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ABSTRACTMicrobial dysbiosis is an established finding in patients with inflammatory bowel disease (IBD), but host-microbial interactions are poorly understood. We aimed to unravel the effect of microbiota exposure on intestinal epithelial cells. Confluent Transwell® organoid monolayers of eight UC patients and eight non-IBD controls were co-cultured for six hours with microbiota (3x108cells) of UC patients or a healthy volunteer (HV), in the presence or absence of an inflammatory cytokine mix. Transepithelial electrical resistance (TEER), fluorescein isothiocyanate (FITC) dextran measurements, and RNA sequencing were performed on epithelial cells, and 16S rRNA sequencing on microbiota samples before and after co-culture. Transcriptomic response following microbiota exposure was not different between epithelial cells from UC patients or non-IBD controls. Following UC microbiota exposure, but not HV microbiota, a strong decrease in epithelial barrier integrity was observed in both UC and HV epithelial cells by TEER and FITC dextran measurements. Exposure of inflamed epithelium to UC microbiota induced transcriptomic stress pathways including activation of EGR1, MAPK and JAK/STAT signaling, as well as AP-1 family and FOSL transcripts. Stress responses after HV microbiota stimulation were milder. We conclude that not the epithelial cell origin (UC versus non-IBD) but the microbial donor drives transcriptomic responses, as exposure to UC microbiota was sufficient to induce stress responses in all epithelial cells. Further research on therapies to restore the microbial balance, to remove the constant trigger of dysbiosis, is required.

OBJECTIVES:Altered upper esophageal sphincter (UES) and esophageal body (EB) sensorimotor function and psychosocial factors may both be involved in symptom generation in globus, but their common impact is not yet assessed. The aim of the study is (1) to compare UES and EB sensitivity and compliance of globus patients with healthy controls (HC); (2) to study the association of globus symptom severity (GSS) with UES and EB sensitivity and compliance, UES motor function and psychosocial factors.METHODS:In 58 globus patients, GSS, somatization, and anxiety disorders were determined using validated questionnaires. In 26 HC and 42/58 patients, UES and EB sensitivity and compliance were assessed twice using barostat measurements. UES function of 27 globus patients was evaluated using high-resolution manometry. Bivariate correlations and a general linear model tested the association of these factors with GSS.RESULTS:UES and EB compliance did not differ between globus patients and HC. Upon repeated distension, UES habituation was seen in both groups, whereas EB sensitization (23.3±1.3 vs. 19.5±1.5 mm Hg, P<0.0001) only occurred in globus patients, (P=0.038). UES compliance (ρ=0.37, P=0.04), change in EB compliance upon repeated distension (ρ=0.45, P=0.007), somatization (ρ=0.43, P=0.003), panic disorder (t=3.04, P=0.004), and post-traumatic stress severity (ρ=0.40, P=0.005) were associated with GSS. UES compliance and somatization were independently associated with GSS. A trend (P=0.061) was found for the association of GSS with change in EB compliance.CONCLUSIONS:UES compliance, change in EB compliance, and somatization explain 40% of the variance in GSS. This indicates that globus is a complex disorder of the brain-gut axis rather than a “psychosomatic” disorder or a peripheral esophageal disorder.

Dumping syndrome is a frequent complication of esophageal, gastric or bariatric surgery. Rapid gastric emptying, with the delivery to the small intestine of a significant proportion of solid food as large particles that are difficult to digest, is a key event in the pathogenesis of this syndrome. This occurrence causes a shift of fluid from the intravascular component to the intestinal lumen, which results in cardiovascular symptoms, release of several gastrointestinal and pancreatic hormones and late postprandial hypoglycemia. Early dumping symptoms comprise both gastrointestinal and vasomotor symptoms. Late dumping symptoms are the result of reactive hypoglycemia. Besides the assessment of clinical alertness and endoscopic or radiological imaging, a modified oral glucose tolerance test might help to establish a diagnosis. The first step in treating dumping syndrome is the introduction of dietary measures. Acarbose can be added to these measures for patients with hypoglycemia, whereas several studies advocate guar gum or pectin to slow gastric emptying. Somatostatin analogs are the most effective medical therapy for dumping syndrome, and a slow-release preparation is the treatment of choice. In patients with treatment-refractory dumping syndrome, surgical reintervention or continuous enteral feeding can be considered, but the outcomes of such approaches are variable.

Most patients who have active Crohn's disease are treated initially with corticosteroids. Although this approach usually controls symptoms, many patients become resistant to or dependent on corticosteroids, and long exposure is associated with an increased risk of mortality. We aimed to compare the effectiveness of early use of combined immunosuppression with conventional management in patients with active Crohn's disease who had not previously received glucocorticoids, antimetabolites, or infliximab.

Let $A$ be a commutative comodule algebra over a commutative bialgebra $H$. The group of invertible relative Hopf modules maps to the Picard group of $A$, and the kernel is described as a quotient group of the group of invertible group-like elements of the coring $A\otimes H$, or as a Harrison cohomology group. Our methods are based on elementary $K$-theory. The Hilbert 90 theorem follows as a corollary. The part of the Picard group of the coinvariants that becomes trivial after base extension embeds in the Harrison cohomology group, and the image is contained in a well-defined subgroup $E$. It equals $E$ if $H$ is a cosemisimple Hopf algebra over a field.

