Antroduodenal manometry findings in children with suspected pediatric intestinal pseudo-obstruction.

BACKGROUND: In 2018 diagnostic criteria for pediatric intestinal pseudo-obstruction (PIPO) were established. Neuromuscular dysfunction of the gastrointestinal tract is one of these, and often examined through antroduodenal manometry (ADM). There is little data on antroduodenal manometries in children. Our objectives were to retrospectively apply these criteria to children evaluated for suspected motility disorder, to reevaluate the ADM patterns and compare children who did and did not meet the PIPO criteria and also with healthy adults. METHODS: Children with a suspected gastrointestinal motility disorder previously investigated with 24-h 8-lead ADM were reevaluated by applying the 2018 ESPGHAN/NASPGHAN PIPO diagnostic criteria and the 2018 ANMS-NASPGHAN guidelines. ADM findings were compared between children who retrospectively fulfilled a PIPO diagnosis, children who did not, and a control group of healthy adults. KEY RESULTS: Of 34 children (age 7.9 (±5.1) years, 18 males), 12 retrospectively fulfilled the 2018 PIPO diagnostic criteria. Twenty-five children (10 in the PIPO group) had abnormal diagnostic findings on ADM, whereas 9 (2 in the PIPO group) had no such findings. A PIPO diagnosis implied a significantly higher degree of abnormal ADM patterns (2.33 vs. 1.23, p = 0.02). There were no major differences in quantitative ADM measurements between the groups except higher pressures in children. CONCLUSIONS AND INFERENCES: Children who retrospectively fulfilled a PIPO diagnosis had a significantly higher abundance of abnormal ADM findings compared with symptomatic children without PIPO and healthy adults. Our data indicate a need for set criteria for evaluation of ADM in children with suspected PIPO.

Alterations in gastrointestinal motility assessed by high-resolution antroduodenal manometry in patients with severe disorders of gut-brain interaction.

Data are limited regarding gastrointestinal motility disturbance in disorders of gut-brain interaction (DGBI). This study aimed to characterize antroduodenal motor alterations in patients with high-resolution antroduodenal manometry (HR-ADM). HR-ADM was performed in patients with severe DGBI and compared with healthy volunteers (HV). HR-ADM used a commercially available probe composed of 36 electronic sensors spaced 1 cm apart and positioned across the pylorus. Antral and duodenal motor high-resolution profiles were analyzed, based on the frequency, amplitude, and contractile integral/sensor (CI/s) calculated for each phase of the migrating motor complex (MMC). Eighteen HV and 64 patients were investigated, 10 with irritable bowel syndrome (IBS), 24 with functional dyspepsia (FD), 15 with overlap IBS-FD, and 15 with other DGBI. Compared with HV, patients had a lower frequency of phase II duodenal contractions (27 vs. 51 per hour; P = 0.002) and a lower duodenal phase II contraction amplitude (70 vs. 100 mmHg; P = 0.01), resulting in a lower CI/s of phase II (833 vs. 1,901 mmHg·cm·s; P < 0.001) in the duodenum. In addition, the frequency of phase II propagated antroduodenal contractions was lower (5 vs. 11 per hour; P < 0.001) in patients compared with HV. Interestingly, the antral CI/s of phase III was decreased in FD patients but not in IBS patients. Patients with severe DGBI display alterations in antral and intestinal motility assessed by commercially available HR-ADM. Whether these alterations may explain symptom profiles in such patients remains to be confirmed (NCT04918329 and NCT01519180).NEW & NOTEWORTHY Gastrointestinal dysmotility has been assessed poorly in disorders of gut-brain interaction (DGBI), especially with high-resolution antroduodenal manometry. Plots of DGBI patients showed lower duodenal contractions during phase II regarding amplitude, frequency, and contractile integral/sensor (CI/s) compared with healthy volunteers. A lower frequency of propagated antroduodenal contractions was also reported. Finally, antral CI/s was lower in patients with functional dyspepsia during phase III. Further studies are needed to assess the clinical significance of these alterations.

