Defining Small Intestinal Bacterial Overgrowth by Culture and High Throughput Sequencing.

BACKGROUND& AIMS: Despite accelerated research in small intestinal bacterial overgrowth (SIBO), questions remain regarding optimal diagnostic approaches and definitions. Here, we aim to define SIBO using small bowel culture and sequencing, identifying specific contributory microbes, in the context of gastrointestinal symptoms. METHODS: Subjects undergoing esophagogastroduodenoscopy (without colonoscopy) were recruited and completed symptom severity questionnaires. Duodenal aspirates were plated on MacConkey and blood agar. Aspirate DNA was analyzed by 16S ribosomal RNA and shotgun sequencing. Microbial network connectivity for different SIBO thresholds and predicted microbial metabolic functions were also assessed. RESULTS: A total of 385 subjects with <103 colony forming units (CFU)/mL on MacConkey agar and 98 subjects with ≥103 CFU/mL, including ≥103 to <105 CFU/mL (N = 66) and ≥105 CFU/mL (N = 32), were identified. Duodenal microbial α-diversity progressively decreased, and relative abundance of Escherichia/Shigella and Klebsiella increased, in subjects with ≥103 to <105 CFU/mL and ≥105 CFU/mL. Microbial network connectivity also progressively decreased in these subjects, driven by the increased relative abundance of Escherichia (P < .0001) and Klebsiella (P = .0018). Microbial metabolic pathways for carbohydrate fermentation, hydrogen production, and hydrogen sulfide production were enhanced in subjects with ≥103 CFU/mL and correlated with symptoms. Shotgun sequencing (N = 38) identified 2 main Escherichia coli strains and 2 Klebsiella species representing 40.24% of all duodenal bacteria in subjects with ≥103 CFU/mL. CONCLUSIONS: Our findings confirm ≥103 CFU/mL is the optimal SIBO threshold, associated with gastrointestinal symptoms, significantly decreased microbial diversity, and network disruption. Microbial hydrogen- and hydrogen sulfide-related pathways were enhanced in SIBO subjects, supporting past studies. Remarkably few specific E coli and Klebsiella strains/species appear to dominate the microbiome in SIBO, and correlate with abdominal pain, diarrhea, and bloating severities.

Characterization of the Small Bowel Microbiome Reveals Different Profiles in Human Subjects Who Are Overweight or Have Obesity.

INTRODUCTION: Gut microbiome changes are linked to obesity, but findings are based on stool data. In this article, we analyzed the duodenal microbiome and serum biomarkers in subjects with normal weight, overweight, and obesity. METHODS: Duodenal aspirates and serum samples were obtained from subjects undergoing standard-of-care esophagogastroduodenoscopy without colon preparation. Aspirate DNAs were analyzed by 16S rRNA and shotgun sequencing. Predicted microbial metabolic functions and serum levels of metabolic and inflammatory biomarkers were also assessed. RESULTS: Subjects with normal weight (N = 105), overweight (N = 67), and obesity (N = 42) were identified. Overweight-specific duodenal microbial features include lower relative abundance (RA) of Bifidobacterium species and Escherichia coli strain K-12 and higher Lactobacillus intestinalis , L. johnsonii , and Prevotella loescheii RA. Obesity-specific features include higher Lactobacillus gasseri RA and lower L. reuteri (subspecies rodentium ), Alloprevotella rava , and Leptotrichia spp RA. Escalation features (progressive changes from normal weight through obesity) include decreasing Bacteroides pyogenes , Staphylococcus hominis , and unknown Faecalibacterium species RA, increasing RA of unknown Lactobacillus and Mycobacterium species, and decreasing microbial potential for biogenic amines metabolism. De-escalation features (direction of change altered in normal to overweight and overweight to obesity) include Lactobacillus acidophilus , L. hominis , L. iners , and Bifidobacterium dentium . An unknown Lactobacillus species is associated with type IIa dyslipidemia and overweight, whereas Alloprevotella rava is associated with type IIb and IV dyslipidemias. DISCUSSION: Direct analysis of the duodenal microbiome has identified key genera associated with overweight and obesity, including some previously identified in stool, e.g., Bifidobacterium and Lactobacillus . Specific species and strains exhibit differing associations with overweight and obesity, including escalation and de-escalation features that may represent targets for future study and therapeutics.

Prevalence of small intestinal bacterial overgrowth in intestinal failure syndrome: A systematic review and meta-analysis.

