The largest source of melatonin, according to animal studies, is the gastrointestinal (GI) tract but this is not yet thoroughly characterized in humans. This study aims to map the expression of ...melatonin and its two receptors in human GI tract and pancreas using microarray analysis and immunohistochemistry.
Gene expression data from normal intestine and pancreas and inflamed colon tissue due to ulcerative colitis were analyzed for expression of enzymes relevant for serotonin and melatonin production and their receptors. Sections from paraffin-embedded normal tissue from 42 individuals, representing the different parts of the GI tract (n=39) and pancreas (n=3) were studied with immunohistochemistry using antibodies with specificity for melatonin, MT1 and MT2 receptors and serotonin.
Enzymes needed for production of melatonin are expressed in both GI tract and pancreas tissue. Strong melatonin immunoreactivity (IR) was seen in enterochromaffin (EC) cells partially co-localized with serotonin IR. Melatonin IR was also seen in pancreas islets. MT1 and MT2 IR were both found in the intestinal epithelium, in the submucosal and myenteric plexus, and in vessels in the GI tract as well as in pancreatic islets. MT1 and MT2 IR was strongest in the epithelium of the large intestine. In the other cell types, both MT2 gene expression and IR were generally elevated compared to MT1. Strong MT2, IR was noted in EC cells but not MT1 IR. Changes in gene expression that may result in reduced levels of melatonin were seen in relation to inflammation.
Widespread gastroenteropancreatic expression of melatonin and its receptors in the GI tract and pancreas is in agreement with the multiple roles ascribed to melatonin, which include regulation of gastrointestinal motility, epithelial permeability as well as enteropancreatic cross-talk with plausible impact on metabolic control.
The gastrointestinal tract is particularly vulnerable to off-target effects of antineoplastic drugs because intestinal epithelial cells proliferate rapidly and have a complex immunological ...interaction with gut microbiota. As a result, up to 40-100% of all cancer patients dosed with chemotherapeutics experience gut toxicity, called chemotherapeutics-induced intestinal mucositis (CIM). The condition is associated with histological changes and inflammation in the mucosa arising from stem-cell apoptosis and disturbed cellular renewal and maturation processes. In turn, this results in various pathologies, including ulceration, pain, nausea, diarrhea, and bacterial translocation sepsis. In addition to reducing patient quality-of-life, CIM often leads to dose-reduction and subsequent decrease of anticancer effect. Despite decades of experimental and clinical investigations CIM remains an unsolved clinical issue, and there is a strong consensus that effective strategies are needed for preventing and treating CIM. Recent progress in the understanding of the molecular and functional pathology of CIM had provided many new potential targets and opportunities for treatment. This review presents an overview of the functions and physiology of the healthy intestinal barrier followed by a summary of the pathophysiological mechanisms involved in the development of CIM. Finally, we highlight some pharmacological and microbial interventions that have shown potential. Conclusively, one must accept that to date no single treatment has substantially transformed the clinical management of CIM. We therefore believe that the best chance for success is to use combination treatments. An optimal combination treatment will likely include prophylactics (e.g., antibiotics/probiotics) and drugs that impact the acute phase (e.g., anti-oxidants, apoptosis inhibitors, and anti-inflammatory agents) as well as the recovery phase (e.g., stimulation of proliferation and adaptation).
Giardia intestinalis is a non-invasive, protozoan parasite infecting the upper small intestine of most mammals. Symptomatic infections cause the diarrhoeal disease giardiasis in humans and animals, ...but at least half of the infections are asymptomatic. However, the molecular underpinnings of these different outcomes of the infection are still poorly defined. Here, we studied the early transcriptional response to G. intestinalis trophozoites, the disease-causing life-cycle stage, in human enteroid-derived, 2-dimensional intestinal epithelial cell (IEC) monolayers. Trophozoites preconditioned in media that maximise parasite fitness triggered only neglectable inflammatory transcription in the IECs during the first hours of co-incubation. By sharp contrast, "non-fit" or lysed trophozoites induced a vigorous IEC transcriptional response, including high up-regulation of many inflammatory cytokines and chemokines. Furthermore, "fit" trophozoites could even suppress the stimulatory effect of lysed trophozoites in mixed infections, suggesting active G. intestinalis suppression of the IEC response. By dual-species RNA-sequencing, we defined the IEC and G. intestinalis gene expression programs associated with these differential outcomes of the infection. Taken together, our results inform on how G. intestinalis infection can lead to such highly variable effects on the host, and pinpoints trophozoite fitness as a key determinant of the IEC response to this common parasite.
Irritable bowel syndrome (IBS) has been associated with diets rich in fermentable oligo-, di-, monosaccharides, and polyols (FODMAPs), and gluten. Most previous studies have been single-blind and ...have focused on the elimination of FODMAPs or provocation with single FODMAPs. The effect of gluten is unclear, large trials isolating the effect of gluten from that of FODMAPs are needed.
