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.

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.

Qualitative Validation of a Novel VR Program for Irritable Bowel Syndrome: A VR1 Study.

INTRODUCTION: Although gut-directed psychotherapies are effective for irritable bowel syndrome (IBS), they are rarely prescribed, given a paucity of trained clinicians. Virtual reality (VR) offers a solution by allowing patients to self-practice these techniques in a standardized manner. METHODS: A multidisciplinary team developed IBS/VR, a program that transports users into immersive VR worlds that teach patients about the brain-gut axis, cognitive behavioral therapy, and gut-directed meditation. We tested IBS/VR in Rome IV IBS patients and used inductive analysis to evaluate perceptions and identify recommendations. RESULTS: We achieved thematic saturation after 9 interviews; 3 additional interviews revealed no emergent themes. After making 23 software changes based on patient feedback, we conducted 3 additional interviews which confirmed thematic saturation (N = 15 total). DISCUSSION: This study offers initial validation of the first VR program designed for IBS.

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.

Immunization with cytolethal distending toxin B produces autoantibodies to vinculin and small bowel bacterial changes in a rat model of postinfectious irritable bowel syndrome.

BACKGROUND: Recent data substantiate the importance of acute gastroenteritis in the development of irritable bowel syndrome (IBS). An animal model of postinfectious IBS determined the importance of cytolethal distending toxin B (CdtB) during live Campylobacter jejuni infection and its development of autoimmunity to vinculin. In this study, we examine whether subcutaneous exposure to CdtB alone is sufficient to produce the postinfectious IBS effect and autoimmunity. METHODS: Sixty adult Sprague Dawley rats were randomized into 2 groups to receive subcutaneous injection of either CdtB or vehicle and administered a booster injection of the same product 3 weeks later. Serum was collected for anti-CdtB and anti-vinculin titers. Duodenal and ileal luminal contents for total eubacterial qPCR, and ileal bowel segments were harvested for vinculin and ileal expression. In a second experiment, 4 adult, Sprague Dawley rats were injected with either Cy7-labeled anti-CdtB and anti-vinculin antibodies were injected into the tail vein and imaged to determine organ localization of the antibodies. KEY RESULTS: Rats that received CdtB increased in serum anti-CdtB after injection. CdtB exposure also precipitated significant elevation in anti-vinculin antibodies (P < .001). This was associated with a reduction in intestinal vinculin expression (P < .001) that negatively correlated with serum anti-CdtB levels. CdtB exposure was also associated with greater levels of duodenal (P < .001) and ileal (P < .01) bacteria by qPCR that positively correlated with anti-CdtB levels. CONCLUSIONS AND INFERENCES: Rats injected with CdtB developed a postinfectious IBS-like phenotype and autoimmunity to vinculin with corresponding reduction in intestinal vinculin expression.

Comparing the rates of methane production in patients with and without appendectomy: results from a large-scale cohort.

There is no clear study identifying the microbiome of the appendix. However, in other diverticular conditions, such as diverticulosis, methanogens appear important. We investigated whether patients who had undergone appendectomies had decreased levels of exhaled methane (CH4). Consecutive patients who underwent breath testing (BT) from November 2005 to October 2013 were deterministically linked to electronic health records. The numbers of patients with CH4 ≥ 1 ppm (detectable) and ≥ 3 and ≥ 10 ppm (excess) were compared between patients who did and did not undergo appendectomy using a multivariable model adjusted for age and sex. Of the 4977 included patients (48.0 ± 18.4 years, 30.1% male), 1303 (26.2%) had CH4 ≥ 10 ppm, and 193 (3.9%) had undergone appendectomy. Appendectomy was associated with decreased odds of CH4 ≥ 1, ≥ 3, and ≥ 10 ppm (ORs (95% CI) = 0.67 (0.47-0.93), p = 0.02; 0.65 (0.46-0.92), p = 0.01; and 0.66 (0.46-0.93), p = 0.02, respectively). Additionally, the percentage of CH4 producers increased 4-fold from the first to ninth decade of life. This is the first study to report that appendectomy is associated with decreased exhaled CH4. The appendix may play an active physiologic role as a reservoir of methanogens.

An Approach to the Patient With Chronic Undiagnosed Abdominal Pain.

Abdominal pain is a common reason for referral to a gastroenterologist. The workup of patients with chronic abdominal pain can be extremely challenging as clinicians are responsible for determining whether the patient can be observed or treated symptomatically or this abdominal pain heralds a more systemic disease. The differential is typically wide and given the innervation of the abdomen, localization of abdominal pain does not always provide clear insight into the etiology. This review attempts to help the gastroenterologist narrow down that broad differential and focus on key elements of the patient visit. We emphasize the importance of a detailed history from the patient, along with review-specific details of their history and physical examination that can clue one in about the etiology of the abdominal pain. We review the causes of diffuse abdominal pain that may not first be considered along with uncommon causes of localized abdominal pain. We also review the functional causes of abdominal pain and the importance of identifying these disorders, to avoid unnecessary testing that commonly occurs with these patients.

Declining Rates of Referral for Irritable Bowel Syndrome Without Constipation at a Tertiary Care Center.