BACKGROUND AND AIM: Patients with intestinal failure (IF) have abnormal intestinal anatomy, secretion, and dysmotility, which impairs intestinal homeostatic mechanisms and may lead to small intestinal bacterial overgrowth (SIBO). We conducted a systematic review and meta-analysis to determine the prevalence of SIBO in patients with IF and to identify risk factors for SIBO. METHODS: MEDLINE (PubMed) and Embase electronic databases were searched from inception to December 2023 for studies that reported the prevalence of SIBO in IF. The prevalence rates, odds ratio (OR), and 95% confidence intervals of SIBO in IF and the risk factors for SIBO in IF were calculated using random effects model. RESULTS: Final dataset included nine studies reporting on 407 patients with IF. The prevalence of SIBO in IF was 57.5% (95% CI 44.6-69.4), with substantial heterogeneity in this analysis (I2 = 80.9, P = 0.0001). SIBO prevalence was sixfold higher in patients with IF who received parenteral nutrition (PN) compared with IF patients not on PN (OR = 6.0, 95% CI 3.0-11.9, P = 0.0001). Overall, the prevalence of SIBO in patients with IF using PPI/acid-suppressing agents (72.0%, 95% CI 57.5-83.8) was numerically higher compared with IF patients not using these agents (47.6%, 95% CI 25.7-70.2). CONCLUSIONS: This systematic review and meta-analysis suggests that there is an increased risk of SIBO in patients with IF and that PN, and potentially, the use of PPI/acid-suppressing agents is risk factors for SIBO development in patients with IF. However, the quality of evidence is low and can be attributed to lack of case-control studies and clinical heterogeneity seen in the studies.

Hydrogen Sulfide Producers Drive a Diarrhea-Like Phenotype and a Methane Producer Drives a Constipation-Like Phenotype in Animal Models.

BACKGROUND: We recently demonstrated that diarrhea-predominant irritable bowel syndrome (IBS-D) subjects have higher relative abundance (RA) of hydrogen sulfide (H2S)-producing Fusobacterium and Desulfovibrio species, and constipation-predominant IBS (IBS-C) subjects have higher RA of methanogen Methanobrevibacter smithii. AIMS: In this study, we investigate the effects of increased methanogens or H2S producers on stool phenotypes in rat models. METHODS: Adult Sprague-Dawley rats were fed high-fat diet (HFD) for 60 days to increase M. smithii levels, then gavaged for 10 days with water (controls) or methanogenesis inhibitors. To increase H2S producers, rats were gavaged with F. varium or D. piger. Stool consistency (stool wet weight (SWW)) and gas production were measured. 16S rRNA gene sequencing was performed on stool samples. RESULTS: In HFD diet-fed rats (N = 30), stool M. smithii levels were increased (P < 0.001) after 52 days, correlating with significantly decreased SWW (P < 0.0001) at 59 days (R = - 0.38, P = 0.037). Small bowel M. smithii levels decreased significantly in lovastatin lactone-treated rats (P < 0.0006), and SWW increased (normalized) in lovastatin hydroxyacid-treated rats (P = 0.0246), vs. controls (N = 10/group). SWW increased significantly in D. piger-gavaged rats (N = 16) on day 10 (P < 0.0001), and in F. varium-gavaged rats (N = 16) at all timepoints, vs. controls, with increased stool H2S production. 16S sequencing revealed stool microbiota alterations in rats gavaged with H2S producers, with higher relative abundance (RA) of other H2S producers, particularly Lachnospiraceae and Bilophila in F. varium-gavaged rats, and Sutterella in D. piger-gavaged rats. CONCLUSIONS: These findings suggest that increased M. smithii levels result in a constipation-like phenotype in a rat model that is partly reversible with methanogenesis inhibitors, whereas gavage with H2S producers D. piger or F. varium results in increased colonization with other H2S producers and diarrhea-like phenotypes. This supports roles for the increased RA of methanogens and H2S producers identified in IBS-C and IBS-D subjects, respectively, in contributing to stool phenotypes.

Irritable Bowel Syndrome Is Not Associated with an Increased Risk of Polyps and Colorectal Cancer: A Systematic Review and Meta-Analysis.

