This meta-analysis provides the latest evidence on the association between SIBO and CP. Although SIBO prevalence was highly heterogeneous, it was more likely to be present in patients with CP than controls with an OR of 5.58 (95% CI 2.26–13.75). The type of the diagnostic test used significantly affected SIBO prevalence with LHBT, showing a higher prevalence than GHBT. Studies including patients with a surgical history had higher SIBO prevalence, although this was not statistically significant. We found DM and PEI to be associated with significant increases in SIBO in CP. In addition, we note that PEI correlates with SIBO prevalence and explains 54%–71% of the heterogeneity noted (Figure 3a–c). We found symptomatic improvement in 86% of patients treated with rifaximin compared with 40% of those treated with doxycycline and metronidazole (Figure 6), suggesting an alternative treatment strategy for patients with CP unresponsive to PERT.
The etiology of SIBO in CP is unclear. CP-associated intestinal dysmotility can lead to small bowel stasis (28–30), thereby increasing the likelihood of SIBO. The increased consumption of alcohol and narcotics in patients with CP was also suggested (18). In this review, 6 studies reported on alcoholic CP's relationship to SIBO (16–18,21,23,31), and only Ní Chonchubhair et al. (17) found it to have higher SIBO rates than nonalcohol CP. Narcotic use, investigated in 3 studies (16,17,27), showed no relation to SIBO prevalence (Figure S2C, see Supplementary Digital Content 1, http://links.lww.com/CTG/A93). In addition, the use of PPI is common in CP and might be a risk factor for SIBO, which was evaluated by 3 studies (16,17,31) in this review showing no significant relation to SIBO prevalence (Figure S2B, see Supplementary Digital Content 1, http://links.lww.com/CTG/A93). DM is associated with SIBO (32) and can affect up to 83% of patients with CP (33). We found it was associated with increased SIBO in CP (Figure 5a). Whether DM is reflective of pancreatic endocrine dysfunction leading to increased risk of SIBO is yet to be verified. Although the decline in pancreatic trypsin can disrupt the activation of defensin, hindering pancreatic antibacterial activity (34,35), the inhibition of pancreatic proteolytic enzymes does not impair this antibacterial activity (34). In addition, in canine models of PEI, PERT did not prevent intestinal microbial disruption (36). However, substituting cathelicidin-related antimicrobial peptide in mice deficient in acinar Orai1 protected them from fatal bacterial overgrowth (37). This suggests a direct effect of antimicrobials secreted by pancreatic acini and independent of digestive enzymes, which is consistent with recent findings by Frost et al. (3) showing exocrine pancreatic function to be a significant determinant of gut microbial load and diversity. In this review, we found PEI to be associated with increased SIBO in CP. We also found PEI to correlate well with SIBO prevalence, suggesting that antimicrobial pancreatic secretions might play a role in the pathogenesis of SIBO in CP. These results raise the question of whether direct endocrine/exocrine pancreatic gland destruction in CP is more important for SIBO development than external factors such as PPI, narcotics, or PERT.
All but one of the studies in this review used BTs to diagnose SIBO. LHBT showed significantly higher prevalence of SIBO in CP than GHBT (Figure 2c). This might be the result of accelerated intestinal transit delivering lactulose to colonic bacteria earlier than expected (18,38). Although GHBT is inherently more reliable as glucose is fully absorbed in the small intestine, glucose malabsorption rather than SIBO can result in positive GHBT (39–41). Despite attempts to standardize BT (42), they are still confounded by multiple technical issues, including the size of carbohydrate load, the osmotic and transit-accelerating effects of a highly concentrated substrate solution, test duration, and the adherence to dietary and other restrictions imposed by the test (42). Jejunal aspirate culture has long been the gold standard for SIBO diagnosis (43). It was used in one study (26) in our review. However, it also has its setbacks because of inaccessibility to the distal small bowel, potential for contamination, and false negatives for obligate anaerobes (44–46). In addition, when comparing culture to polymerase chain reaction analysis of jejunal aspirates, only 24.4% of jejunal bacteria are able to grow on standard media, raising questions about the ability of jejunal aspirate cultures to accurately reflect the intestinal bacterial load (41).
This degree of unreliability of current diagnostic techniques is reflected in the considerable heterogeneity among studies in this review. Accounting for differing results among diagnostic methods was able to explain 55% of the variance in SIBO prevalence in CP. Recent innovation using a swallowed capsule was able to measure in real time the concentrations of intraluminal gases such as H2, CO2, O2, and CH4. This technology provides much higher sensitivity than BT (47). Its clinical utility in SIBO diagnosis is yet to be verified. Therefore, although GHBT might provide practical and more reliable testing than LHBT, the diagnosis of SIBO in CP remains an elusive enterprise. Bacterial metabolomics and nucleic acid amplification techniques offer hope for more reliable testing in the near future.
Although this subject has previously been presented in a systematic review by Capurso et al. (15), in this review, we provide the broadest and latest evidence on the prevalence, diagnosis, and treatment of SIBO in CP by including data from 4 additional studies and expanding on the analysis to factor in modifiers of SIBO prevalence in CP. Our rigorous analytic techniques using meta-regression were able to explain the heterogeneity among studies providing valuable insight into the possible role of PEI in SIBO in CP and diagnostic discrepancies. Moreover, we provide the first analysis in the literature into the outcomes of SIBO treatment in CP.
The limitations of our study include the retrospective nature of the included literature, which incurs associational data. Suboptimal design and quality of available evidence manifested in failure of most studies to address confounders such as concomitant celiac disease and the unreliability of LHBT. We also noted heterogeneity in diagnostic testing and control group characteristics. These limitations have likely affected our conclusions; new research must take them into consideration.
In summary, under current diagnostic guidelines, SIBO complicates 38.6% (95% CI 25.5%–53.5%) of CP with an OR of 5.58 (95% CI 2.26%–13.75), indicating a predisposition for this condition. Although the etiology of SIBO in CP remains unknown, emerging evidence suggests a role for pancreatic exocrine dysfunction and DM as manifested by the association of PEI/DM with increased SIBO in CP. Discrepancies between diagnostic methods for SIBO are clear and pose a diagnostic dilemma. However, as the search and optimization of diagnostic testing continues, GHBT remains the test of choice. Our study shows antibiotic treatment of SIBO is associated with improved clinical outcomes (Table 3, Figure 6), suggesting an alternative strategy to treatment of patients with CP unresponsive to PERT.
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