Comparison of pancreatic enzyme abnormalities and protease-activated receptor-2-positive eosinophils in the duodenum of patients with functional dyspepsia-irritable bowel syndrome overlap with functional dyspepsia alone in Asian populations.

BACKGROUND AND AIM: Some patients with functional gastrointestinal disorders exhibit pancreatic dysfunctions and pancreatic enzyme abnormalities. Thus, we aimed to clarify whether significant differences in clinical characteristics, prevalence of pancreatic enzyme abnormalities, duodenal inflammation, and protease-activated receptor 2 (PAR2) expression levels related to hypersensitivity exist between functional dyspepsia (FD) alone and FD-irritable bowel syndrome (IBS) overlap group. METHODS: Ninety-three patients based on the Rome IV criteria, FD alone (n = 44) and FD overlapped with IBS (n = 49) group were enrolled. The patients scored their own clinical symptoms after consuming high-fat meals. Serum trypsin, PLA2, lipase, p-amylase, and elastase-1 levels were measured. PAR2, eotaxin-3, and TRPV4 mRNA levels in duodenum were determined using real-time polymerase chain reaction methods. PRG2- and PAR2 in the duodenum were evaluated using immunostaining. RESULTS: FD score and global GSRS in patients with FD-IBS overlap were significantly higher than FD alone. Although the prevalence of pancreatic enzyme abnormalities in patients with FD alone was significantly (P < 0.01) higher than that in FD-IBS overlap, the ratio of aggravation of clinical symptoms following high-fat intake in patients with FD-IBS overlap was significantly higher (P = 0.007) than that in patients with FD alone. PAR2- and PRG2-double positive cells were localized in the degranulated eosinophils in the duodenum of patients with FD-IBS overlap. The number of PAR2- and PRG2-double positive cells in FD-IBS overlap was significantly (P < 0.01) higher than FD alone. CONCLUSIONS: Pancreatic enzyme abnormalities and PAR2 expression on degranulated eosinophils infiltrations in the duodenum may be associated with the pathophysiology of patients with FD-IBS overlap in Asian populations.

Iron Deficiency Anemia in Celiac Disease.

The iron absorption process developsmainly in the proximal duodenum. This portion of the intestine is typically destroyed in celiac disease (CD), resulting in a reduction in absorption of iron and subsequent iron deficiency anemia (IDA). In fact, the most frequent extra-intestinal manifestation (EIM) of CD is IDA, with a prevalence between 12 and 82% (in relation with the various reports) in patients with new CD diagnosis. The primary treatment of CD is the gluten-free diet (GFD), which is associated with adequate management of IDA, if present. Iron replacement treatment historically has been based on oral products containing ferrous sulphate (FS). However, the absorption of FS is limited in patients with active CD and unpredictable in patients on a GFD. Furthermore, a poor tolerability of this kind of ferrous is particularly frequent in patients with CD or with other inflammatory bowel diseases. Normalization from anemic state typically occurs after at least 6 months of GFD, but the process can take up to 2 years for iron stores to replenish.

Differential Recovery of Small Intestinal Segments after Partial-Body Irradiation in Non-Human Primates.

In the event of a radiological attack or accident, it is more likely that the absorbed radiation dose will be heterogeneous, rather than uniformly distributed throughout the body. This type of uneven dose distribution is known as partial-body irradiation (PBI). Partial exposure of the vital organs, specifically the highly radiosensitive intestines, may cause death, if the injury is significant and the post-exposure recovery is considerably compromised. Here we investigated the recovery rate and extent of recovery from PBI-induced intestinal damage in large animals. Rhesus macaques (Macaca mulatta) were randomly divided into four groups: sham-irradiated (0 Gy), 8 Gy PBI, 11 Gy PBI and 14 Gy PBI. A single dose of ionizing radiation was delivered in the abdominal region using a uniform bilateral anteroposterior and posteroanterior technique. Irradiated animals were scheduled for euthanasia on days 10, 28 or 60 postirradiation, and sham-irradiated animals on day 60. Intestinal structural injuries were assessed via crypt depth, villus height, and mucosal surface length in the four different intestinal regions (duodenum, proximal jejunum, distal jejunum and ileum) using H&E staining. Higher radiation doses corresponded with more injury at 10 days post-PBI and a faster recovery rate. However, at 60 days post-PBI, damage was still evident in all regions of the intestine. The proximal and distal ends (duodenum and ileum, respectively) sustained less damage and recovered more fully than the jejunum.

