Intestinal Transit Time Research Articles

Early life stress induces irritable bowel syndrome from childhood to adulthood in mice.

Irritable bowel syndrome (IBS) is one of the most common functional gastrointestinal disorder. Traditionally, early life stress (ELS) is predisposed to IBS in adult. However, whether ELS induces IBS in early life remains unclear. Separated cohort studies were conducted in neonatal male pups of C57BL/6 mice by maternal separation (MS) model. MS and non-separation mice were scheduled to be evaluated for prime IBS-phenotypes, including visceral hypersensitivity, intestinal motility, intestinal permeability, and anxiety-like behavior. Ileal contents and fecal samples were collected and analyzed by 16S rRNA gene sequencing and bacterial community analyses. Subcellular structures of intestinal epithelial, such as epithelial tight junctions and mitochondria, were observed under transmission electron microscopy. MS induced visceral hypersensitivity and decreased total intestinal transit time from childhood to adulthood. In addition, MS induced intestinal hyperpermeability and anxiety-like behavior from adolescence to adulthood. Besides, MS affected intestinal microbial composition from childhood to adulthood. Moreover, MS disrupted intestinal mitochondrial structure from childhood to adulthood. The study showed for the first time that MS induced IBS from early life to adulthood in mice. The disrupted intestinal mitochondrial structure and the significant dysbiosis of intestinal microbiota in early life may contribute to the initiation and progress of IBS from early life to adulthood.

Slowed Intestinal Transit Induced by Less Mucus in Intestinal Goblet Cell Piezo1-Deficient Mice through Impaired Epithelial Homeostasis.

Mucus secreted by goblet cells (GCs) may play an important role in intestinal transit function. Our previous study found that Piezo1 protein is essential for GC function; however, the effect of GC Piezo1 on intestinal transit function is unclear. Our study aimed to investigate the effect of Piezo1 in GCs on intestinal transit and the potential mechanism. We compared intestinal mucus, fecal form, intestinal transit time, intestinal epithelial cell composition, and stem cell function in WT and GC-specific Piezo1-deficient (Piezo1ΔGC) mice. Our results revealed a correlation between mucus and intestinal transit: the less mucus there was, the slower the intestinal transit. Piezo1 deficiency in GCs led to decreased mucus synthesis and also disrupted the ecological niche of colon stem cells (CSCs). Through organoid culture, we found that the capacity of proliferation and differentiation in Piezo1ΔGC mouse CSCs was significantly decreased, which also led to a reduced source of GCs. Further studies found that the reduced Wnt and Notch signals in colon crypts might be the potential mechanism. These results indicated the importance of GC Piezo1 in intestinal transit function, which acts by maintaining the homeostasis of intestinal epithelial cells and mucus.

Genetic Approaches to Increase Arabinoxylan and β-Glucan Content in Wheat.

Wheat is one of the three staple crops feeding the world. The demand for wheat is ever increasing as a relatively good source of protein, energy, nutrients, and dietary fiber (DF) when consumed as wholemeal. Arabinoxylan and β-glucan are the major hemicelluloses in the cell walls and dietary fiber in wheat grains. The amount and structure of DF varies between grain tissues. Reducing post-prandial glycemic response as well as intestinal transit time and contribution to increased fecal bulk are only a few benefits of DF consumption. Dietary fiber is fermented in the colon and stimulates growth of beneficial bacteria producing SCFA, considered responsible for a wide range of health benefits, including reducing the risk of heart disease and colon cancer. The recommended daily intake of 25-30 g is met by only few individuals. Cereals cover nearly 40% of fiber in the Western diet. Therefore, wheat is a good target for improving dietary fiber content, as it would increase the fiber intake and simultaneously impact the health of many people. This review reflects the current status of the research on genetics of the two major dietary fiber components, as well as breeding approaches used to improve their quantity and quality in wheat grain.

Arecoline alleviated loperamide induced constipation by regulating gut microbes and the expression of colonic genome

This study aimed to investigate the effects of arecoline on constipation by intervening at different times to explore its preventive and therapeutic effects. Symptoms related to constipation, gut microbes, short-chain fatty acid (SCFA) content in the cecum, and gene expression in the colon were measured to examine the effect of arecoline on relieving constipation. The results showed that arecoline intervention alleviated loperamide-induced constipation, as evidenced by significantly shortened intestinal transit time, increased fecal water content, improved small bowel propulsion, and increased defecation frequency. In addition, arecoline significantly reduced the levels of gastrointestinal regulatory peptides such as somatostatin and vasoactive intestinal peptide in the serum, thereby regulating intestinal peristalsis. Histopathological analysis showed that arecoline ameliorated intestinal injury caused by constipation. Gut microbial analysis indicated that arecoline altered the taxonomic composition and levels of its metabolite SCFAs in the gut microbiota. Furthermore, the colonic transcriptome results indicated that genes expression related to intestinal diseases were significantly down-regulated by arecoline intervention. In conclusion, the results of the correlation analysis propose a possible mechanism of arecoline in alleviating constipation by modulating the gut microbes and their metabolites and regulating the gut genome.