BACKGROUND: Irritable bowel syndrome (IBS) is a common chronic disorder of the gastrointestinal tract. Several treatments have been developed, including rifaximin for the treatment of IBS without constipation (non-IBS-C), but no studies have evaluated the effect of these therapies on patient referral rates to tertiary care gastroenterology clinics. AIM: To assess referral patterns for IBS patients at a tertiary motility clinic over a 10-year period. METHODS: Data from consecutive patients referred to the clinic during 2006-2016 were analyzed. Trends in the proportion of referrals and prior rifaximin use in IBS-C versus non-IBS-C groups were compared. RESULTS: A total of 814 adult patients were referred to a single physician panel for IBS-related symptoms. Of these, 776 were included in the study [528 females (68%), average age 45.7 ± 15.9 years), comprising 431 IBS-C (55.5%) and 345 non-IBS-C (44.5%) patients. The proportion of non-IBS-C referrals declined significantly from 53.0% in 2006 to 27.3% in 2016 (Chi-square, p < 0.0001, Cochran-Armitage trend test p = 0.0001), and the proportion of IBS-C referrals increased significantly from 46.9% in 2006 to 72.7% in 2016 (Chi-square, p < 0.0001, Cochran-Armitage trend test p = 0.0004). Non-IBS-C referrals with prior rifaximin use significantly increased from 22.7% in 2006 to 66.7% in 2016 (Cochran-Armitage trend test, p = 0.008). CONCLUSIONS: The results indicate a significantly declining tertiary care referral rate for non-IBS-C over the past decade. While not directly linked, there has been an increase in rifaximin use in the same population during the same time interval.

Continued midazolam versus diphenhydramine in difficult-to-sedate patients: a randomized double-blind trial.

BACKGROUND AND AIMS: Current guidelines recommend diphenhydramine in patients undergoing endoscopy who are not adequately sedated with a benzodiazepine and opioid combination. Because this practice has not been adequately assessed, we performed a randomized, double-blind trial comparing diphenhydramine with continued midazolam in such patients. METHODS: Patients undergoing elective colonoscopy with moderate sedation were eligible. Sedation was measured with the Modified Observer's Assessment of Alertness/Sedation (MOAA/S) score with adequate sedation defined as 3 on a 0- to 5-point scale. Patients not adequately sedated with midazolam 5 mg and fentanyl 100 µg were randomly assigned to diphenhydramine 25 mg versus continued midazolam 1.5 mg. Adequacy of sedation was assessed 3 minutes after each study medication dose. If MOAA/S was 4 to 5, study medication was repeated, to a maximum of 3 doses. The primary endpoint was adequate sedation. RESULTS: The planned enrollment of 200 patients (100 in each study group) was attained. Adequate sedation was achieved less often with diphenhydramine than midazolam (27% vs 65%, difference = -38%; 95% CI, -50% to -24%; P < .0001). After study medications were completed, more patients required additional medication for sedation or analgesia with diphenhydramine versus midazolam (84% vs 68%, P = .008), whereas the time to discharge from the recovery unit was similar (134 vs 129 minutes). Treatment effect was consistent across subgroups including age ≤55, substance abuse, benzodiazepine use, opioid use, and psychiatric medication use. CONCLUSIONS: Endoscopists performing moderate sedation should continue midazolam rather than switching to diphenhydramine in patients who do not achieve adequate sedation with usual doses of midazolam and an opioid. (Clinical trial registration number: NCT01769586.).

Bleeding from a duodenal varix: a unique case of variceal hemostasis achieved using EUS-guided placement of an embolization coil and cyanoacrylate.

We report a case of a bleeding duodenal varix demonstrating excellent hemostasis achieved by endoscopic ultrasound (EUS)-directed placement of an embolization coil followed by cyanoacrylate. A 31-year-old man with decompensated Child's class C cirrhosis presented with hematemesis. An initial endoscopy revealed an actively bleeding duodenal varix. Subsequent attempt at hemostasis with ethanolamine oleate injection failed. A later attempt at hemostasis involving EUS-guided placement of an embolization coil followed by cyanoacrylate injection into the varix was successful. We reviewed the literature involving the treatment of bleeding ectopic varices and conclude that EUS provides a unique and advantageous modality for achieving variceal hemostasis of duodenal varices in patients who are not candidates for transjugular intrahepatic portosystemic shunt.

Optimizing the dose and duration of therapy for chronic hepatitis C.

Recent studies indicate that antiviral treatment with pegylated interferon alfa and ribavirin for hepatitis C can be individualized based on viral and host characteristics and the pattern of virologic response during the initial months of antiviral treatment. Patients with a low initial viral load who demonstrate a rapid virologic response to antiviral therapy may be treated with a shorter duration of therapy and are less sensitive to reduced dosing of ribavirin. Patients with delayed virologic response will require a longer duration of therapy - up to 72 weeks for patients with genotype 1 - in order to optimize chances of a sustained virologic response. Patients who were nonresponders or relapsed after an acceptable course of antiviral therapy may be retreated using a more intensive regimen and/or a longer duration of therapy. Previous nonresponders to pegylated interferon alfa and ribavirin are less likely to respond to retreatment unless they demonstrate a virologic response within the first three months of retreatment, lack advanced fibrosis, and can tolerate a more intensive and/or lengthier treatment. Individualized treatment based on viral genotype, viral load, the presence of advanced fibrosis, and initial virologic response can improve therapy for some patients and save resources in others.