OBJECTIVES: Colorectal cancer (CRC) is the third most common malignancy in the US. Several factors are associated with increased/decreased CRC risk and often linked to adenomatous colorectal polyps (CRP). Recent studies suggest a lower risk of neoplastic lesions among irritable bowel syndrome (IBS) patients. We aimed to systematically assess the occurrence of CRC and CRP in IBS patients. METHODS: Searches of the Medline, Cochrane, and EMBASE databases were performed, blindly and independently, by two investigators. Studies of CRC or CRP incidence in IBS patients (diagnosed by Rome or other symptom-based criteria) were eligible for inclusion. CRC and CRP effect estimates were pooled in meta-analyses using random models. RESULTS: Of 4941 non-duplicate studies, 14 were included, comprising 654,764 IBS patients and 2,277,195 controls in 8 cohort studies, and 26,641 IBS patients and 87,803 controls in 6 cross-sectional studies. Pooled analysis revealed a significantly decreased prevalence of CRP in IBS subjects vs. controls, with a pooled odds ratio (OR) of 0.29 (95% CI (0.15, 0.54)). There was significant heterogeneity between studies (I2 = 96%, p < 0.01). This finding persisted when studies which did not report pre-cancerous polyps separately were excluded (OR 0.23, 95% CI (0.15, 0.35), I2 = 85%, p < 0.01). CRC prevalence was lower in IBS subjects, but this did not reach statistical significance (OR 0.40, 95% CI (0.09, 1.77]). CONCLUSION: Our analyses reveal a decreased incidence of colorectal polyps in IBS, although CRC did not reach significance. Mechanistic studies with detailed genotypic analysis and clinical phenotyping are needed to better elucidate the potentially protective effect of IBS on CRC development.

Interleukin-10 Knockout Mice Do Not Reliably Exhibit Macroscopic Inflammation: A Natural History Endoscopic Surveillance Study.

BACKGROUND: Interleukin (IL)-10 knockout (KO) mice, a model for inflammatory bowel disease (IBD), develop chronic enterocolitis due to an aberrant immune response to enteric antigens. Endoscopy, the gold standard for evaluation of human mucosal health, is not widely available for murine models. AIMS: To assess the natural history of left-sided colitis in IL-10 KO mice via serial endoscopies. METHODS: BALB/cJ IL-10 KO mice underwent regular endoscopic assessments from 2 up to 8 months of age. Procedures were recorded and blindly evaluated using a 4-component endoscopic score: mucosal wall transparency, intestinal bleeding, focal lesions and perianal lesions (0-3 points each). An endoscopic score ≥ 1 point was considered as the presence of colitis/flare. RESULTS: IL-10 KO mice (N = 40, 9 female) were assessed. Mean age at first endoscopy was 62.5 ± 2.5 days; average number of procedures per mouse was 6.0 ± 1.3. A total of 238 endoscopies were conducted every 24.8 ± 8.3 days, corresponding to 124.1 ± 45.2 days of surveillance per mouse. Thirty-three endoscopies in 24 mice (60%) detected colitis, mean endoscopy score 2.5 ± 1.3 (range: 1-6.3). Nineteen mice (47.5%) had one episode of colitis and 5 (12.5%) had 2-3 episodes. All exhibited complete spontaneous healing on subsequent endoscopies. CONCLUSIONS: In this large-scale endoscopic surveillance study of IL-10 KO mice, 40% of mice did not develop endoscopic left-sided colitis. Furthermore, IL-10 KO mice did not exhibit persistent colitis and universally exhibited complete spontaneous healing without treatment. The natural history of colitis in IL-10 KO mice may not be comparable with that of IBD in humans and requires careful consideration.

Coronavirus Disease 2019 (COVID-19) Pandemic Lifestyle Changes May Have Influenced Small Bowel Microbial Composition and Microbial Resistance.

BACKGROUND: The coronavirus disease 2019 (COVID-19) global pandemic necessitated many severe lifestyle changes, including lockdowns, social distancing, altered food consumption and exercise patterns, and extensive hygiene practices. These extensive changes may have affected the human gut microbiome, which is highly influenced by lifestyle. AIMS: To examine the potential effects of pandemic-related lifestyle changes on the metabolically relevant small bowel microbiome. METHODS: Adult subjects presenting for upper endoscopy without colonoscopy were identified and divided into two matched groups: pre-pandemic (February 2019-March 2020) and intra-pandemic (April 2021-September 2021, all COVID-19 negative). Duodenal aspirates and blood samples were collected. Duodenal microbiomes were analyzed by 16S rRNA sequencing. Serum cytokine levels were analyzed by Luminex FlexMap3D. RESULTS: Fifty-six pre-pandemic and 38 COVID-negative intra-pandemic subjects were included. There were no significant changes in duodenal microbial alpha diversity in the intra-pandemic vs. pre-pandemic group, but beta diversity was significantly different. The relative abundance (RA) of phylum Deinococcus-Thermus and family Thermaceae, which are resistant extremophiles, was significantly higher in the intra-pandemic vs. pre-pandemic group. The RA of several Gram-negative taxa including Bacteroidaceae (phylum Bacteroidetes) and the Proteobacteria families Enterobacteriaceae and Pseudomonadaceae, and the RA of potential disruptor genera Escherichia-Shigella and Rothia, were significantly lower in the intra-pandemic vs. pre-pandemic group. Circulating levels of interleukin-18 were also lower in the intra-pandemic group. CONCLUSIONS: These findings suggest the small bowel microbiome underwent significant changes during the pandemic, in COVID-19-negative individuals. Given the key roles of the small bowel microbiota in host physiology, this may have implications for human health.

