Background Picosulfate, magnesium oxide, and citric acid solution is a small-volume agent for colon cleansing before colonoscopy that is extremely well tolerated by patients, safe, and efficacious. ...Studies of other cleansing agents have suggested that split-dose regimens may further enhance efficacy. Objective To examine whether split-dosing of picosulfate, magnesium oxide, and citric acid solution increases bowel cleansing efficacy while maintaining tolerability and safety. Design Prospective, randomized, single-blinded, controlled trial. Setting Outpatient tertiary care center. Patients A total of 236 patients underwent colonoscopy (mean age 56 years, 53.8% female). Interventions Patients in the traditional arm (n = 123) consumed 1 sachet of solution at 5:00 pm and 10:00 pm the night before the colonoscopy. Patients in the split-dose arm (n = 127) consumed 1 sachet at 7:00 pm the night before and another sachet 4 hours before their colonoscopy appointment. Main Outcome Measurements Ottawa Bowel Preparation Scale (OBPS) score, Aronchick score, safety, tolerability. Results The 113 and 109 patients in the split-dose and traditional arms, respectively, had OBPS scores for analysis. Overall, the OBPS scores in the split-dose group were significantly improved compared with the traditional dose group (4.05 vs 5.51, P < .001). This was mostly attributed to improvements in right-sided colon cleansing (1.22 in split-dose vs 2.14 in traditional arm, P < .001). Both regimens were well tolerated by patients, and no safety issues were identified. Limitations This was a single-center study. Disturbances in sleep related to the preparation were not assessed. Conclusions The split-dose regimen of picosulfate, magnesium oxide, and citric acid solution is superior to the traditional dosing regimen for colon cleansing before colonoscopy. (Clinical trial registration number: NCT00885274 .)
Mast cells that are in close proximity to autonomic and enteric nerves release several mediators that cause neuronal hyperexcitability.
This study examined whether mast cell tryptase evokes acute and ...long-term hyperexcitability in submucosal neurons from the
guinea-pig ileum by activating proteinase-activated receptor 2 (PAR2) on these neurons. We detected the expression of PAR2
in the submucosal plexus using RT-PCR. Most submucosal neurons displayed PAR2 immunoreactivity, including those colocalizing
VIP. Brief (minutes) application of selective PAR2 agonists, including trypsin, the activating peptide SL-NH 2 and mast cell tryptase, evoked depolarizations of the submucosal neurons, as measured with intracellular recording techniques.
The membrane potential returned to resting values following washout of agonists, but most neurons were hyperexcitable for
the duration of recordings (> 30 minâhours) and exhibited an increased input resistance and amplitude of fast EPSPs. Trypsin,
in the presence of soybean trypsin inhibitor, and the reverse sequence of the activating peptide (LR-NH 2 ) had no effect on neuronal membrane potential or long-term excitability. Degranulation of mast cells in the presence of antagonists
of established excitatory mast cell mediators (histamine, 5-HT, prostaglandins) also caused depolarization, and following
washout of antigen, long-term excitation was observed. Mast cell degranulation resulted in the release of proteases, which
desensitized neurons to other agonists of PAR2. Our results suggest that proteases from degranulated mast cells cleave PAR2
on submucosal neurons to cause acute and long-term hyperexcitability. This signalling pathway between immune cells and neurons
is a previously unrecognized mechanism that could contribute to chronic alterations in visceral function.
Background & Aims Although proteases control inflammation and pain, the identity, cellular origin, mechanism of action, and causative role of proteases that are activated during disease are not ...defined. We investigated the activation and function of cysteine cathepsins (Cat) in colitis. Methods Because protease activity, rather than expression, is regulated, we treated mice with fluorescent activity-based probes that covalently modify activated cathepsins. Activated proteases were localized by tomographic imaging of intact mice and confocal imaging of tissues, and were identified by electrophoresis and immunoprecipitation. We examined the effects of activated cathepsins on excitability of colonic nociceptors and on colonic pain, and determined their role in colonic inflammatory pain by gene deletion. Results Tomography and magnetic resonance imaging localized activated cathepsins to the inflamed colon of piroxicam-treated il10 −/− mice. Confocal imaging detected activated cathepsins in colonic macrophages and spinal neurons and microglial cells of mice with colitis. Gel electrophoresis and immunoprecipitation identified activated Cat-B, Cat-L, and Cat-S in colon and spinal cord, and Cat-S was preferentially secreted into the colonic lumen. Intraluminal Cat-S amplified visceromotor responses to colorectal distension and induced hyperexcitability of colonic nociceptors, which required expression of protease-activated receptor-2. Cat-S deletion attenuated colonic inflammatory pain induced with trinitrobenzene sulfonic acid. Conclusions Activity-based probes enable noninvasive detection, cellular localization, and proteomic identification of proteases activated during colitis and are potential diagnostic tools for detection of predictive disease biomarkers. Macrophage cathepsins are activated during colitis, and Cat-S activates nociceptors to induce visceral pain via protease-activated receptor-2. Cat-S mediates colitis pain and is a potential therapeutic target.