Gastrointestinal Transit Times in Health as Determined Using Ingestible Capsule Systems: A Systematic Review.

Ingestible capsule (IC) systems can assess gastrointestinal (GI) transit times as a surrogate for gut motility for extended periods of time within a minimally invasive, radiation-free and ambulatory setting. A literature review of IC systems and a systematic review of studies utilizing IC systems to measure GI transit times in healthy volunteers was performed. Screening for eligible studies, data extraction and bias assessments was performed by two reviewers. A narrative synthesis of the results was performed. The literature review identified 23 different IC systems. The systematic review found 6892 records, of which 22 studies were eligible. GI transit time data were available from a total of 1885 healthy volunteers. Overall, seventeen included studies reported gastric emptying time (GET) and small intestinal transit time (SITT). Colonic transit time (CTT) was reported in nine studies and whole gut transit time (WGTT) was reported in eleven studies. GI transit times in the included studies ranged between 0.4 and 15.3 h for GET, 3.3-7 h for SITT, 15.9-28.9 h for CTT and 23.0-37.4 h for WGTT. GI transit times, notably GET, were influenced by the study protocol. This review provides an up-to-date overview of IC systems and reference ranges for GI transit times. It also highlights the need to standardise protocols to differentiate between normal and pathological function.

Assessment of phytochemicals, antioxidant properties, and in vivo antidiarrheal activity of date palm (Phoenix dactylifera L.)

ABSTRACT Date palm (Phoenix dactylifera L.) has a significant role in our daily life due to its diverse nutritional composition and potential health benefits. This study was designed to evaluate the phytochemicals, antioxidant, and antidiarrheal potential of various extracts of Ajwa whole fruit, date palm pit, and flesh. The extracts with the highest phytochemical quantities were further subjected to bio-assay assessment against castor oil-induced diarrhea using different animal models. The results indicated that Ajwa whole fruit extract (AWFE) exhibited higher amount of total phenolic contents (TPC: 36 ± 16 mg/g GAE), total flavonoid contents (TFC: 360 ± 135 mg/g RE), and 2, 2-diphenyl-1-picrylhydrazyl (DPPH: 60 ± 7%) in hydro-ethanolic extracts. In vivo results revealed that Ajwa whole fruit 60% hydro-ethanolic extract at high dose (2000 mg/kg) showed significantly (p < .05) highest protective effect against diarrheal changes in mice. In case of AWFE, the intestinal contents % inhibition was slightly higher (72%) as compared to that of loperamide control (70%). High dose of Ajwa whole (2000 mg/kg) demonstrated less effectiveness (66 ± 11%) in comparison with loperamide (78 ± 8%) regarding % inhibition of fluid accumulation in enteropooling studies. High dose (2000 mg/kg) of Ajwa also reduced intestinal transit time by decreasing the % distance (53 ± 1%) in comparison with loperamide (57 ± 1%). The % inhibition of charcoal meal traveling of AWFE (38 ± 2%) was also significantly higher as compared to loperamide (26 ± 1%). The findings of the current study reveal that AWFE might be consumed as an ingredient in daily food products to counter effect the symptoms of diarrhea.

Effects of Bit Chewing on Gastric Emptying, Small Intestinal Transit, and Orocecal Transit Times in Clinically Normal Horses.

Ileus is a common life-threatening problem in horses, and currently available treatments may be ineffective. The purpose of this study was to determine whether bit chewing, a form of sham feeding, decreases the gastric emptying time (GET), small intestinal transit time (SITT), and total orocecal transit time (OCTT) in clinically normal horses in a prospective crossover study. Nine healthy horses were acclimated and fed a standardized diet. Following 24 h of fasting, self-contained video endoscopy capsules and acetaminophen were administered into the stomach via a nasogastric tube. Each horse underwent experimental (bit chewing for 20 min every 6 h) or control (no bit chewing) conditions, with a 3-week minimum washout period between conditions. The horses were enrolled in either part of the study until all video capsules were retrieved and/or 30 days lapsed. The video capsules were recovered from manure, and GET, SITT, and OCTT were determined from a video analysis. Bit chewing significantly decreased OCTT (p = 0.015) compared to the control conditions. Bit chewing decreased GET and SITT, but the differences were not significant. The mean (median) times determined via the video capsule analysis for the bit-chewing conditions were as follows: GET, 2.34 h (2.86 h); SITT, 3.22 h (3.65 h); and OCTT, 5.13 h (6.15 h), and for the control conditions, they were as follows: GET, 3.93 h (5 h); SITT, 3.79 h (4.4 h); and OCTT, 8.02 h (9.92 h). Bit chewing decreased OCTT in healthy horses. Because this segment of the gastrointestinal tract is frequently affected by ileus, bit chewing may be a safe and inexpensive intervention for that condition in horses. Further investigation in clinical patients with ileus is warranted.

Effectiveness of vonoprazan-based regimens compared with proton pump inhibitor-based regimens as first-line Helicobacter pylori agents.