A Single Fasting Exhaled Methane Level Correlates With Fecal Methanogen Load, Clinical Symptoms and Accurately Detects Intestinal Methanogen Overgrowth.

INTRODUCTION: A 2-hour breath test is the gold standard for diagnosing intestinal methanogen overgrowth (IMO). This method can be cumbersome especially if used repetitively to monitor treatment response. Therefore, we aimed to assess the reliability of a fasting single methane measurement (SMM) in diagnosing IMO and its utility as a biomarker to monitor treatment response in subjects with IMO. METHODS: First, we calculated the test characteristics of SMM compared with lactulose and glucose breath test in 2 large-scale retrospective cohorts. Second, the symptomology associated with SMM using various cutoffs was analyzed. Third, in a double-blind randomized control trial, the temporal stability of SMM levels in subjects taking placebo was analyzed. Fourth, stool Methanobrevibacter smithii loads were quantified using quantitative polymerase chain reaction and compared with SMM levels. Last, the change in SMM over time during antibiotic therapy was analyzed. RESULTS: Using the cutoff of SMM ≥10 ppm, SMM had a sensitivity of 86.4% and specificity of 100% for diagnosing IMO on the glucose and lactulose breath tests and was associated with constipation (5.65 ± 3.47 vs 4.32 ± 3.62, P = 0.008). SMM remained stable for 14 weeks without treatment (P = 0.45), and antibiotics lead to a decrease in SMM after 2 days (P < 0.0001). SMM was positively associate with stool M. smithii load (R = 0.65, P < 0.0001). DISCUSSION: Fasting SMM ≥10 ppm seems to accurately diagnose IMO, is associated with constipation, and correlates with stool M. smithii. SMM seems to be stable without treatment and decreases after antibiotics. SMM may be a useful test to diagnose IMO and monitor treatment response.

A Smartphone Application Using Artificial Intelligence Is Superior To Subject Self-Reporting When Assessing Stool Form.

INTRODUCTION: Stool form assessment relies on subjective patient reports using the Bristol Stool Scale (BSS). In a novel smartphone application (app), trained artificial intelligence (AI) characterizes digital images of users' stool. In this study, we evaluate this AI for accuracy in assessing stool characteristics. METHODS: Subjects with diarrhea-predominant irritable bowel syndrome image-captured every stool for 2 weeks using the app, which assessed images for 5 visual characteristics (BSS, consistency, fragmentation, edge fuzziness, and volume). In the validation phase, using 2 expert gastroenterologists as a gold standard, sensitivity, specificity, accuracy, and diagnostic odds ratios of subject-reported vs AI-graded BSS scores were compared. In the implementation phase, agreements between AI-graded and subject-reported daily average BSS scores were determined, and subject BSS and AI stool characteristics scores were correlated with diarrhea-predominant irritable bowel syndrome symptom severity scores. RESULTS: In the validation phase (n = 14), there was good agreement between the 2 experts and AI characterizations for BSS (intraclass correlation coefficients [ICC] = 0.782-0.852), stool consistency (ICC = 0.873-0.890), edge fuzziness (ICC = 0.836-0.839), fragmentation (ICC = 0.837-0.863), and volume (ICC = 0.725-0.851). AI outperformed subjects' self-reports in categorizing daily average BSS scores as constipation, normal, or diarrhea. In the implementation phase (n = 25), the agreement between AI and self-reported BSS scores was moderate (ICC = 0.61). AI stool characterization also correlated better than subject reports with diarrhea severity scores. DISCUSSION: A novel smartphone application can determine BSS and other visual stool characteristics with high accuracy compared with the 2 expert gastroenterologists. Moreover, trained AI was superior to subject self-reporting of BSS. AI assessments could provide more objective outcome measures for stool characterization in gastroenterology.

Methanogens and Hydrogen Sulfide Producing Bacteria Guide Distinct Gut Microbe Profiles and Irritable Bowel Syndrome Subtypes.