Background
The low FODMAP (fermentable oligo‐, di‐, monosaccharides, and polyols) diet reduces functional gastrointestinal symptoms (FGID) when implemented by dietitian‐delivered education in ...clinical trials, but it is unknown how well the diet is followed in routine clinical care and if differences exist when implemented by physician or dietitian. This study aimed to evaluate the real‐world experience of patients recommended the diet.
Methods
This case‐series interviewed FGID patients attending a gastroenterology clinic with previous recommendation to trial the low FODMAP diet, examining who recommended the diet and what their percentage improvement was. To evaluate implementation of the diet's 3 phases, questions were constructed based on current literature and clinical guidelines regarding length of initial restriction and food knowledge (Phase‐1), number of foods re‐challenged (Phase‐2) and food re‐introduction as tolerated (Phase‐3). The comprehensive nutrition assessment questionnaire provided daily FODMAP intake. Data were analyzed using chi‐squared tests.
Key Results
In 80 patients (21 male), the diet was recommended by the gastroenterologist in 53%, general practitioner 22%, dietitian 9% and other 15%. 30% saw a dietitian for guidance. 55% reported a ≥50% symptom improvement. The diet was followed appropriately during Phase‐1 by 78% (with vs without a dietitian, 96% vs 71%; P = .02), Phase‐2 by 48% (70% vs 39%; P = .02) and Phase‐3 by 40% (65% vs 29%; P < .01). A FODMAP intake of <12 g/d (considered therapeutic) was achieved by 44% (72% vs 31%; P < .01).
Conclusions & inferences
Symptom improvement was reported in half of patients, but many did not reach the therapeutic FODMAP intake target, especially without dietitian education. Compliance was poor in Phase‐2 and Phase‐3 but improved with dietitian guidance.
Only 1/3 patients see a dietitian for guidance on a low FODMAP diet, and compliance to the diets 3 phases is poor in Phase‐2 (re‐challenge) and Phase‐3 (long‐term) but improved with dietitian guidance. This highlights the importance of referral to a dietitian for diet therapies.
Clostridioides difficile is the leading cause of antibiotic-associated infectious diarrhea. The development of C.difficile infection is tied to perturbations of the bacterial community in the ...gastrointestinal tract, called the gastrointestinal microbiota. Repairing the gastrointestinal microbiota by introducing lab-designed bacterial communities, or defined microbial communities, has recently shown promise as therapeutics against C.difficile infection, however, the mechanisms of action of defined microbial communities remain unclear. Using an antibiotic- C.difficile mouse model, we report the ability of an 18-member community and a refined 4-member community to protect mice from two ribotypes of C.difficile (CD027, CD078; p < 0.05). Furthermore, bacteria-free supernatant delivered orally to mice from the 4-member community proteolyzed C.difficile toxins in vitro and protected mice from C.difficile infection in vivo (p < 0.05). This study demonstrates that bacteria-free supernatant is sufficient to protect mice from C.difficile; and could be further explored as a therapeutic strategy against C.difficile infection.
Up to 20% of people worldwide develop gastrointestinal symptoms following a meal
, leading to decreased quality of life, substantial morbidity and high medical costs. Although the interest of both ...the scientific and lay communities in this issue has increased markedly in recent years, with the worldwide introduction of gluten-free and other diets, the underlying mechanisms of food-induced abdominal complaints remain largely unknown. Here we show that a bacterial infection and bacterial toxins can trigger an immune response that leads to the production of dietary-antigen-specific IgE antibodies in mice, which are limited to the intestine. Following subsequent oral ingestion of the respective dietary antigen, an IgE- and mast-cell-dependent mechanism induced increased visceral pain. This aberrant pain signalling resulted from histamine receptor H
-mediated sensitization of visceral afferents. Moreover, injection of food antigens (gluten, wheat, soy and milk) into the rectosigmoid mucosa of patients with irritable bowel syndrome induced local oedema and mast cell activation. Our results identify and characterize a peripheral mechanism that underlies food-induced abdominal pain, thereby creating new possibilities for the treatment of irritable bowel syndrome and related abdominal pain disorders.