The antroduodenal transition time is prolonged in adults with type 1 diabetes.

BACKGROUND: The gastroparetic syndrome encompasses antral hypomotility, gastric dysrhythmia, impaired antroduodenal coordination, pyloric dysfunction, and abnormal duodenal motility; the last three collectively referred to as pylorospasms. We hypothesized that antroduodenal motility is diminished and transition time is prolonged in adults with type 1 diabetes (T1D) and polyneuropathy. METHODS: This cross-sectional study included 124 participants, of which 21 were healthy, 53 had T1D and 50 had T1D with distal symmetrical polyneuropathy (T1D + DSPN). We used the wireless motility capsule to assess antroduodenal transition time, gastric emptying time, gastric and small bowel motility indices (MI), and numbers of alkalic/acidic exposures. RESULTS: In comparison with controls, patients with T1D had prolonged antroduodenal transition time (1.85±1.5 vs. 6.6±4.8 minutes; p=0.02), which was even more pronounced in patients with T1D+DSPN (1.85±1.5 vs. 17.8±28.5 minutes; p<0.008. T1D+DSPN tended to have diminished gastric MI (11.9±2.4 vs. 12.7±1.0, p=0.07) and small bowel MI (13.1±1.4 vs. 13.6±0.6, p=0.05) and experienced more antral/pyloric alkalic episodes (1.2±1.3 vs. 2.0±2.1, p=0.02) compared with controls. CONCLUSION: The current method may assess a proxy for severity of pylorospasms in patients with diabetes and other diseases associated with upper gastrointestinal motility disorders, which ultimately may optimize future management.

Small intestine remodeling in male Goto-Kakizaki rats.

BACKGROUND: Obesity is associated with the development of insulin resistance (IR) and type-2 diabetes mellitus (T2DM); however, not all patients with T2DM are obese. The Goto-Kakizaki (GK) rat is an experimental model of spontaneous and non-obese T2DM. There is evidence that the intestine contributes to IR development in GK animals. This information prompted us to investigate small intestine remodeling in this animal model. METHODS: Four-month-old male Wistar (control) and GK rats were utilized for the present study. After removing the small intestine, the duodenum, proximal jejunum, and distal ileum were separated. We then measured villi and muscular and mucosa layer histomorphometry, goblet cells abundance, total myenteric and submucosal neuron populations, and inflammatory marker expression in the small intestinal segments and intestinal transit of both groups of animals. KEY RESULTS: We found that the GK rats exhibited decreased intestinal area (p < 0.0001), decreased crypt depth in the duodenum (p = 0.01) and ileum (p < 0.0001), increased crypt depth in the jejunum (p < 0.0001), longer villi in the jejunum and ileum (p < 0.0001), thicker villi in the duodenum (p < 0.01) and ileum (p < 0.0001), thicker muscular layers in the duodenum, jejunum, and ileum (p < 0.0001), increased IL-1ß concentrations in the duodenum and jejunum (p < 0.05), and increased concentrations of NF-κB p65 in the duodenum (p < 0.01), jejunum and ileum (p < 0.05). We observed high IL-1ß reactivity in the muscle layer, myenteric neurons, and glial cells of the experimental group. GK rats also exhibited a significant reduction in submucosal neuron density in the jejunum and ileum, ganglionic hypertrophy in all intestinal segments studied (p < 0.0001), and a slower intestinal transit (about 25%) compared to controls. CONCLUSIONS: The development of IR and T2DM in GK rats is associated with small intestine remodeling that includes marked alterations in small intestine morphology, local inflammation, and reduced intestinal transit.

Novel Case Report: A Previously Reported, but Pathophysiologically Unexplained, Association Between Collagenous Colitis and Protein-Losing Enteropathy May Be Explained by an Undetected Link with Collagenous Duodenitis.