INTRODUCTION: Irritable bowel syndrome (IBS) includes diarrhea-predominant (IBS-D) and constipation-predominant (IBS-C) subtypes. We combined breath testing and stool microbiome sequencing to identify potential microbial drivers of IBS subtypes. METHODS: IBS-C and IBS-D subjects from 2 randomized controlled trials (NCT03763175 and NCT04557215) were included. Baseline breath carbon dioxide, hydrogen (H 2 ), methane (CH 4 ), and hydrogen sulfide (H 2 S) levels were measured by gas chromatography, and baseline stool microbiome composition was analyzed by 16S rRNA sequencing. Microbial metabolic pathways were analyzed using Kyoto Encyclopedia of Genes and Genomes collection databases. RESULTS: IBS-C subjects had higher breath CH 4 that correlated with higher gut microbial diversity and higher relative abundance (RA) of stool methanogens, predominantly Methanobrevibacter , as well as higher absolute abundance of Methanobrevibacter smithii in stool. IBS-D subjects had higher breath H 2 that correlated with lower microbial diversity and higher breath H 2 S that correlated with higher RA of H 2 S-producing bacteria, including Fusobacterium and Desulfovibrio spp. The predominant H 2 producers were different in these distinct microtypes, with higher RA of Ruminococcaceae and Christensenellaceae in IBS-C/CH 4 + (which correlated with Methanobacteriaceae RA) and higher Enterobacteriaceae RA in IBS-D. Finally, microbial metabolic pathway analysis revealed enrichment of Kyoto Encyclopedia of Genes and Genomes modules associated with methanogenesis and biosynthesis of methanogenesis cofactor F420 in IBS-C/CH 4 + subjects, whereas modules associated with H 2 S production, including sulfate reduction pathways, were enriched in IBS-D. DISCUSSION: Our findings identify distinct gut microtypes linked to breath gas patterns in IBS-C and IBS-D subjects, driven by methanogens such as M. smithii and H 2 S producers such as Fusobacterium and Desulfovibrio spp, respectively.

Exhaled Methane Is Associated with a Lower Heart Rate.

BACKGROUND: In humans, methane (CH4) is exclusively produced by the intestinal microbiota and has been implicated in several conditions including cardiovascular disease. After microbial production of CH4 in the gut, it steadily crosses into the systemic circulation and reaches the lungs where it can be detected in the exhaled breath, as a surrogate measure for intestinal CH4 production. Recent reports have shown an association between CH4 and vagal dysfunction as well as the inhibition of CH4 activity on ileal contractions with atropine, suggesting its action on the parasympathetic nervous system. Given these findings, we hypothesized that CH4 may be affecting resting heart rate (HR) based on the potential effect of CH4 on the vagus nerve. OBJECTIVES: Given its possible role in the parasympathetic nervous system, we aimed to study the relationship between breath CH4 and resting HR in humans. Additionally, we performed a longitudinal study analyzing the change in HR and its association with breath CH4 over time. METHODS: First, we reviewed 1,126 subjects and compared HR in subjects with detectable and undetectable breath CH4. Second, we performed a post hoc analysis of a randomized control trial to compare the change in HR for those who had an increase in breath CH4 versus those that had a decrease in breath CH4 over 14 weeks. Last, we assessed whether a larger decrease in CH4 is associated with a larger increase in HR over time. RESULTS: In the retrospective cohort, subjects with detectable CH4 had a lower HR compared to those with undetectable CH4 (73.0 ± 0.83 vs. 76.0 ± 0.44 beats/min, p = 0.01). In the post hoc analysis, a decrease in CH4 over time was associated with an increase in HR (median ∆ = 6.5 ± 8.32 beats/min, p = 0.0006). Last, we demonstrated a biological gradient whereby a larger drop in CH4 was associated with a greater increase in HR (R = -0.31, p = 0.03). CONCLUSION: Our findings suggest a potential role for the microbiome (and specifically CH4 from methanogens) to regulate HR. Considering these findings, mechanistic studies are warranted to further investigate this potential novel microbiome-neurocardiac axis.

Effects of Proton Pump Inhibitors on the Small Bowel and Stool Microbiomes.