The gut microbiota has been implicated in chronic pain disorders, including irritable bowel syndrome (IBS), yet specific pathophysiological mechanisms remain unclear. We showed that decreasing intake ...of fermentable carbohydrates improved abdominal pain in patients with IBS, and this was accompanied by changes in the gut microbiota and decreased urinary histamine concentrations. Here, we used germ-free mice colonized with fecal microbiota from patients with IBS to investigate the role of gut bacteria and the neuroactive mediator histamine in visceral hypersensitivity. Germ-free mice colonized with the fecal microbiota of patients with IBS who had high but not low urinary histamine developed visceral hyperalgesia and mast cell activation. When these mice were fed a diet with reduced fermentable carbohydrates, the animals showed a decrease in visceral hypersensitivity and mast cell accumulation in the colon. We observed that the fecal microbiota from patients with IBS with high but not low urinary histamine produced large amounts of histamine in vitro. We identified
, carrying a histidine decarboxylase gene variant, as a major producer of this histamine. This bacterial strain was highly abundant in the fecal microbiota of three independent cohorts of patients with IBS compared with healthy individuals. Pharmacological blockade of the histamine 4 receptor in vivo inhibited visceral hypersensitivity and decreased mast cell accumulation in the colon of germ-free mice colonized with the high histamine-producing IBS fecal microbiota. These results suggest that therapeutic strategies directed against bacterial histamine could help treat visceral hyperalgesia in a subset of patients with IBS with chronic abdominal pain.
Whether G protein-coupled receptors signal from endosomes to control important pathophysiological processes and are therapeutic targets is uncertain. We report that opioids from the inflamed colon ...activate δ-opioid receptors (DOPr) in endosomes of nociceptors. Biopsy samples of inflamed colonic mucosa from patients and mice with colitis released opioids that activated DOPr on nociceptors to cause a sustained decrease in excitability. DOPr agonists inhibited mechanically sensitive colonic nociceptors. DOPr endocytosis and endosomal signaling by protein kinase C (PKC) and extracellular signal-regulated kinase (ERK) pathways mediated the sustained inhibitory actions of endogenous opioids and DOPr agonists. DOPr agonists stimulated the recruitment of Gαi/o and β-arrestin1/2 to endosomes. Analysis of compartmentalized signaling revealed a requirement of DOPr endocytosis for activation of PKC at the plasma membrane and in the cytosol and ERK in the nucleus. We explored a nanoparticle delivery strategy to evaluate whether endosomal DOPr might be a therapeutic target for pain. The DOPr agonist DADLE was coupled to a liposome shell for targeting DOPr-positive nociceptors and incorporated into a mesoporous silica core for release in the acidic and reducing endosomal environment. Nanoparticles activated DOPr at the plasma membrane, were preferentially endocytosed by DOPr-expressing cells, and were delivered to DOPr-positive early endosomes. Nanoparticles caused a long-lasting activation of DOPr in endosomes, which provided sustained inhibition of nociceptor excitability and relief from inflammatory pain. Conversely, nanoparticles containing a DOPr antagonist abolished the sustained inhibitory effects of DADLE. Thus, DOPr in endosomes is an endogenous mechanism and a therapeutic target for relief from chronic inflammatory pain.
While effective in treating abdominal pain, opioids have significant side effects. Recent legalization of cannabis will likely promote use of cannabinoids as an adjunct or alternative to opioids, ...despite a lack of evidence. We aimed to investigate whether cannabinoids inhibit mouse colonic nociception, alone or in combination with opioids at low doses. Experiments were performed on C57BL/6 male and female mice. Visceral nociception was evaluated by measuring visceromotor responses (VMR), afferent nerve mechanosensitivity in flat-sheet colon preparations, and excitability of isolated DRG neurons. Blood oxygen saturation, locomotion, and defecation were measured to evaluate side effects. An agonist of cannabinoid 1 receptor (CB1R), arachidonyl-2'-chloroethylamide (ACEA), dose-dependently decreased VMR. ACEA and HU-210 (another CB1R agonist) also attenuated colonic afferent nerve mechanosensitivity. Additionally, HU-210 concentration-dependently decreased DRG neuron excitability, which was reversed by the CB1R antagonist AM-251. Conversely, cannabinoid 2 receptor (CB2R) agonists did not attenuate VMR, afferent nerve mechanosensitivity, or DRG neuron excitability. Combination of subanalgesic doses of CB1R and µ-opioid receptor agonists decreased VMR; importantly, this analgesic effect was preserved after 6 d of twice daily treatment. This combination also attenuated afferent nerve mechanosensitivity and DRG neuron excitability, which was inhibited by neuronal nitric oxide synthase and guanylate cyclase inhibitors. This combination avoided side effects (decreased oxygen saturation and colonic transit) caused by analgesic dose of morphine. Activation of CB1R, but not CB2R, decreased colonic nociception both alone and in synergy with µ-opioid receptor. Thus, CB1R agonists may enable opioid dose reduction and avoid opioid-related side effects.
One of the most cited needs for patients with abdominal pain are safe and effective treatment options. The effectiveness of opioids in the management of abdominal pain is undermined by severe adverse side effects. Therefore, strategies to replace opioids or reduce the doses of opioids to suppress abdominal pain is needed. This study in mice demonstrates that cannabinoid 1 receptor (CB1R) agonists inhibit visceral sensation. Furthermore, a combination of subanalgesic doses of µ-opioid receptor agonist and CB1R agonist markedly reduce abdominal pain without causing the side effects of high-dose opioids. Thus, CB1R agonists, alone or in combination with low-dose opioids, may be a novel and safe treatment strategy for abdominal pain.
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