Collagenous colitis (CC) is associated with non-bloody, watery diarrhea, which is pathophysiologically reasonable because normal colonic absorption (or excretion) of water and electrolytes can be blocked by the abnormally thick collagen layer in CC. However, CC has also been associated with six previous cases of protein-losing enteropathy (PLE), with no pathophysiologic explanation. The colon does not normally absorb (or excrete) amino acids/proteins, which is primarily the function of the small bowel. Collagenous duodenitis (CD) has not been associated with PLE. This work reports a novel case of CD (and CC) associated with PLE; a pathophysiologically reasonable mechanism for CD causing PLE (by the thick collagen layer of CD blocking normal intestinal amino acid absorption); and a novel association of PLE with severe COVID-19 infection (attributed to relative immunosuppression from hypoproteinemia, hypoalbuminemia, hypogammaglobulinemia, and malnutrition from PLE).

Duodenal mucosal mitochondrial gene expression is associated with delayed gastric emptying in diabetic gastroenteropathy.

Hindered by a limited understanding of the mechanisms responsible for diabetic gastroenteropathy (DGE), management is symptomatic. We investigated the duodenal mucosal expression of protein-coding genes and microRNAs (miRNA) in DGE and related them to clinical features. The diabetic phenotype, gastric emptying, mRNA, and miRNA expression and ultrastructure of duodenal mucosal biopsies were compared in 39 DGE patients and 21 controls. Among 3175 differentially expressed genes (FDR < 0.05), several mitochondrial DNA-encoded (mtDNA-encoded) genes (12 of 13 protein coding genes involved in oxidative phosphorylation [OXPHOS], both rRNAs and 9 of 22 transfer RNAs) were downregulated; conversely, nuclear DNA-encoded (nDNA-encoded) mitochondrial genes (OXPHOS) were upregulated in DGE. The promoters of differentially expressed genes were enriched in motifs for transcription factors (e.g., NRF1), which regulate mitochondrial biogenesis. Seventeen of 30 differentially expressed miRNAs targeted differentially expressed mitochondrial genes. Mitochondrial density was reduced and correlated with expression of 9 mtDNA OXPHOS genes. Uncovered by principal component (PC) analysis of 70 OXPHOS genes, PC1 was associated with neuropathy (P = 0.01) and delayed gastric emptying (P < 0.05). In DGE, mtDNA- and nDNA-encoded mitochondrial genes are reduced and increased - associated with reduced mitochondrial density, neuropathy, and delayed gastric emptying - and correlated with cognate miRNAs. These findings suggest that mitochondrial disturbances may contribute to delayed gastric emptying in DGE.

Aster tataricus alleviates constipation by antagonizing the binding of acetylcholine to muscarinic receptor and inhibiting Ca2+ influx.

BACKGROUND: The dried root and rhizome of Aster tataricus (RA), is a traditional Chinese medicine has been used for more than 2000 years with the function of antitussive, expectorant and antiasthmatic. Ancient books and modern pharmacological researches demonstrated that RA may have the function of moistening intestines and relieving constipation, but there was a lack of systematic evidence. The aim of this study was to comprehensively evaluate the efficacy and possible mechanisms of ethanol extract of Aster tataricus (ATE) in treating constipation from in vivo to in vitro. METHODS: In vivo, the ATE was studied in loperamide-induced constipation of mice. In vitro, different concentrations of ATE was tested separately or cumulatively on spontaneous and agonists-induced contractions of isolated rat duodenum strips. RESULTS: In vivo, at doses of 0.16, 0.8 g/mL, ATE showed significantly promotion of the small intestinal charcoal transit, decrease of the amount of remnant fecal, and increase of the content of fecal water in colon. In addition, ATE could effectively relieve colonic pathological damage caused by loperamide as well. In vitro, with the cumulative concentration increase of ATE from 0.8 to 6.4 mg/mL, it could significantly decrease the contraction caused by KCl or Ach, and gradually restore to near base tension value.Meanwhile, it could also partially but significantly inhibit the contractions induced by Ach and CaCl2 on rat duodenum in a concentration related manner. CONCLUSIONS: Taking all these findings together, it could be speculated that ATE may attenuate constipation mainly through antagonizing the binding of acetylcholine to muscarinic receptor, inhibiting Ca2+ influx and anti-inflammation.

