantly associated disorders included inflammatory bowel disease, chronic pancreatitis, and jejunal diverticulosis [34]. In a study limited to children with intestinal failure, Gutierrez et al. [35] identified parenteral nutrition as the only clinical variable independently associated with SIBO. Interestingly, in this same study, SIBO was not a predictor of risk for catheter-related bacteremia. As the surgical procedures that were formerly associated with SIBO have become much less common, the more recent literature has been dominated by associations between SIBO and a host of medical disorders. Some of these will come as little surprise as they relate to traditional risk factors for SIBO. For example, SIBO is common in systemic sclerosis and is associated with impaired motility [36] and pneumatosis cystoides intestinalis [37]; in diabetes mellitus (both types I and II), an increased prevalence of SIBO is also linked to delayed transit [38,39] and appears to result in impaired nutritional status [38]. Concomitant small intestinal dysmotility may well also explain reported associations between gastroparesis [40] and erosive esophagitis [41] and SIBO. Small intestinal dysmotility and impaired transit leading to stasis have long been invoked to explain the high prevalence of SIBO described among patients with liver disease; SIBO in combination with enhanced intestinal permeability has, in turn, been regarded as fundamental to the occurrence of bacterial translocation and the development of such complications as bacteremia and spontaneous bacterial peritonitis [42,43 ]. Although there is a considerable volume of experimental data to support this concept, clinical observations have been more divergent. Thus, whereas some have associated decompensated cirrhosis with delayed intestinal transit [44], others have failed to link SIBO with translocation in cirrhosis [12]. It seems plausible, though undocumented, that disturbances in small intestinal motility might also explain the link proposed between Parkinson’s disease and SIBO [45 ,46,47]. The presence of SIBO has been linked with greater rigidity [46] and more on-off fluctuations [45 ]. The impact of treating SIBO seems unclear. Whereas Fasano et al. [45 ] noted an improvement in motor fluctuations following SIBO eradication, Dobbs et al. [48] found that antimicrobial therapy for SIBO, despite normalizing breath tests, worsened rigidity. SIBO is common in inflammatory bowel disease and has been linked in Crohn’s disease to coloenteric fistula, intestinal stasis secondary to strictures, and surgical loss or disease of the ileocolonic sphincter. Rana et al. [49] reported positive breath tests in 45.2 and 17.8% of their Crohn’s disease and ulcerative colitis patients, respectively, and related its occurrence to delayed
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orocecal transit, suggesting that dysmotility may be a factor in predisposing to SIBO in these diseases also. In the past, achlorhydria or hypochlorhydria was associated with SIBO primarily in the aftermath of peptic ulcer surgery; nowadays, the focus is on the possibility that acid-reducing medications, and proton pump inhibitors (PPIs), in particular, may be likewise incriminated. To date, the findings have been inconclusive with some studies supporting a link between PPI use and SIBO [50 ] and others failing to detect this association [34,51,52]. In their meta-analysis of the data, Lo and Chan [53 ] calculated a pooled odds ratio for SIBO of 2.282 for PPI users in comparison to nonusers, but found that this association held only for those studies that employed duodenal or jejunal aspirates rather than breath tests. In the past, SIBO has been linked to diseases and surgical procedures that result in damage to or loss of the ileocecal junction. In an intriguing study of the ileocecal valve in man, Miller et al. [54 ] found that a defective ileocecal valve response to cecal distension was associated with LBT-defined SIBO. Reported associations between SIBO and bariatric surgical procedures [55] and cystic fibrosis [56] may well involve multiple pathophysiological factors; how and why SIBO is linked with chronic urticaria [57] and restless legs syndrome [58] is not clear. &
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greater reliability, the glucose breath test has been criticized on the basis of its inability to detect overgrowth in the more distal reaches of the small intestine – distal overgrowth, a much discussed, but ill-defined entity. Though no longer in vogue, the quantitative culture of jejunal aspirates did benefit from correlations between bacterial counts and objective measures of intestinal dysfunction and, thereby, still provides the most convincing pathophysiological link between SIBO and symptoms and/or disease. For now all that can be said with regard to tests for SIBO: proceed (or, rather, interpret) with caution. The limitations of currently available diagnostic methods were illustrated in one study in which both a LBT and a jejunal aspirate were performed on 11 healthy controls and 15 patients predisposed to SIBO. Breath testing was associated with a high false-positive rate and, disappointingly, the use of molecular methods did not increase the yield of aspirates [61].