Background & Aims: Studies in health have shown that tension-sensitive mechanoreceptors mediate sensitivity to gastric distention. A role for these mechanoreceptors in perception or symptoms in hypersensitive functional dyspepsia (FD) has not been established. Tension-sensitive mechanoreceptors are activated during phasic contractions and inactivated during gastric relaxation. The aim of the present study was to investigate whether hypersensitive FD patients perceive spontaneous changes in fundic wall tension and whether fundus-relaxing drugs decrease sensitivity to gastric distention and meal-related symptoms. Methods: Fifty patients were selected after a barostat study established gastric hypersensitivity. In 12 patients, an intragastric balloon was inflated with a fixed volume just below perception thresholds and patients were asked to indicate changes in perception on a keypad, and the relationship between perception and contractions was analyzed. In 20 patients, we studied the influence of the fundus-relaxing drug sumatriptan on sensitivity to gastric distention. In, respectively, 10 and 8 patients, we studied the influence of the fundus-relaxing drugs sumatriptan and clonidine on meal-related symptoms. Results: The majority of patients had a statistically significant association between perception and phasic isovolumetric contractions. Pretreatment with sumatriptan increased both pressures and volumes needed to induce first perception and discomfort. Pretreatment with sumatriptan and clonidine both significantly decreased meal-induced symptoms. Conclusions: Patients with hypersensitivity to gastric distention perceive isovolumetric phasic contractions of the proximal stomach. Fundus-relaxing drugs decrease sensitivity to gastric distention and decrease meal-induced symptoms in these patients. The findings are compatible with involvement of tension mechanoreceptors in symptom generation in hypersensitive FD.

Let A be a ring and Λ a finitely generated A -module. We give necessary and sufficient conditions for projectivity and flatness of a module over the endomorphism ring of Λ .

Let H be a Hopf algebra. Ju and Cai (2000) introduced the notion of twisting of an H -module coalgebra. In this paper, we study the relationship between twistings, crossed coproducts, and Hopf-Galois coextensions. In particular, we show that a twisting of an H -Galois coextension remains H -Galois if the twisting is invertible.

Background & Aims:Functional bowel disorders may follow acute intestinal infection. In animals, postinflammatory dysmotility is associated with nitrergic dysfunction. The aim of this study was to identify and characterize patients with presumed postinfectious dyspepsia (PD) compared with unspecified-onset dyspepsia (UD). Methods:A total of 400 consecutive dyspeptic patients filled out a questionnaire to assess whether their symptoms were of postinfectious origin. They underwent testing for Helicobacter pyloriinfection as well as gastric emptying and gastric barostat studies. Pharmacological studies of nitrergic gastric function were performed in controls, in patients with presumed PD, and in patients with UD using sumatriptan, an activator of nitrergic neurons, and amylnitrite, a nitric oxide donor. Results:Presumed PD was present in 17% of the patients and associated with more prevalent early satiety, weight loss, nausea, and vomiting compared with UD. Both groups did not differ in H. pyloriinfection, gastric emptying, or gastric sensitivity. Impaired accommodation was significantly more prevalent in patients with presumed PD (67% vs. 30%; P< 0.05). Sumatriptan relaxed the stomach in controls and patients with UD but not in patients with presumed PD, whereas amyl nitrite relaxed the stomach in all subjects. Conclusions:A subset of dyspeptic patients has a history suggestive of postinfectious dyspepsia. These patients have a high prevalence of impaired accommodation attributable to a dysfunction at the level of gastric nitrergic neurons.

A full-length rat type 2 inositol 1,4,5-trisphosphate (InsP3) receptor cDNA construct was generated and expressed in COS-1 cells. Targeting of the full-length recombinant type 2 receptor protein to the endoplasmic reticulum was confirmed by immunocytochemistry using isoform specific affinity-purified antibodies and InsP3R-green fluorescent protein chimeras. The receptor protein was solubilized and incorporated into proteoliposomes for functional characterization. Single-channel recordings from proteoliposomes fused into planar lipid bilayers revealed that the recombinant protein formed InsP3- and Ca2+-sensitive ion channels. The unitary conductance (∼250 pS; 220/20mM Cs+ as charge carrier), gating, InsP3, and Ca2+ sensitivities were similar to those previously described for the native type 2 InsP3R channel. However, the maximum open probability of the recombinant channel was slightly lower than that of its native counterpart. These data show that our full-length rat type 2 InsP3R cDNA construct encodes a protein that forms an ion channel with functional attributes like those of the native type 2 InsP3R channel. The possibility of measuring the function of single recombinant type 2 InsP3R is a significant step toward the use of molecular tools to define the determinants of isoform-specific InsP3R function and regulation.