Duodenal acidification induces gastric relaxation and alters epithelial barrier function by a mast cell independent mechanism.

Duodenal hyperpermeability and low-grade inflammation in functional dyspepsia is potentially related to duodenal acid exposure. We aimed to evaluate in healthy volunteers the involvement of mast cell activation on the duodenogastric reflex and epithelial integrity during duodenal acidification. This study consisted of 2 parts: (1) Duodenal infusion of acid or saline during thirty minutes in a randomized, double-blind cross-over manner with measurement of intragastric pressure (IGP) using high resolution manometry and collection of duodenal biopsies to measure epithelial barrier function and the expression of cell-to-cell adhesion proteins. Mast cells and eosinophils were counted and activation and degranulation status were assessed. (2) Oral treatment with placebo or mast cell stabilizer disodiumcromoglycate (DSCG) prior to duodenal perfusion with acid, followed by the procedures described above. Compared with saline, acidification resulted in lower IGP (P < 0.01), increased duodenal permeability (P < 0.01) and lower protein expression of claudin-3 (P < 0.001). Protein expression of tryptase (P < 0.001) was increased after acid perfusion. Nevertheless, an ultrastructural examination did not reveal degranulation of mast cells. DSCG did not modify the drop in IGP and barrier dysfunction induced by acid. Duodenal acidification activates an inhibitory duodenogastric motor reflex and, impairs epithelial integrity in healthy volunteers. However, these acid mediated effects occur independently from mast cell activation.

Exploration of the mechanism of traditional Chinese medicine by AI approach using unsupervised machine learning for cellular functional similarity of compounds in heterogeneous networks, XiaoErFuPi granules as an example.

'Polypharmacology' is usually used to describe the network-wide effect of a single compound, but traditional Chinese medicine (TCM) has a polypharmacological effect naturally based on the 'multi-components, multi-targets and multi-pathways' principle. It is a challenge to investigate the polypharmacology mechanism of TCM with multiple components. In this study, we used XiaoErFuPi (XEFP) granules as an example to describe an unsupervised learning strategy for polypharmacology research of TCM and to explore the mechanism of XEFP polypharmacology against multifactorial disease function dyspepsia (FD). Unsupervised clustering of compounds based on similarity evaluation of cellular function fingerprints showed that compounds of TCM without similar targets and chemical structure could also exert similar therapeutic effects on the same disease, as different targets participate in the same pathway closely associated with the pathological process. In this study, we proposed an unsupervised machine learning strategy for exploring the polypharmacology-based mechanism of TCM, utilizing hierarchical clustering based on cellular functional similarity, to establish a connection from the chemical clustering module to cellular function. Meanwhile, FDA-approved drugs against FD were used as references for the mechanism of action (MoA) of FD. First, according to the compound-compound network built by the similarity of cellular function of XEFP compounds and FDA-approved FD drugs, the possible therapeutic function of TCM may represent a known mechanism of FDA-approved drugs. Then, as unsupervised learning, hierarchical clustering of TCM compounds based on cellular function fingerprint similarity could help to classify the compounds into several modules with similar therapeutic functions to investigate the polypharmacology effect of TCM. Furthermore, the integration of quantitative omics data of TCM and approved drugs (from LINCS datasets) provides more quantitative evidence for TCM therapeutic function consistency with approved drugs. A spasmolytic activity experiment was launched to confirm vanillic acid activity to repress smooth muscle contraction; vanillic acid was also predicted to be active compound of XEFP, supporting the accuracy of our strategy. In summary, the approach proposed in this study provides a new unsupervised learning strategy for polypharmacological research investigating TCM by establishing a connection between the compound functional module and drug-activated cellular processes shared with FDA-approved drugs, which may elucidate the unique mechanism of traditional medicine using FDA-approved drugs as references, facilitate the discovery of potential active compounds of TCM and provide new insights into complex diseases.

Prophylactic effect of physical exercise on Aß1-40-induced depressive-like behavior and gut dysfunction in mice.