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MANAGEMENT It is clear from all that has been described above that SIBO, though a relatively common and important clinical entity, presents considerable problems in definition, which, clearly, have implications for management. So where does this leave the clinician? In a situation in which the clinical features suggest the possibility of SIBO, the clinician has two options: test and treat, or treat empirically. This approach assumes that the clinical context is well defined and the results of the two management approaches are well documented. Let us now examine each of these approaches.
Test and treat Intellectually, this should be the preferred option, but as emphasized by several critical reviews [59,60 ], current diagnostic options suffer from important limitations in relation to their performance and interpretation. These various tests suffer either from being invasive and cumbersome (jejunal aspiration), not being validated (duodenal aspiration), or unreliable (LBT). Though associated with &&
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Treat empirically (the therapeutic trial) Given the problems associated with all of the available tests for the diagnosis of SIBO, it should come as no surprise that clinicians have turned to therapeutic trials of antibiotics as an alternative diagnostic strategy. However appealing the therapeutic trial may seem, it currently lacks standardization with respect to choice of antibiotic, as well as its dose and duration of therapy or appropriate outcome measures. It remains an entirely empirical approach. Its limitations are vividly illustrated by the comprehensive review and meta-analysis performed by Shah et al. [60 ]. In all, only 10 trials of antibiotic therapy proved suitable for inclusion in their analysis and many suffered from significant limitations. In terms of clinical response, antibiotics, as a whole, were more effective than placebo (effectiveness ratio: 2.55; 95% confidence interval: 1.29– 5.04); the antibiotic with the greatest number of studies, rifaximin, did not achieve statistical significance in their meta-analysis (effectiveness ratio: 1.97; 95% confidence interval: 0.93–4.17). Overall, antibiotic therapy normalized breath tests in 51.1% of patients with results for individual antibiotic regimens ranging from 21.7% (low-dose rifaximin) to 100% (ciprofloxacin). Although data on clinical outcomes were rather limited, responses did appear dependent on eradication with clinical responses ranging from 62 to 91% for those who were successfully eradicated (as judged by breath test normalization) in comparison with only 7 to 34% for those who were not. Their findings with respect to the &&
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empirical treatment approach were not reassuring as overall clinical responses (irrespective of breath test results) were quite mixed [60 ]. Although prolonged ‘remissions’ following a single course of antibiotics have been reported, recurrence rates, in general, are high [45 ]. For this reason, it has been suggested that antibiotic therapy be followed by treatment with a prebiotic or probiotic. Although this approach sounds attractive in principle, data to support it are scanty [62]. &&
REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest
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CONCLUSION Two clinical scenarios may be encountered that may involve SIBO. The first, which may be regarded as classical SIBO, refers to the situation in which clinical features can be pathophysiologically linked with SIBO; affected patients typically present with features of malabsorption and/or maldigestion. Here the diagnostic and therapeutic approaches have been rather well developed and, to some degree, validated. In this more restricted concept of SIBO, culture of jejunal fluid remains a valuable benchmark as abnormal results correlate well with such clinical and pathological consequences as steatorrhea and anemia. The second relates to the patient with no overt evidence of malabsorption/ maldigestion in whom symptoms have been linked to SIBO. Here it is clear that we do not have validated criteria for the incrimination of SIBO as the accuracy of all current tests remains limited in this context. When we extend the concept of SIBO into these areas, we are bereft of a gold standard and issues such as the clinical implications of lower levels of contamination and distal overgrowth come into play; these issues are unresolved. From a clinical perspective, only a full clinical response to a course of appropriate antibiotics can satisfy the clinician that SIBO is the villain but here, again, effects on the colonic flora may complicate interpretation. Modern genomic and metabolomic techniques offer much promise in defining true normality and then fully identifying alterations in the flora in disease states; we look forward to their application to the diagnosis and management of SIBO. Acknowledgements None. Conflicts of interest The study is supported, in part, through a grant from Science Foundation Ireland to the Alimentary Pharmabiotic Centre at University College Cork, Cork, Ireland. There are no conflicts of interest.