The aims of this study were to ensure high intakes of a wide range of FODMAPs, gluten, or placebo, and to evaluate the effects on IBS symptoms using the IBS-severity scoring system (IBS-SSS).
The study was carried out with a double-blind, placebo-controlled, randomized 3-way crossover design in a clinical facility in Uppsala from September 2018 to June 2019. In all, 110 participants fulfilling the IBS Rome IV criteria, with moderate to severe IBS, were randomly assigned; 103 (90 female, 13 male) completed the trial. Throughout, IBS participants maintained a diet with minimal FODMAP content and no gluten. Participants were block-randomly assigned to 1-wk interventions with FODMAPs (50 g/d), gluten (17.3 g/d), or placebo, separated by 1-wk washout. All participants who completed ≥1 intervention were included in the intention-to-treat analysis.
In participants with IBS (n = 103), FODMAPs caused higher IBS-SSS scores (mean 240 95% CI: 222, 257) than placebo (198 180, 215; P = 0.00056) or gluten (208 190, 226; P = 0.013); no differences were found between the placebo and gluten groups (P = 1.0). There were large interindividual differences in IBS-SSS scores associated with treatment. No adverse events were reported.
In participants with IBS, FODMAPs had a modest effect on typical IBS symptoms, whereas gluten had no effect. The large interindividual differences in responses to the interventions warrant further detailed studies to identify possible underlying causes and enable individual prediction of responses. This trial was registered at www.clinicaltrials.gov as NCT03653689.
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Metoclopramide is primarily a dopamine receptor antagonist, with 5HT
receptor antagonist and 5HT
receptor agonist activity, and used as an antiemetic and gastroprokinetic since almost 50 years. ...Regulatory authorities issued restrictions and recommendations regarding long-term use of the drug at oral doses exceeding 10 mg 3-4 times daily because of the risk for development of tardive dyskinesia. The aim of our study was to review mechanism(s) of action and pharmacokinetic-pharmacodynamic properties of metoclopramide, as well as the risk of metoclopramide-induced tardive dyskinesia, factors that may change drug exposure in humans, and to summarize the clinical context for appropriate use of the drug.
A PubMed, Google Scholar, and Cross Reference search was done using the key words and combined searches: drug-drug interaction, gastroparesis, metoclopramide, natural history, pharmacokinetics, pharmacodynamics, drug-drug interaction, outcome, risk factors, tardive dyskinesia.
Data show that the risk of tardive dyskinesia from metoclopramide is low, in the range of 0.1% per 1000 patient years. This is far below a previously estimated 1%-10% risk suggested in treatment guidelines by regulatory authorities. High-risk groups are elderly females, diabetics, patients with liver or kidney failure, and patients with concomitant antipsychotic drug therapy, which reduces the threshold for neurological complications.
The risk of tardive dyskinesia due to metoclopramide is far below approximated numbers in treatment guidelines. This risk and the influence of known risk factors should be considered when starting a course of metoclopramide for treatment of gastroparesis.
Irritable bowel syndrome (IBS) is a chronic gastrointestinal symptom complex defined by abdominal pain and disturbed bowel habits over 3 months within a period of 6 months, in absence of any ...identifiable organic pathology. Over the years, speculations of the pathophysiology of IBS has moved from elusive central nervous symptoms impinging on psychosomatic disease, to objective signs of intestinal fermentation with abdominal bloating and intestinal dysmotility. The specific subgroup of post-infectious IBS is of special interest since it opens the possibility of dysbiosis as the pivotal point for development of IBS in association with traveler's diarrhea or antibiotic treatment with ensuing dysbiosis and abdominal symptoms that may resolve over decades. The undefined disease mechanisms that take place within the gut seem responsible for the gut-brain signaling leading to activation of brain centers that drive the clinical picture of IBS, further modulated by the patient's social background and previous lifetime events.
In hospitalized COVID-19, neutrophil-to-lymphocyte ratio (NLR) and serum creatinine is sometimes measured under assumption they predict disease severity and mortality. We determined the potential ...value of NLR and serum creatinine as predictors of disease severity and mortality in COVID-19.
Prospective cohort study of COVID-19 patients admitted to premier COVID-19 treatment hospitals in Ethiopia. Predictive capability of biomarkers in progression and prognosis of COVID-19 was analyzed using receiver operating characteristics. Survival of COVID-19 patients with different biomarker levels was computed. Logistic regression assessed associations between disease severity and mortality on NLR and serum creatinine adjusted for odds ratio (AOR).