Alzheimer's disease (AD) is a prevalent neurodegenerative disease that is highly comorbid with depression. Gut dysfunction has been proposed as a possible risk factor for both clinical conditions. In the present study, we investigated the ability of treadmill exercise for 4 weeks (5 days/week, 40 min/day) to counteract amyloid ß1-40 peptide (Aß1-40)-induced depressive-like behavior, alterations in morphological parameters of the duodenum, and the abundance of Firmicutes and Bacteroidetes phyla. Aß1-40 administration (400 pmol/mouse, i.c.v.) increased immobility time in the tail suspension test (TST) and reduced time spent sniffing in the female urine sniffing test (FUST), indicating behavioral despair and impairment in reward-seeking behavior. These behavioral alterations, indicative of depressive-like behavior, were accompanied by reduced villus width in the duodenum. Moreover, photomicrographs obtained by transmission electron microscopy revealed abnormal epithelial microvilli in the duodenum from sedentary Aß1-40-exposed mice, characterized by shorter microvilli and heterogeneity in the length of these structures that exhibit a disordered packing. Regarding the ultrastructure of Paneth cells, Aß1-40 administration caused a reduction in the secretory granule diameter, as well as an enlarged peripheral halo. These animals also presented reduced Firmicutes and increased Bacteroidetes abundance, and increased Bacteroidetes/Firmicutes ratio. Most of the alterations observed in Aß1-40-exposed mice were prevented by the practice of physical exercise. Altogether the results provide evidence of the prophylactic effect of physical exercise on Aß1-40-induced depressive-like behavior and gut dysfunction in mice, suggesting that physical exercise could be useful for preventing depression associated with AD.

Chyme Reinfusion in Intestinal Failure Related to Temporary Double Enterostomies and Enteroatmospheric Fistulas.

Some temporary double enterostomies (DES) or entero-atmospheric fistulas (EAF) have high output and are responsible for Type 2 intestinal failure. Intravenous supplementations (IVS) for parenteral nutrition and hydration compensate for intestinal losses. Chyme reinfusion (CR) artificially restores continuity pending surgical closure. CR treats intestinal failure and is recommended by European Society for Clinical Nutrition and Metabolism (ESPEN) and American Society for Parenteral and Enteral Nutrition (ASPEN) when possible. The objective of this study was to show changes in nutritional status, intestinal function, liver tests, IVS needs during CR, and the feasibility of continuing it at home. A retrospective study of 306 admitted patients treated with CR from 2000 to 2018 was conducted. CR was permanent such that a peristaltic pump sucked the upstream chyme and reinfused it immediately in a tube inserted into the downstream intestine. Weight, plasma albumin, daily volumes of intestinal and fecal losses, intestinal nitrogen, and lipid absorption coefficients, plasma citrulline, liver tests, and calculated indices were compared before and during CR in patients who had both measurements. The patients included 185 males and 121 females and were 63 ± 15 years old. There were 37 (12%), 269 (88%) patients with EAF and DES, respectively. The proximal small bowel length from the duodeno-jejunal angle was 108 ± 67 cm (n = 232), and the length of distal small intestine was 117 ± 72 cm (n = 253). The median CR start was 5 d (quartile 25-75%, 2-10) after admission and continued for 64 d (45-95), including 81 patients at home for 47 d (28-74). Oral feeding was exclusive 171(56%), with enteral supplement 122 (42%), or with IVS 23 (7%). Before CR, 211 (69%) patients had IVS for nutrition (77%) or for hydration (23%). IVS were stopped in 188 (89%) 2 d (0-7) after the beginning of CR and continued in 23 (11%) with lower volumes. Nutritional status improved with respect to weight gain (+3.5 ± 8.4%) and albumin (+5.4 ± 5.8 g/L). Intestinal failure was cured in the majority of cases as evidenced by the decrease in intestinal losses by 2096 ± 959 mL/d, the increase in absorption of nitrogen 32 ± 20%, of lipids 43 ± 30%, and the improvement of citrulline 13.1 ± 8.1 µmol/L. The citrulline increase was correlated with the length of the distal intestine. The number of patients with at least one liver test >2N decreased from 84-40%. In cases of Type 2 intestinal failure related to DES or FAE with an accessible and functional distal small bowel segment, CR restored intestinal functions, reduced the need of IVS by 89% and helped improve nutritional status and liver tests. There were no vital complications or infectious diarrhea described to date. CR can become the first-line treatment for intestinal failure related to double enterostomy and high output fistulas.