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Small intestinal bacterial overgrowth: what it is and what it is not Eamonn M.M. Quigley
Purpose of review To critically review recent literature on small intestinal bacterial overgrowth (SIBO). Recent findings When originally described, SIBO was added to the list of causes of the malabsorption syndrome and the pathophysiology of its consequences for the digestion and absorption of various nutrients was gradually revealed. More recently, SIBO was incriminated as a cause of diarrhea, especially in the elderly. However, the suggestion that SIBO may be a causative factor in irritable bowel syndrome and of its constituent symptoms has sparked debate and controversy on the very definition of SIBO. This debate revolves around the tests employed and the diagnostic cut-off values (for bacterial numbers) used to diagnose SIBO in clinical practice. Summary A fundamental problem with SIBO, and one that allows controversy to simmer, is the lack of a universally accepted and applied gold standard for the diagnosis of SIBO. Hopefully, the application of molecular microbiological methods to the characterization of the small intestinal microbiome will tell us, once and for all, what is normal and when ‘abnormality’ is truly responsible for symptoms and disease. Meanwhile, therapy remains, for the most part, empirical and is based on the correction, wherever possible, of any underlying cause, attention to nutritional deficiencies, and the use of antibiotics. Keywords diarrhea, hydrogen breath test, jejunal culture, malabsorption, small intestinal bacterial overgrowth
INTRODUCTION When originally described in a series of classical clinical and pathophysiological studies performed toward the middle of the last century, small intestinal bacterial overgrowth (SIBO) could be succinctly defined as ‘clinical and/or laboratory evidence of maldigestion/malabsorption related to qualitative and/or quantitative alterations in the small intestinal microbiota’. In these elegant studies, the consequences of SIBO in terms of B12 absorption, bile salt deconjugation, protein, carbohydrate and fat assimilation, and intestinal injury were delineated and a number of underlying disorders (e.g., achlorhydria, dysmotility, fistulae, and strictures) revealed [1]. Diagnosis rested largely on the aspiration and quantitative culture of jejunal contents and therapy was based on the empiric use of broad-spectrum antibiotics. Much has changed since then. First, breath tests and the analysis of duodenal fluid obtained through an endoscope replaced jejunal aspirates. Second, the clinical context wherein the diagnosis of SIBO is
entertained shifted dramatically from those aforementioned situations in which a plausible basis for the development of SIBO was evident and its clinical consequences (steatorrhea, B12 deficiency, proteinlosing enteropathy) visible, to a situation in which SIBO is incriminated as the cause of a broad spectrum of intestinal and extraintestinal ills. A good example of this seismic shift in our concept of SIBO is the much publicized proposal that SIBO is associated with irritable bowel syndrome (IBS), a suggestion that has generated considerable controversy and thrown the definition of SIBO into sharp relief [2]. In these instances, SIBO is linked to symptoms or Division of Gastroenterology and Hepatology, Houston Methodist Hospital, Houston, Texas, USA Correspondence to Eamonn M. M. Quigley, MD, FRCP, FACP, FACG, FRCPI, Chief, Division of Gastroenterology, Houston Methodist Hospital, 6550 Fannin St, Smith Tower 401, Houston, TX 77030, USA. E-mail: [email protected] Curr Opin Gastroenterol 2014, 30:141–146 DOI:10.1097/MOG.0000000000000040
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KEY POINTS SIBO is a well recognized cause of maldigestion and malabsorption. Until the clinical definition of SIBO is more precise, its role in other clinical contexts will remain controversial. There is currently no gold standard for the definition of SIBO. Treatment of SIBO remains largely empirical.
clinical entities in the absence of evidence of maldigestion/malabsorption and in a context in which the pathophysiological relationship with SIBO is far from clearly defined. Consequently, and critically, these associations then become totally reliant on two factors: the definition of SIBO and the performance characteristics of the test used to define it and, specifically, on the ability of that test to distinguish health from disease. Typically, correlations between original test results and the clinical responses to SIBO eradication have not been reported or, if they have, their interpretation remains rather murky. Absent such evidence and lacking biochemical and/or pathological findings that can be plausibly linked to SIBO, it has often been unclear in these situations whether SIBO is a cause, a consequence, or an epiphenomenon in relation to the other supposedly associated disorder.