We classify pointed Hopf algebras of dimension 16 over an algebraically closed field of characteristic zero. Apart from the 11 group algebras, there are 29 such Hopf algebras. All of them can be obtained using the Ore extension construction, as described recently by Beattie, the second author, and Grunenfelder.

In this study we describe the expression and function of the two rat type-1 inositol 1,4,5-trisphosphate receptor (InsP3R) ligand binding domain splice variants (SI±/SII+). Receptor protein from COS-1 cells transfected with the type-1 InsP3R expression plasmids (pInsP3R-T1, pInsP3R-T1ALT) or control DNA were incorporated into planar lipid bilayers and the single channel properties of the recombinant receptors were defined. The unitary conductance of the two splice variants were ∼290pS with Cs+ as charge carrier and ∼65pS with Ca2+ as charge carrier. Both InsP3R expression products consistently behaved like those of the native type-1 receptor isoform isolated from cerebellum in terms of their InsP3, Ca2+, and heparin sensitivity. An InsP3 receptor ligand binding domain truncation lacking the 310 amino-terminal amino acids (pInsP3R-ΔT1ALT) formed tetrameric complexes but failed to bind InsP3 with high affinity, and did not form functional Ca2+ channels when reconstituted in lipid bilayers. These data suggest that 1) the ligand binding alternative splice site is functionally inert in terms of InsP3 binding and single channel function, and 2) the single channel properties of the expressed recombinant type-1 channel are essentially identical to those of the native channel. This work establishes a foundation from which molecular/biophysical approaches can be used to define the structure-function properties of the InsP3 receptor channel family.

We prove a Maschke type theorem for the category of Doi–Hopf modules. In fact, we give necessary and sufficient conditions for the functor that forgets the C-coaction to be separable. This leads to a generalized notion of integrals. Our results can be applied to obtain Maschke type theorems for Yetter–Drinfel'd modules, Long dimodules, and modules graded by G-sets. Existing Maschke type theorems due to Doi and the authors are recovered as special cases.

Background Aims:Impaired accommodation of the proximal stomach to a meal has been reported in functional dyspepsia, but its relevance to symptoms is unclear. The aim of this study was to test the hypothesis that impaired gastric accommodation causes early satiety. Methods:A gastric barostat was used to study postprandial fundus relaxation in 35 healthy subjects and 40 patients with functional dyspepsia. Gastric emptying, Helicobacter pyloristatus, sensitivity to gastric distention, and a dyspepsia symptom score were obtained from all patients. In addition, the effect of sumatriptan, a fundus-relaxing 5-hydroxytryptamine1agonist, on gastric accommodation and on early satiety in dyspeptic patients was studied. Results:Impaired gastric accommodation to a meal was found in 40% of the patients. In univariate analysis, this was associated with early satiety and weight loss but not with hypersensitivity to gastric distention, presence of H. pylori, or delayed gastric emptying. In a multivariate analysis, only early satiety was associated with impaired gastric accommodation. Sumatriptan restored gastric accommodation, thereby significantly improving meal-induced satiety. Conclusions:Impaired relaxation of the proximal stomach to a meal is present in a high proportion of patients with functional dyspepsia. It is associated with symptoms of early satiety. Restoring gastric accommodation with a fundus-relaxing drug improves early satiety.

We give a structure theorem for pointed Hopf algebras of dimensionp3, having coradicalkCp, wherekis an algebraically closed field of characteristic zero. Combining this with previous results, we obtain the complete classification of all pointed Hopf algebras of dimensionp3.

Hepatic sulfation is thought to promote fecal excretion of lithocholate in humans by impairing the enterohepatic recirculation of the compound. Sulfatases produced by the gut flora may, at least in part, counteract this process. To investigate this interaction, female germfree rats, which are known to excrete considerable amounts of sulfated bile salts, were selectively associated with a bile salt desulfating flora. In these rats nearly all cecal, colonie, and fecal bile salt sulfate esters were hydrolyzed, resulting in a decrease of total fecal bile salt excretion of >25% compared with gnotobiotic rats without a bile salt desulfating flora. Desulfation of allochenodeoxycholate, the major sulfated bile salt in germfree rats, led to an enhanced recirculation and 12α-hydroxylation of the compound in the liver, resulting in an increased fecal output of allocholate. Microbial desulfation of intraperitoneally injected [24-14C]taurolithocholate-3-sulfate caused a fivefold decrease of the fecal plus urinary excretion rate of the isotope to approximately that found for unsulfated [24-14C]taurolithocholate. Coassociation of the gnotobiotic rats with a microflora that normalized the small intestinal transit time and cecal size led to a rise of total fecal bile salt excretion of >30% and a twofold accelerated excretion of both sulfated and unsulfated injected [24-14C]taurolithocholate. We conclude that in rats the gut flora rapidly desulfates intestinal bile salt sulfates, enhancing the enterohepatic recirculation and subsequent hydroxylation of the desulfated bile salts. In addition, these data illustrate the importance of having a well-defined microflora to normalize intestinal transit time and cecal size of gnotobiotic animals when performing kinetic studies of enterohepatic circulating compounds.