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Background: Functional defecation disorders (FDD) are a common etiology of refractory chronic constipation (CC). FDD diagnosis (dyssynergic defecation [DD] and inadequate defecatory propulsion [IDP]), requires diagnostic tests including anorectal manometry (ARM) and balloon expulsion test (BET). Biofeedback (BF) is the treatment of choice for DD. The aims of our study were to evaluate: the outcome of BF in a group of constipated patients with defecatory disorders of any etiology; the efficacy of two simple diagnostic tools in predicting BF outcome in the short‐term. Methods: One hundred and thirty‐one refractory CC patients failing the BET underwent BF therapy. Before BF, all patients underwent the following: ARM.Straining questionnaire. The answers were: "belly muscles"; "anal muscles"; "both"; "Don't know/No answer."Digital rectal examination augmented by abdominal palpation on straining (augmented‐DRE). The BF therapist was blinded to ARM, straining questionnaire, and augmented‐DRE results. Key Results: Eighty‐one patients responded to BF. Gender, age, and IBS‐C showed no significant impact on BF response. Both DD and IDP responded equally to BF, while the rate of response in patients with isolated structural pelvic floor abnormalities was lower (p < 0.001). The answer "anal muscles" to straining questionnaire showed a strong association with BF response (p < 0.001). A lack in abdominal contraction and in anal relaxation on augmented‐DRE were strongly associated with BF response (p < 0.01). Absence of manual maneuvers to facilitate defecation was associated with BF response (p < 0.001). Conclusions & Inferences: BF is the therapy of choice for refractory constipation due to FDD of any etiology, inducing both clinical and anorectal physiology improvement in the short term. Comorbid IBS‐C did not affect outcome while symptomatic isolated pelvic floor abnormalities appeared refractory to behavior treatment. The straining questionnaire and augmented‐DRE outcomes showed a strong correlation with BF response and can be implemented in clinical practice to improve the management of constipated patients by prompting early referral to BF. [ABSTRACT FROM AUTHOR]

Primary sclerosing cholangitis (PSC) and Primary biliary cholangitis (PBC) are chronic inflammatory biliary diseases characterized by progressive damage of the bile ducts, resulting in hepatobiliary fibrosis and cirrhosis. Currently, specific biomarkers that allow to distinguish between PSC and PBC do not exist. In this study, we examined the salivary proteome by carrying out a comprehensive and non-invasive screening aimed at highlighting possible quali-quantitative protein deregulations that could be the starting point for the identification of effective biomarkers in future. Saliva samples collected from 6 PBC patients were analyzed using a liquid chromatography–tandem mass spectrometry technique, and the results were compared with those previously obtained in the PSC group. We identified 40 proteins as significantly deregulated in PSC patients compared to the PBC group. The Gene Ontology and pathway analyses highlighted that several proteins (e.g., small integral membrane protein 22, cofilin-1, macrophage-capping protein, plastin-2, and biliverdin reductase A) were linked to innate immune responses and actin cytoskeleton remodeling, which is a critical event in liver fibrosis and cancer progression. These findings provide new foundations for a deeper understanding of the pathophysiology of PSC and demonstrate that saliva is a suitable biological sample for obtaining proteomic fingerprints useful in the search for biomarkers capable of discriminating between the two cholestatic diseases. [ABSTRACT FROM AUTHOR]

Patients with irritable bowel syndrome (IBS) often associate their symptoms to certain foods. In congenital sucrase-isomaltase deficiency (CSID), recessive mutations in the SI gene (coding for the disaccharidase digesting sucrose and 60% of dietary starch)1 cause clinical features of IBS through colonic accumulation of undigested carbohydrates, triggering bowel symptoms.2 Hence, in a previous study,3 we hypothesized that CSID variants reducing SI enzymatic activity may contribute to development of IBS symptoms. We detected association with increased risk of IBS for 4 rare loss-of-function variants typically found in (homozygous) CSID patients, because carriers (heterozygous) of these rare variants were more common in patients than in controls.1,4 Through a 2-step computational and experimental strategy, the present study aimed to determine whether other (dys-)functional SI variants are associated with risk of IBS in addition to known CSID mutations. We first aimed to identify all SI rare pathogenic variants (SI-RPVs) on the basis of integrated Mendelian Clinically Applicable Pathogenicity (M-CAP) and Combined Annotation Dependent Depletion (CADD) predictive (clinically relevant) scores; next, we inspected genotype data currently available for 2207 IBS patients from a large ongoing project to compare SI-RPV case frequencies with ethnically matched population frequencies from the Exome Aggregation Consortium (ExAC).