THE NORMAL HUMAN MICROBIOME Although our understanding of the human microbiome, its various functions, and interactions with the host has increased at a very rapid pace, it must be remembered that most human studies of the gut microbiome have been based on fecal samples. In contrast, and due to its inaccessibility, relatively few studies have attempted to define the normal microbiological profile of the stomach, duodenum, jejunum, and ileum. If experience gained in studies of the colon is, as is very likely, reproduced in the small intestine, two important observations derived from studies on the microbiota of the large intestine need to be emphasized. First, it is likely that the majority of the strains that normally comprise the small intestinal microbiota have not been identified by conventional culture approaches and, second, it is very probable that luminal and juxtamucosal bacterial populations are not the same. We already know from time-honored culture-based studies that there is a very dramatic change in bacterial numbers and diversity as one moves longitudinally along the small intestine indicating that, when the complete 142
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small intestinal microbiome is finally revealed, regional differences will be even more evident. So what do we know of the composition of the small intestinal microbiome, the very starting point for considering the diagnostic validity of any test that purports to define SIBO? The complete characterization of the microbiota of the small intestine and the final resolution of current controversies regarding the diagnostic validity of various tests for SIBO will come from studies that not only define the complete microbiome of the duodenum, jejunum, and ileum, but also enumerate its functions, employing such techniques as metabolomics and metatranscriptome analysis [3]. In this manner, abnormal microbial populations can be identified and their metabolic and immunological functions linked to symptoms and disease. Although much has been learned regarding the fecal microbiome and, to a lesser extent, colonic bacterial populations, very few studies have sought to explore the bacterial populations of the small intestine employing modern sequencing approaches [4]. To date, there is limited information on the ileum, thanks to studies of ileostomy effluent [3,5–8,9 ] or terminal ileal biopsies [8,10], and duodenum, based on duodenal biopsies [11–21]. Many of the latter studies are related to explorations of relationships between the microbiota and celiac diseases, whether treated or untreated [11–20]. All of these studies involved relatively small numbers of normal controls. Furthermore, the validity of ileostomy effluent sampling has been questioned [5] and relationships between duodenal mucosal and luminal communities have scarcely been examined. Apart from one autopsy study involving just three participants [21], the distal duodenum, jejunum, and proximal ileum continue to represent terra incognita, as far as the full characterization of their microbiomes is concerned. Available data [21], as well as results from animal studies [22], indicate significant differences in microbial populations along the small intestine. Though relatively inaccessible, techniques for sampling the jejunum and ileum have been developed [10,23,24], so it is to be hoped that more data are imminent. So for now, old, far from gold standards must prevail [25]. So what of the old and sometimes trusted? &
RISK FACTORS The prevalence of SIBO in the general population is unknown; depending on the study population or the test employed, SIBO has been detected in anywhere from 0 to 20% of apparently healthy controls [26 ]. Wide variations in prevalence rates have also &&
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been reported for disorders apparently associated with SIBO; in IBS, for example, the prevalence of SIBO has ranged from 4 to 64%. These numbers underscore the dilemma that SIBO presents; not only is there no ‘gold’ standard for its definition or diagnosis, but the interpretation of widely employed tests such as breath tests also lacks consensus. Not surprisingly, the sensitivity and specificity of breath tests and of the lactulose breath hydrogen test (LBT), in particular, leave much to be desired. Rana et al. [27], for example, found that 34.3% of their IBS patients had a positive LBT; in contrast, only 6.2% were positive on a glucose breath test. In IBS and other disorders in which transit may be accelerated, lactulose will arrive prematurely in the cecum and provide a false-positive result for SIBO [28].