Duodenal bile acids as determinants of intestinal mucosal homeostasis and disease.

The duodenal epithelium plays a pivotal role in the uptake and transport of dietary nutrients while simultaneously acting as physical and biochemical barrier to protect against harmful bacteria and antigens. In the case of functional dyspepsia (FD), the duodenum is of particular interest, due to observed local immune involvement and the proximity to the stomach and exposure to acidopeptic secretions. Recent observations in FD pathophysiology, including those reported by Beeckmans et al in this issue of the journal, have identified a loss of barrier function in the duodenal epithelium, an altered duodenal microbiome and alterations in intestinal bile acid pools. Because FD symptoms coincide with food intake and, thus, secretion of bile acids, these findings may indicate loss or imbalance of bile-acid-microbiota-epithelial homeostasis as a process driving FD. Here, we review the evidence linking these observations to FD symptoms.

Relationship between bile salts, bacterial translocation, and duodenal mucosal integrity in functional dyspepsia.

BACKGROUND: Functional dyspepsia (FD) is a complex disorder, in which multiple mechanisms underlie symptom generation, including impaired duodenal barrier function. Moreover, an altered duodenal bile salt pool was recently discovered in patients with FD. We aimed to evaluate the relationship between bile salts, bacterial translocation, and duodenal mucosal permeability in FD. METHODS: Duodenal biopsies from patients with FD and healthy volunteers (HV) were mounted in Ussing chambers to measure mucosal resistance and bacterial passage in the absence and presence of fluorescein-conjugated Escherichia coli and glyco-ursodeoxycholic acid (GUDCA) exposure. In parallel, duodenal fluid aspirates were collected from patients and bile salts were analyzed. KEY RESULTS: The transepithelial electrical resistance of duodenal biopsies from patients was lower compared with HV (21.4 ± 1.3 Ω.cm2 vs. 24.4 ± 1.2 Ω.cm2 ; P = .02; N = 21). The ratio of glyco-cholic and glyco-chenodeoxycholic acid (GCDCA) to tauro- and GUDCA correlated positively with transepithelial electrical resistance in patients. Glyco-ursodeoxycholic acid slightly altered the mucosal resistance, resulting in similar values between patient and healthy biopsies (22.1 ± 1.0 Ω.cm2 vs. 23.0 ± 1.0 Ω.cm2 ; P = .5). Bacterial passage after 120 minutes was lower for patient than for healthy biopsies (0.0 [0.0-681.8] vs. 1684.0 [0.0-4773.0] E coli units; P = .02). Glyco-ursodeoxycholic acid increased bacterial passage in patient biopsies (102.1 [0.0-733.0] vs. 638.9 [280.6-2124.0] E coli units; P = .009). No correlation was found between mucosal resistance and bacterial passage. CONCLUSIONS & INFERENCES: Patients with FD displayed decreased duodenal mucosal resistance associated with bile salts, however, not associated with bacterial passage in vitro. In addition, the hydrophilic bile salt glyco-ursodeoxycholic acid abolished differences in mucosal resistance and bacterial passage between patient and control group.

Novel concepts in the pathophysiology and treatment of functional dyspepsia.

Emerging data increasingly point towards the duodenum as a key region underlying the pathophysiology of functional dyspepsia (FD), one of the most prevalent functional GI disorders. The duodenum plays a major role in the control and coordination of gastroduodenal function. Impaired duodenal mucosal integrity and low-grade inflammation have been associated with altered neuronal signalling and systemic immune activation, and these alterations may ultimately lead to dyspeptic symptoms. Likely luminal candidates inducing the duodenal barrier defect include acid, bile, the microbiota and food antigens although no causal association with symptoms has been convincingly demonstrated. Recognition of duodenal pathology in FD will hopefully lead to the discovery of new biomarkers and therapeutic targets, allowing biologically targeted rather than symptom-based therapy. In this review, we summarise the recent advances in the diagnosis and treatment of FD with a focus on the duodenum.