The study enrolled 126 adults with severe (n = 68) or mild/moderate (n = 58) COVID-19, with median age 50 interquartile range (IQR 20-86); 57.1% males. The NLR value was significantly higher in severe cases 6.68 (IQR 3.03-12.21) compared to the mild/moderate 3.23 (IQR 2.09-5.39), with the NLR value markedly associated with disease severity (p<0.001). Mortality was higher in severe cases 13 (19.1%) compared to mild/moderate cases 2 (3.4%) (p = 0.007). The NLR value was significantly higher in non-survivors 15.17 (IQR 5.13-22.5) compared to survivors 4.26 (IQR 2.40-7.90) (p = 0.002). Serum creatinine was significantly elevated in severe cases 34 (50%) compared with mild/moderate 11 (19%) (p<0.001). Disease severity AOR 6.58, 95%CI (1.29-33.56), p = 0.023 and NLR AOR 1.07, 95%CI (1.02-1.12), p = 0.004) might be associated with death. NLR had a sensitivity and specificity of 69.1% and 60.3% as predictor of disease severity (cut-off >4.08), and 86.7% and 55.9% as prognostic marker of mortality (cut-off >4.63).
In COVID-19, NLR is a biomarker with only modest accuracy for predicting disease severity and mortality. Still, patients with NLR >4.63 are more likely to die. Monitoring of this biomarker at the earliest stage of the disease may predict outcome. Additionally, high creatinine seems related to disease severity and mortality.
End-stage liver disease is a medical problem with high morbidity and mortality. We have investigated the feasibility, safety, and efficacy of using autologous mesenchymal stem cells (MSCs) as a ...treatment.
Eight patients (four hepatitis B, one hepatitis C, one alcoholic, and two cryptogenic) with end-stage liver disease having Model for End-Stage Liver Disease score > or =10 were included. Autologous MSCs were taken from iliac crest. Approximately, 30-50 million MSCs were proliferated and injected into peripheral or the portal vein. Liver function and clinical features were evaluated at baseline and 1, 2, 4, 8, and 24 weeks after injection.
Treatment was well tolerated by all patients. Liver function improved as verified by the Model for End-Stage Liver Disease score, which decreased from 17.9+/-5.6 to 10.7+/-6.3 (P<0.05) and prothrombin complex from international normalized ratio 1.9+/-0.4 to 1.4+/-0.5 (P<0.05). Serum creatinine decreased from 114+/-35 to 80+/-18 micromol/l (P<0.05). Serum albumin changed from 30+/-5 to 33+/-5 g/l and bilirubin from 46+/-29 to 41+/-31 micromol/l. No adverse effects were noted.
Our data show that MSCs injection can be used for the treatment of end-stage liver disease with satisfactory tolerability. Furthermore, this treatment may improve clinical indices of liver function in end-stage liver disease.
Peptide drugs and biologics provide opportunities for treatments of many diseases. However, due to their poor stability and permeability in the gastrointestinal tract, the oral bioavailability of ...peptide drugs is negligible. Nanoparticle formulations have been proposed to circumvent these hurdles, but systemic exposure of orally administered peptide drugs has remained elusive. In this study, we investigated the absorption mechanisms of four insulin-loaded arginine-rich nanoparticles displaying differing composition and surface characteristics, developed within the pan-European consortium TRANS-INT. The transport mechanisms and major barriers to nanoparticle permeability were investigated in freshly isolated human jejunal tissue. Cytokine release profiles and standard toxicity markers indicated that the nanoparticles were nontoxic. Three out of four nanoparticles displayed pronounced binding to the mucus layer and did not reach the epithelium. One nanoparticle composed of a mucus inert shell and cell-penetrating octarginine (ENCP), showed significant uptake by the intestinal epithelium corresponding to 28 ± 9% of the administered nanoparticle dose, as determined by super-resolution microscopy. Only a small fraction of nanoparticles taken up by epithelia went on to be transcytosed via a dynamin-dependent process. In situ studies in intact rat jejunal loops confirmed the results from human tissue regarding mucus binding, epithelial uptake, and negligible insulin bioavailability. In conclusion, while none of the four arginine-rich nanoparticles supported systemic insulin delivery, ENCP displayed a consistently high uptake along the intestinal villi. It is proposed that ENCP should be further investigated for local delivery of therapeutics to the intestinal mucosa.
Currently there are only a limited number of determinations of human P eff in the distal small intestine and none in the large intestine. This has hindered the validation of preclinical models with ...regard to absorption in the distal parts of the intestinal tract, which can be substantial for BCS class II–IV drugs, and drugs formulated into modified-release (MR) dosage forms. To meet this demand, three model drugs (atenolol, metoprolol, and ketoprofen) were dosed in solution intravenously, and into the jejunum, ileum, and colon of 14 healthy volunteers. The P eff of each model drug was then calculated using a validated deconvolution method. The median P eff of atenolol in the jejunum, ileum, and colon was 0.45, 0.15, and 0.013 × 10–4 cm/s, respectively. The corresponding values for metoprolol were 1.72, 0.72, and 1.30 × 10–4 cm/s, and for ketoprofen 8.85, 6.53, and 3.37 × 10–4 cm/s, respectively. This is the first study where the human P eff of model drugs has been determined in all parts of the human intestinal tract in the same subjects. The jejunal values were similar to directly determined values using intestinal single-pass perfusion, indicating that the deconvolution method is a valid approach for determining regional P eff. The values from this study will be highly useful in the validation of preclinical regional absorption models and in silico tools.
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