THE CLINICAL CONTEXT &&
In their comprehensive review, Grace et al. [26 ] evaluated relationships between SIBO and symptoms and other presenting features. Their first observation was that there was surprisingly little literature on the symptomatology of SIBO and, although a myriad of symptoms, clinical signs, and laboratory findings have been reported in relation to SIBO, only diarrhea, abdominal pain, and bloating had been linked with any degree of consistency. These three symptoms, of course, are not only common, but also nonspecific; no wonder that so many clinicians and clinical investigators have been attracted to the possibility that SIBO may be a causative factor in IBS [29–31], an association that has been hotly debated and disputed [32]. Can one identify risk factors that might help to raise suspicion for the presence of SIBO? A number of factors that predispose to SIBO were identified in the older literature and included the consequences of interventions that impaired acid secretion and/or altered intestinal anatomy as well as a number of disease states. Common to these situations were defects in the physiological functions that normally prevent colonization: gastric acid, gut motility (and the migrating motor complex, in particular [33]), and an intact mucosal immune system. Although the likelihood of a positive test for SIBO varies according to the methodology employed (culture vs. breath test) and the geographic location of the study, SIBO is, in general, more common in the elderly among whom it appears to be an important cause of unexplained diarrhea. The relative prevalence of the traditional risk factors for SIBO nowadays is provided by a large retrospective series of patients who had duodenal aspirates performed; here the main risk factors for SIBO were older age, steatorrhea, and the use of
narcotics and significantly associated disorders included inflammatory bowel disease, chronic pancreatitis, and jejunal diverticulosis [34]. In a study limited to children with intestinal failure, Gutierrez et al. [35] identified parenteral nutrition as the only clinical variable independently associated with SIBO. Interestingly, in this same study, SIBO was not a predictor of risk for catheter-related bacteremia. As the surgical procedures that were formerly associated with SIBO have become much less common, the more recent literature has been dominated by associations between SIBO and a host of medical disorders. Some of these will come as little surprise as they relate to traditional risk factors for SIBO. For example, SIBO is common in systemic sclerosis and is associated with impaired motility [36] and pneumatosis cystoides intestinalis [37]; in diabetes mellitus (both types I and II), an increased prevalence of SIBO is also linked to delayed transit [38,39] and appears to result in impaired nutritional status [38]. Concomitant small intestinal dysmotility may well also explain reported associations between gastroparesis [40] and erosive esophagitis [41] and SIBO. Small intestinal dysmotility and impaired transit leading to stasis have long been invoked to explain the high prevalence of SIBO described among patients with liver disease; SIBO in combination with enhanced intestinal permeability has, in turn, been regarded as fundamental to the occurrence of bacterial translocation and the development of such complications as bacteremia and spontaneous bacterial peritonitis [42,43 ]. Although there is a considerable volume of experimental data to support this concept, clinical observations have been more divergent. Thus, whereas some have associated decompensated cirrhosis with delayed intestinal transit [44], others have failed to link SIBO with translocation in cirrhosis [12]. It seems plausible, though undocumented, that disturbances in small intestinal motility might also explain the link proposed between Parkinson’s disease and SIBO [45 ,46,47]. The presence of SIBO has been linked with greater rigidity [46] and more on-off fluctuations [45 ]. The impact of treating SIBO seems unclear. Whereas Fasano et al. [45 ] noted an improvement in motor fluctuations following SIBO eradication, Dobbs et al. [48] found that antimicrobial therapy for SIBO, despite normalizing breath tests, worsened rigidity. SIBO is common in inflammatory bowel disease and has been linked in Crohn’s disease to coloenteric fistula, intestinal stasis secondary to strictures, and surgical loss or disease of the ileocolonic sphincter. Rana et al. [49] reported positive breath tests in 45.2 and 17.8% of their Crohn’s disease and ulcerative colitis patients, respectively, and related its occurrence to delayed
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orocecal transit, suggesting that dysmotility may be a factor in predisposing to SIBO in these diseases also. In the past, achlorhydria or hypochlorhydria was associated with SIBO primarily in the aftermath of peptic ulcer surgery; nowadays, the focus is on the possibility that acid-reducing medications, and proton pump inhibitors (PPIs), in particular, may be likewise incriminated. To date, the findings have been inconclusive with some studies supporting a link between PPI use and SIBO [50 ] and others failing to detect this association [34,51,52]. In their meta-analysis of the data, Lo and Chan [53 ] calculated a pooled odds ratio for SIBO of 2.282 for PPI users in comparison to nonusers, but found that this association held only for those studies that employed duodenal or jejunal aspirates rather than breath tests. In the past, SIBO has been linked to diseases and surgical procedures that result in damage to or loss of the ileocecal junction. In an intriguing study of the ileocecal valve in man, Miller et al. [54 ] found that a defective ileocecal valve response to cecal distension was associated with LBT-defined SIBO. Reported associations between SIBO and bariatric surgical procedures [55] and cystic fibrosis [56] may well involve multiple pathophysiological factors; how and why SIBO is linked with chronic urticaria [57] and restless legs syndrome [58] is not clear. &
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greater reliability, the glucose breath test has been criticized on the basis of its inability to detect overgrowth in the more distal reaches of the small intestine – distal overgrowth, a much discussed, but ill-defined entity. Though no longer in vogue, the quantitative culture of jejunal aspirates did benefit from correlations between bacterial counts and objective measures of intestinal dysfunction and, thereby, still provides the most convincing pathophysiological link between SIBO and symptoms and/or disease. For now all that can be said with regard to tests for SIBO: proceed (or, rather, interpret) with caution. The limitations of currently available diagnostic methods were illustrated in one study in which both a LBT and a jejunal aspirate were performed on 11 healthy controls and 15 patients predisposed to SIBO. Breath testing was associated with a high false-positive rate and, disappointingly, the use of molecular methods did not increase the yield of aspirates [61].