Proton pump inhibitors block iron absorption through direct regulation of hepcidin via the aryl hydrocarbon receptor-mediated pathway.

Proton pump inhibitors (PPIs) have been used worldwide to treat gastrointestinal disorders. A recent study showed that long-term use of PPIs caused iron deficiency; however, it is unclear whether PPIs affect iron metabolism directly. We investigated the effect of PPIs on the peptide hepcidin, an important iron regulatory hormone. First, we used the FDA Adverse Event Reporting System database and analyzed the influence of PPIs. We found that PPIs, as well as H2 blockers, increased the odds ratio of iron-deficient anemia. Next, HepG2 cells were used to examine the action of PPIs and H2 blockers on hepcidin. PPIs augmented hepcidin expression, while H2 blockers did not. In fact, the PPI omeprazole increased hepcidin secretion, and omeprazole-induced hepcidin upregulation was inhibited by gene silencing or the pharmacological inhibition of the aryl hydrocarbon receptor. In mouse experiments, omeprazole also increased hepatic hepcidin mRNA expression and blood hepcidin levels. In mice treated with omeprazole, protein levels of duodenal and splenic ferroportin decreased. Taken together, PPIs directly affect iron metabolism by suppressing iron absorption through the inhibition of duodenal ferroportin via hepcidin upregulation. These findings provide a new insight into the molecular mechanism of PPI-induced iron deficiency.

The iso-osmo-resistivity theory of digestion.

This novel, iso-osmo-resistive theory offers electro-resistivity of food components as a new dimension for digestion. Firstly, fats, carbohydrates and proteins differ markedly in their resistivity, which offers a way to monitor them, especially when digestive enzymes cause consistent and distinctive changes. Secondly the state of iso-resistivity is in theory most likely to pass through the membranes of absorbing cells and be compatible with plasma in portal blood vessels. Hence, the theory proposes that the aim of the digestive process in the upper gut is to present digesta to absorption sites in a state at, or close to, iso-osmo-resistivity. It requires a method of monitoring resistivity which could be achieved by neuronal endings based in the upper gut mucosa. They could be simple nerve endings or, probably less likely, part of the structure of duodenal Brunner's Glands. They would monitor the overall effect of the various digestive processes initiated by the G-protein-coupled receptors (GPCRs). The combination of sensitive electroreceptor and osmoreceptor output would provide a system that would accurately monitor the overall progress of digestion to conserve enzyme production.

Computational simulation of flow-induced arterial remodeling of the pancreaticoduodenal arcade associated with celiac artery stenosis.

Arterial remodeling of the pancreaticoduodenal arcade, which enables collateral flow to the liver, spleen, and stomach, is a well-recognized clinical sign of celiac artery (CA) stenosis. However, the hemodynamic changes due to remodeling are poorly understood, despite their importance in surgical procedures such as pancreaticoduodenectomy. In this study, a framework to simulate remodeling of the arterial network following pathological flow alterations was developed and applied to investigate the hemodynamic characteristics of patients with CA stenosis. A one-dimensional-zero-dimensional cardiovascular model was used for blood flow simulation. After introducing CA stenosis into the normal network, arterial remodeling was simulated by iteratively changing the diameter of each artery until time-averaged wall shear stress reached its value under normal conditions. A representative case was simulated to validate the present framework, followed by simulation cases to investigate the impact of stenosis severity on remodeling outcome. A markedly dilated arcade was observed whose diameter agreed well with the corresponding values measured in subjects with CA stenosis, confirming the ability of the framework to predict arterial remodeling. A series of simulations clarified how the geometry and hemodynamics after remodeling change with stenosis severity. In particular, the arterial remodeling and resulting blood flow redistribution were found to maintain adequate organ blood supply regardless of stenosis severity. Furthermore, it was suggested that flow conditions in patients with CA stenosis could be estimated from geometric factors, namely, stenosis severity and arcade diameter, which can be preoperatively and non-invasively measured using diagnostic medical images.