Background & aimsGenetic factors are believed to affect risk for irritable bowel syndrome (IBS), but there have been no sufficiently powered and adequately sized studies. To identify DNA variants associated with IBS risk, we performed a genome-wide association study (GWAS) of the large UK Biobank population-based cohort, which includes genotype and health data from 500,000 participants.MethodsWe studied 7,287,191 high-quality single nucleotide polymorphisms in individuals who self-reported a doctor's diagnosis of IBS (cases; n = 9576) compared to the remainder of the cohort (controls; n = 336,499) (mean age of study subjects, 40-69 years). Genome-wide significant findings were further investigated in 2045 patients with IBS from tertiary centers and 7955 population controls from Europe and the United States, and a small general population sample from Sweden (n = 249). Functional annotation of GWAS results was carried out by integrating data from multiple biorepositories to obtain biological insights from the observed associations.ResultsWe identified a genome-wide significant association on chromosome 9q31.2 (single nucleotide polymorphism rs10512344; P = 3.57 × 10-8) in a region previously linked to age at menarche, and 13 additional loci of suggestive significance (P < 5.0×10-6). Sex-stratified analyses revealed that the variants at 9q31.2 affect risk of IBS in women only (P = 4.29 × 10-10 in UK Biobank) and also associate with constipation-predominant IBS in women (P = .015 in the tertiary cohort) and harder stools in women (P = .0012 in the population-based sample). Functional annotation of the 9q31.2 locus identified 8 candidate genes, including the elongator complex protein 1 gene (ELP1 or IKBKAP), which is mutated in patients with familial dysautonomia.ConclusionsIn a sufficiently powered GWAS of IBS, we associated variants at the locus 9q31.2 with risk of IBS in women. This observation may provide additional rationale for investigating the role of sex hormones and autonomic dysfunction in IBS.

Introduction: Visceral pain represents the most common digestive issue, frequently resulting from long-term inflammation, such as inflammatory bowel diseases. The lack of effective drugs prompted search of new therapeutic approaches. In this regard, gamma-aminobutyric acid (GABA) and Melissa officinalis (Mo) appear as excellent candidates as they were recognized to have several positive effects on the digestive system. The aim of this research was to evaluate the effects of a compound containing GABA and Mo (GABA-Mo 5:1) in inflammation-induced intestinal damage and visceral pain. Methods: Colitis was induced in rats by intrarectal 2,4-dinitrobenzenesulfonic acid (DNBS) administration. DNBS-treated animals received GABA-Mo (80 mg/kg BID), starting 3 days before DNBS administration, until 14 days after colitis induction (preventive protocol), or starting 7 days after DNBS until day 21 (curative protocol). Visceral pain was assessed by measuring the viscero-motor response (VMR) and the abdominal withdrawal reflex (AWR) to colorectal distension on day 7, 14 (both protocols) and 21 (curative protocol) after DNBS administration. Results: In the preventive protocol, GABA-Mo reduced AWR at day 14 but had no effect on VMR. In the spinal cord, treatment with GABA-Mo significantly prevented microglia reactivity (Iba-1 positive cells). In the colon, the supplement significantly decreased malondialdehyde (MDA, index of oxidative stress) and IL-1β levels and counteracted the decreased expression of claudin-1. Moreover, GABA-Mo normalized the increased levels of plasma lipopolysaccharide binding protein (LBP, index of altered intestinal permeability). In the curative protocol, GABA-Mo significantly counteracted visceral hypersensitivity persistence in DNBS-treated animals (day 14 and 21). In the spinal cord, GABA-Mo significantly reduced GFAP positive cell density (astrocytes). Histological evaluations highlighted a mild but significant effect of GABA-Mo in promoting healing from DNBS-induced colon damage. Colonic MDA and myeloperoxidase (index of leukocyte infiltration) levels were reduced, while the decreased colonic claudin-1 expression was normalized. In addition, the increased levels of plasma LBP were normalized by GABA-Mo administration. Discussion: In conclusion GABA-Mo, particularly in the curative protocol, was able to reduce visceral pain and intestinal inflammation, likely through a reinforcement of intestinal barrier integrity, thus representing a suitable approach for the management of abdominal pain, especially in the remission stages of colitis. [ABSTRACT FROM AUTHOR]