BACKGROUND: Proton pump inhibitor (PPI) use is extremely common. PPIs have been suggested to affect the gut microbiome, and increase risks of Clostridium difficile infection and small intestinal bacterial overgrowth (SIBO). However, existing data are based on stool analyses and PPIs act on the foregut. AIMS: To compare the duodenal and stool microbiomes in PPI and non-PPI users. METHODS: Consecutive subjects presenting for upper endoscopy without colonoscopy were recruited. Current antibiotic users were excluded. Subjects taking PPI were age- and gender-matched 1:2 to non-PPI controls. Subjects completed medical history questionnaires, and duodenal aspirates were collected using a validated protected catheter. A subset also provided stool samples. Duodenal and stool microbiomes were analyzed by 16S rRNA sequencing. RESULTS: The duodenal microbiome exhibited no phylum-level differences between PPI (N = 59) and non-PPI subjects (N = 118), but demonstrated significantly higher relative abundances of families Campylobacteraceae (3.13-fold, FDR P value < 0.01) and Bifidobacteriaceae (2.9-fold, FDR P value < 0.01), and lower relative abundance of Clostridiaceae (88.24-fold, FDR P value < 0.0001), in PPI subjects. SIBO rates were not significantly different between groups, whether defined by culture (> 103 CFU/ml) or 16S sequencing, nor between subjects taking different PPIs. The stool microbiome exhibited significantly higher abundance of family Streptococcaceae (2.14-fold, P = 0.003), and lower Clostridiaceae (2.60-fold, FDR P value = 8.61E-13), in PPI (N = 22) versus non-PPI (N = 47) subjects. CONCLUSIONS: These findings suggest that PPI use is not associated with higher rates of SIBO. Relative abundance of Clostridiaceae was reduced in both the duodenal and stool microbiomes, and Streptococcaceae was increased in stool. The clinical implications of these findings are unknown.

AGA Clinical Practice Update on Small Intestinal Bacterial Overgrowth: Expert Review.

DESCRIPTION: Thanks to ready access to hydrogen breath testing, small intestinal bacterial overgrowth (SIBO) is now commonly diagnosed among individuals presenting with a variety of gastrointestinal and even nongastrointestinal symptoms and is increasingly implicated in lay press and media in the causation of a diverse array of disorders. Its definition, however, remains controversial and true prevalence, accordingly, undefined. The purpose of this review, therefore, was to provide a historical background to the concept of SIBO, critically review current concepts of SIBO (including symptomatology, pathophysiology, clinical consequences, diagnosis and treatment), define unanswered questions and provide a road map toward their resolution. METHODS: Best Practice Advice statements were developed following discussion by the 3 authors. Two authors each developed text around certain Best Practice Advice based on a review of available literature. All 3 authors reviewed the complete draft and after discussion, redrafting, and further review and revision, all of the authors agreed on a final draft. BEST PRACTICE ADVICE 1: The definition of SIBO as a clinical entity lacks precision and consistency; it is a term generally applied to a clinical disorder where symptoms, clinical signs, and/or laboratory abnormalities are attributed to changes in the numbers of bacteria or in the composition of the bacterial population in the small intestine. BEST PRACTICE ADVICE 2: Symptoms traditionally linked to SIBO include bloating, diarrhea, and abdominal pain/discomfort. Steatorrhea may be seen in more severe cases. BEST PRACTICE ADVICE 3: There is insufficient evidence to support the use of inflammatory markers, such as fecal calprotectin to detect SIBO. BEST PRACTICE ADVICE 4: Laboratory findings can include elevated folate and, less commonly, vitamin B-12 deficiency, or other nutritional deficiencies. BEST PRACTICE ADVICE 5: A major impediment to our ability to accurately define SIBO is our limited understanding of normal small intestinal microbial populations-progress in sampling technology and techniques to enumerate bacterial populations and their metabolic products should provide much needed clarity. BEST PRACTICE ADVICE 6: Controversy remains concerning the role of SIBO in the pathogenesis of common functional symptoms, such as those regarded as components of irritable bowel syndrome. BEST PRACTICE ADVICE 7: Management should focus on the identification and correction (where possible) of underlying causes, correction of nutritional deficiencies, and the administration of antibiotics. This is especially important for patients with significant maldigestion and malabsorption. BEST PRACTICE ADVICE 8: Although irritable bowel syndrome has been shown to respond to therapy with a poorly absorbed antibiotic, the role of SIBO or its eradication in the genesis of this response warrants further confirmation in randomized controlled trials. BEST PRACTICE ADVICE 9: There is a limited database to guide the clinician in developing antibiotic strategies for SIBO, in any context. Therapy remains, for the most part, empiric but must be ever mindful of the potential risks of long-term broad-spectrum antibiotic therapy.

Irritable Bowel Syndrome in Pregnancy.

Irritable bowel syndrome (IBS) affects a significant percentage of the general population and is more common in women. A large proportion of women affected with IBS are of childbearing age; however, there is a paucity of studies and guidelines to specifically address the epidemiology, course, maternal/fetal prognosis, or management of IBS in pregnancy. This scarcity of literature on IBS and pregnancy poses significant challenges to healthcare providers in counseling and managing patients. In this comprehensive review, we summarize the current literature and knowledge gaps regarding the effects of pregnancy on IBS and vice versa, along with the efficacy and safety profiles of commonly used IBS diets and medications in pregnancy. The management of pregnant women with IBS should be multidisciplinary, with emphasis on education and judicious use of dietary modifications and pharmacologic options that are deemed relatively safe during pregnancy.