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MANAGEMENT It is clear from all that has been described above that SIBO, though a relatively common and important clinical entity, presents considerable problems in definition, which, clearly, have implications for management. So where does this leave the clinician? In a situation in which the clinical features suggest the possibility of SIBO, the clinician has two options: test and treat, or treat empirically. This approach assumes that the clinical context is well defined and the results of the two management approaches are well documented. Let us now examine each of these approaches.
Test and treat Intellectually, this should be the preferred option, but as emphasized by several critical reviews [59,60 ], current diagnostic options suffer from important limitations in relation to their performance and interpretation. These various tests suffer either from being invasive and cumbersome (jejunal aspiration), not being validated (duodenal aspiration), or unreliable (LBT). Though associated with &&
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Treat empirically (the therapeutic trial) Given the problems associated with all of the available tests for the diagnosis of SIBO, it should come as no surprise that clinicians have turned to therapeutic trials of antibiotics as an alternative diagnostic strategy. However appealing the therapeutic trial may seem, it currently lacks standardization with respect to choice of antibiotic, as well as its dose and duration of therapy or appropriate outcome measures. It remains an entirely empirical approach. Its limitations are vividly illustrated by the comprehensive review and meta-analysis performed by Shah et al. [60 ]. In all, only 10 trials of antibiotic therapy proved suitable for inclusion in their analysis and many suffered from significant limitations. In terms of clinical response, antibiotics, as a whole, were more effective than placebo (effectiveness ratio: 2.55; 95% confidence interval: 1.29– 5.04); the antibiotic with the greatest number of studies, rifaximin, did not achieve statistical significance in their meta-analysis (effectiveness ratio: 1.97; 95% confidence interval: 0.93–4.17). Overall, antibiotic therapy normalized breath tests in 51.1% of patients with results for individual antibiotic regimens ranging from 21.7% (low-dose rifaximin) to 100% (ciprofloxacin). Although data on clinical outcomes were rather limited, responses did appear dependent on eradication with clinical responses ranging from 62 to 91% for those who were successfully eradicated (as judged by breath test normalization) in comparison with only 7 to 34% for those who were not. Their findings with respect to the &&
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empirical treatment approach were not reassuring as overall clinical responses (irrespective of breath test results) were quite mixed [60 ]. Although prolonged ‘remissions’ following a single course of antibiotics have been reported, recurrence rates, in general, are high [45 ]. For this reason, it has been suggested that antibiotic therapy be followed by treatment with a prebiotic or probiotic. Although this approach sounds attractive in principle, data to support it are scanty [62]. &&
REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest
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CONCLUSION Two clinical scenarios may be encountered that may involve SIBO. The first, which may be regarded as classical SIBO, refers to the situation in which clinical features can be pathophysiologically linked with SIBO; affected patients typically present with features of malabsorption and/or maldigestion. Here the diagnostic and therapeutic approaches have been rather well developed and, to some degree, validated. In this more restricted concept of SIBO, culture of jejunal fluid remains a valuable benchmark as abnormal results correlate well with such clinical and pathological consequences as steatorrhea and anemia. The second relates to the patient with no overt evidence of malabsorption/ maldigestion in whom symptoms have been linked to SIBO. Here it is clear that we do not have validated criteria for the incrimination of SIBO as the accuracy of all current tests remains limited in this context. When we extend the concept of SIBO into these areas, we are bereft of a gold standard and issues such as the clinical implications of lower levels of contamination and distal overgrowth come into play; these issues are unresolved. From a clinical perspective, only a full clinical response to a course of appropriate antibiotics can satisfy the clinician that SIBO is the villain but here, again, effects on the colonic flora may complicate interpretation. Modern genomic and metabolomic techniques offer much promise in defining true normality and then fully identifying alterations in the flora in disease states; we look forward to their application to the diagnosis and management of SIBO. Acknowledgements None. Conflicts of interest The study is supported, in part, through a grant from Science Foundation Ireland to the Alimentary Pharmabiotic Centre at University College Cork, Cork, Ireland. There are no conflicts of interest.
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