Background: Chronic constipation (CC) is one of the most common disorders of gut–brain interaction (DGBI). The management of CC requires specific skills due to its complex and multifactorial pathophysiology and its multistep treatment. The aims of this study were to evaluate the availability and the use of diagnostic tools for CC in Italy and the therapeutic management of CC by Italian gastroenterologists (GEs). Methods: A survey was conducted during the 28th meeting of the Italian Federation of Digestive Disease Societies (FISMAD; Rome, Italy, 11–14 May 2022). The survey explored the presence of a clinic dedicated to DGBIs, the availability and the use of specific diagnostic tools, the routine use of digital rectal examination (DRE), and the therapeutic approach to CC by Italian GEs. Results: The survey was taken by 236 GEs. The most significant results were that 42% of respondents had a clinic dedicated to DGBI in their institute; DRE was regularly performed by 56.8% of GEs when evaluating a CC patient; young GEs (≤40 years) performed DRE less frequently than older ones (p < 0.001); anorectal manometry was available to 44.3% of GEs; balloon expulsion test (BET) was available to 19.1% of GEs; GEs with a clinic dedicated to DGBI had more frequent access to anorectal physiology testing (p < 0.001); diet and lifestyle advice were the most frequently prescribed treatments; and fiber and macrogol were the second and third most prescribed treatments, respectively. Conclusions: The survey provides an interesting picture of CC management by Italian GEs. The results are in line with previous data collected about 10 years ago among Italian GEs ("CHRO.CO.DI.T.E study"); DRE is still rarely performed by Italian GEs (particularly by young GEs). The availability of anorectal physiology testing is still limited, and BET, which could be easily performed in everyday clinical settings, is rarely performed. Lifestyle suggestions, macrogol and fiber are the preferred treatment, as recommended by all guidelines. These results will be useful to identify as yet unmet educational needs and critical issues to improve CC management. [ABSTRACT FROM AUTHOR]

Background/Objectives: A low-FODMAPs Diet (LFD) is considered a "second line" dietary strategy for irritable bowel syndrome (IBS) but, after a period of strict restriction of all FODMAP foods, it has to be adapted and tailored to each patient (AdLFD). Fibromyalgia often coexists with IBS in up to 65% of cases. Our aims were to evaluate if comorbid fibromyalgia influenced the long-term clinical outcomes and adherence to an AdLFD in IBS patients. Methods: IBS patients with or without fibromyalgia who had started an AdLFD were enrolled. Patients had been evaluated before starting the LFD (T0). After a mean follow-up of 62.5 ± 22.7 months (T1), they were re-evaluated using questionnaires on disease severity, bowel habits, psychological status, and adherence to AdLFD. Results: In total, 51 IBS patients entered the study. Nineteen of them had comorbid fibromyalgia. Thirty patients reported a reduction in symptom severity at T1 in comparison with T0. Despite some slight differences in single IBS Symptom Severity Score items, comorbid fibromyalgia did not influence the IBS-SSS total score at T1. Patients with comorbid fibromyalgia showed a higher Hospital Anxiety and Depression Scale (HADS) score at baseline. A total of 44 patients showed good long-term adherence to the AdLFD. All patients improved their HADS score and had long-term adherence to the AdLFD. Conclusions: Comorbid fibromyalgia showed only a slight influence on long-term outcomes of an AdLFD on IBS symptoms, without affecting the relief of global symptoms. No influence on long-term adherence to AdLFD was detected. Hence, this approach can be taken into account in fibromyalgia patients for a nonpharmacological management of IBS symptoms. However, multicentric studies on larger samples would be welcome in the future. [ABSTRACT FROM AUTHOR]