ACG Clinical Guideline: Management of Irritable Bowel Syndrome.

Irritable bowel syndrome (IBS) is a highly prevalent, chronic disorder that significantly reduces patients' quality of life. Advances in diagnostic testing and in therapeutic options for patients with IBS led to the development of this first-ever American College of Gastroenterology clinical guideline for the management of IBS using Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) methodology. Twenty-five clinically important questions were assessed after a comprehensive literature search; 9 questions focused on diagnostic testing; 16 questions focused on therapeutic options. Consensus was obtained using a modified Delphi approach, and based on GRADE methodology, we endorse the following: We suggest that a positive diagnostic strategy as compared to a diagnostic strategy of exclusion be used to improve time to initiating appropriate therapy. We suggest that serologic testing be performed to rule out celiac disease in patients with IBS and diarrhea symptoms. We suggest that fecal calprotectin be checked in patients with suspected IBS and diarrhea symptoms to rule out inflammatory bowel disease. We recommend a limited trial of a low fermentable oligosaccharides, disacchardies, monosaccharides, polyols (FODMAP) diet in patients with IBS to improve global symptoms. We recommend the use of chloride channel activators and guanylate cyclase activators to treat global IBS with constipation symptoms. We recommend the use of rifaximin to treat global IBS with diarrhea symptoms. We suggest that gut-directed psychotherapy be used to treat global IBS symptoms. Additional statements and information regarding diagnostic strategies, specific drugs, doses, and duration of therapy can be found in the guideline.

High Prevalence of Small Intestinal Bacterial Overgrowth among Functional Dyspepsia Patients.

BACKGROUND: Small intestinal bacterial overgrowth (SIBO), characterized by either increased numbers or presence of colonic type bacteria in the small bowel has been previously described in functional dyspepsia (FD), based on breath testing. In this study, we aim to examine the prevalence of SIBO among FD patients using small bowel aspirate culture. METHODS: We prospectively enrolled outpatients fulfilling Rome IV criteria for FD. Severity of symptoms was graded using the patient assessment of upper gastrointestinal symptom severity index (PAGI-SYM) questionnaire. Patients underwent upper gastrointestinal endoscopy and duodenal fluid was aspirated in sterile traps. SIBO was defined as ≥103 colony forming units/mL of duodenal aspirate and/or presence of colonic type bacteria. Patients undergoing gastroscopy due to gastroesophageal reflux symptoms - control group (CG) - and patients with irritable bowel syndrome (IBS) fulfilling Rome IV criteria were also recruited. RESULTS: We enrolled 227 FD subjects, 30 CG, and 90 IBS patients. Among FD patients, 144 (63.4%), 64 (28.2%), and 19 (8.4%) had postprandial distress syndrome (PDS), epigastric pain syndrome (EPS), and overlapping PDS-EPS syndrome, respectively. SIBO prevalence was 20.8%, 12.5%, and 31.6% among PDS, EPS, and overlapping PDS-EPS FD subtypes, respectively. Overall, SIBO prevalence was significantly higher in FD (44/227 [19.4%]) compared to CG (1/30 [3.3%]) (p = 0.037) and similar to IBS (44/227 [19.4%] vs. 15/90 [16.7%], p = 0.63) subjects. SIBO presence was associated neither with total nor with any subscale score of the PAGI-SYM questionnaire. CONCLUSION: In a cohort of Greek FD patients, SIBO prevalence was similar to that of IBS subjects and higher compared to that of controls.

ACG Clinical Guideline: Small Intestinal Bacterial Overgrowth.

Small intestinal bacterial overgrowth is defined as the presence of excessive numbers of bacteria in the small bowel, causing gastrointestinal symptoms. This guideline statement evaluates criteria for diagnosis, defines the optimal methods for diagnostic testing, and summarizes treatment options for small intestinal bacterial overgrowth. This guideline provides an evidence-based evaluation of the literature through the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) process. In instances where the available evidence was not appropriate for a formal GRADE recommendation, key concepts were developed using expert consensus.

Microbiome and Its Role in Irritable Bowel Syndrome.

Irritable bowel syndrome (IBS) is an extremely common and often very debilitating chronic functional gastrointestinal disorder. Despite its prevalence, significant associated healthcare costs, and quality-of-life issues for affected individuals, our understanding of its etiology remained limited. However, it is now evident that microbial factors play key roles in IBS pathophysiology. Acute gastroenteritis following exposure to pathogens can precipitate the development of IBS, and studies have demonstrated changes in the gut microbiome in IBS patients. These changes may explain some of the symptoms of IBS, including visceral hypersensitivity, as gut microbes exert effects on the host immune system and gut barrier function, as well as the brain-gut axis. Microbial differences also appear to underlie the two main functional categories of IBS: diarrhea-predominant IBS (IBS-D) is associated with small intestinal bacterial overgrowth, which can be diagnosed by a positive hydrogen breath test, and constipation-predominant IBS (IBS-C) is associated with increased levels of methanogenic archaea, which can be diagnosed by a positive methane breath test. Mechanistically, the pathogens that cause gastroenteritis and trigger subsequent IBS development produce a common toxin, cytolethal distending toxin B (CdtB), and antibodies raised against CdtB cross-react with the cytoskeletal protein vinculin and impair gut motility, facilitating bacterial overgrowth. In contrast, methane gas slows intestinal contractility, which may facilitate the development of constipation. While antibiotics and dietary manipulations have been used to relieve IBS symptoms, with varying success, elucidating the specific mechanisms by which gut microbes exert their effects on the host may allow the development of targeted treatments that may successfully treat the underlying causes of IBS.

Breath Test Gas Patterns in Inflammatory Bowel Disease with Concomitant Irritable Bowel Syndrome-Like Symptoms: A Controlled Large-Scale Database Linkage Analysis.

INTRODUCTION: Breath testing (BT) has gained interest for diagnosing small intestinal bacterial overgrowth (SIBO) in IBD patients with irritable bowel syndrome (IBS) overlap. We aim to characterize the rate of SIBO and BT gas patterns in IBD patients with IBS-like symptoms compared to non-IBD patients. METHODS: A database of 14,847 consecutive lactulose BTs was developed from patients with IBS-like symptoms between November 2005 and October 2013. BTs were classified as normal, H2 predominant, CH4 predominant, and flatline based on criteria established from the literature. BT data linkage with electronic health records and chart review identified IBD patients along with disease phenotype, location, severity, and antibiotic response. Poisson loglinear model evaluated differences in gas patterns between the two groups. RESULTS: After excluding patients with repeat breath tests, we identified 486 IBD and 10,505 non-IBD patients with at least one BT. Positive BT was present in 57% (n = 264) of IBD patients. Crohn's disease (odds ratio (OR) 0.21, [95% confidence interval (CI) 0.11-0.38]) and ulcerative colitis (OR 0.39, [95% CI 0.22-0.70]) patients were less likely to produce excess CH4. IBD patients were more likely to have flatline BT (OR 1.82, [95% CI 1.20-2.77]). In IBD patients with SIBO, 57% improved symptomatically with antibiotics. CONCLUSION: In a cohort of IBD patients with IBS-like symptoms, a high rate of patients had positive BT and symptomatic improvement with antibiotics. In IBD, methanogenesis is suppressed and flatline BT is more frequent, suggesting excess hydrogenotrophic bacteria. These findings suggest methanogenic and hydrogenotrophic microorganisms as potential targets for microbiome-driven biomarkers and therapies.

Mapping the Segmental Microbiomes in the Human Small Bowel in Comparison with Stool: A REIMAGINE Study.

BACKGROUND: Most gut microbiome studies have been performed using stool samples. However, the small intestine is of central importance to digestion, nutrient absorption, and immune function, and characterizing its microbial populations is essential for elucidating their roles in human health and disease. AIMS: To characterize the microbial populations of different small intestinal segments and contrast these to the stool microbiome. METHODS: Male and female subjects undergoing esophagogastroduodenoscopy without colon preparation were prospectively recruited. Luminal aspirates were obtained from the duodenum, jejunum, and farthest distance reached. A subset also provided stool samples. 16S rRNA sequencing was performed and analyses were carried out using CLC Genomics Workbench. RESULTS: 16S rRNA sequencing identified differences in more than 2000 operational taxonomic units between the small intestinal and stool microbiomes. Firmicutes and Proteobacteria were the most abundant phyla in the small intestine, and Bacteroidetes were less abundant. In the small intestine, phylum Firmicutes was primarily represented by lactic acid bacteria, including families Streptococcaceae, Lactobacillaceae, and Carnobacteriaceae, and Proteobacteria was represented by families Neisseriaceae, Pasteurellaceae, and Enterobacteriaceae. The duodenal and FD microbial signatures were markedly different from each other, but there were overlaps between duodenal and jejunal and between jejunal and FD microbial signatures. In stool, Firmicutes were represented by families Ruminococcaceae, Lachnospiraceae, Christensenellaceae, and Proteobacteria by class Deltaproteobacteria. CONCLUSIONS: The small bowel microbiome is markedly different from that in stool and also varies between segments. These findings may be important in determining how compositional changes in small intestinal microbiota contribute to human disease states.