In this study, we compared the success rate of eradicating Helicobacter pylori (H. pylori) in adults and children using vonoprazan (VPZ)-based H. pylori regimens to that of proton pump inhibitors (PPIs). In Japan, the success rate of a VPZ-based regimen as first-line therapy was lower in children than in adults. Compared with adults, children around puberty have higher CYP2C19 and CYP3A4 enzymatic activity to metabolize PPIs and VPZ. Further, children generally have shorter intestinal transit times than adults and may absorb antibiotics to a lesser extent. When comparing success rates of pediatric and adult eradication therapy using VPZ, it is very important to maintain a higher intragastric pH with sufficient gastric acid suppression to maintain H. pylori in a replicating state and amoxicillin and clarithromycin in the intestinal tract for as long as possible by reducing diarrhea as a side effect. Based on the above, it is reasonable that VPZ, which can suppress stomach acids more strongly than PPI, is a more relevant H. pylori eradication therapy.

Endoscopic reversal of roux-en-Y gastric bypass prevents worsening of nutritional outcomes in patients with severe malnutrition

Roux-en-Y gastric bypass (RYGB) can precipitate protein-calorie malnutrition and micronutrient deficiencies. Sonographically guided endoscopic reversal (ER) via deployment of a stent from the gastric pouch to the remnant stomach in RYGB anatomy has emerged as a novel option for increasing both intestinal transit time and absorptive surface area. In this investigation, short-term nutritional outcomes after ER of a RYGB in patients (age ≥ 18) with severe protein-calorie malnutrition from a single academic health center in Minneapolis, Minnesota over a seven-year period (2015-2021) were retrospectively reviewed pre-procedurally, and at six and twelve months post-procedurally. 17 patients underwent ER for severe protein-calorie malnutrition, or dependence on tube feeds (TF) or total parenteral nutrition (TPN). At 6 months post-ER, two patients were no longer malnourished and only on oral nutrition; three patients were liberated from TPN. Laboratory markers of protein-calorie malnutrition, renal function, and micronutrients were not significantly different at six- or twelve-month follow-up (P &amp;gt; 0.05). In all patients, access to the gastric remnant was maintained via stent placement through the gastric pouch or proximal Roux limb throughout the study period and no complications were noted after ER. Despite the small sample size, this investigation revealed that ER of RYGB may prevent progressive deleterious weight loss, and worsening macro- and micro-nutrient deficiencies, though improvement in weight and nutritional parameters was not observed. Overall, ER was found to be a nuanced and safe, advanced technique useful for when remnant access is desired in RYGB patients.

Evaluation of the effect of Prithvi Mahabhuta (earth element) on intestinal transit time in Swiss albino mice

Background: Pugaphala (fruit of Areca catechu Linn.) and Udumbara Twaka (bark of Ficus glomerata Roxb.) are popular for their medicinal properties. Both drugs are used in a variety of compound formulations in Ayurveda. On the basis of their Rasa Panchaka (five factors of substance), pharmacognostical, and pharmaceutical research, Pugaphala and Udumbara Twaka were chosen as Prithvi Mahabhuta (earth element) dominant drugs in the current study. Aim: The aim of this study was to assess the impact of Prithvi Mahabhuta-dominating Dravya, Pugaphala, and Udumbara Twaka on intestinal transit time in Swiss albino mice. Materials and methods: A total of 18 Swiss albino mice were divided into three groups of six in each. Pugaphala and Udumbara Twaka were administered in mice in doses of 260 mg/kg and 520 mg/kg, respectively. Results: The result shows that both the drugs significantly reduce intestinal motility due to their Guna (properties) as Ruksha (dry), Vishada (nonslimy), Sthira (stable), Sheeta (cold), and Kashaya Rasa (astringent taste) of Prithvi Mahabhuta; however, Udumbara sample is found to be more efficient. Conclusion: The dominance of Prithvi Mahabhuta is thus confirmed by pharmacological studies in both Pugaphala and Udumbara Twaka, and it is also confirmed that Udumbara Twaka has more Parthiva dominancy than Pugaphala Churna. The Stambhana effect of Prithvi Mahabhuta on intestinal motility can be assessed by latency of onset of white-colored fecal matter in mice.

Ultraprocessed Foods and Obesity Risk: A Critical Review of Reported Mechanisms.

Epidemiologic evidence supports a positive association between ultraprocessed food (UPF) consumption and body mass index. This has led to recommendations to avoid UPFs despite very limited evidence establishing causality. Many mechanisms have been proposed, and this review critically aimed to evaluate selected possibilities for specificity, clarity, and consistency related to food choice (i.e., low cost, shelf-life, food packaging, hyperpalatability, and stimulation of hunger/suppression of fullness); food composition (i.e., macronutrients, food texture, added sugar, fat and salt, energy density, low-calorie sweeteners, and additives); and digestive processes (i.e., oral processing/eating rate, gastric emptying time, gastrointestinal transit time, and microbiome). For some purported mechanisms (e.g., fiber content, texture, gastric emptying, and intestinal transit time), data directly contrasting the effects of UPF and non-UPF intake on the indices of appetite, food intake, and adiposity are available and do not support a unique contribution of UPFs. In other instances, data are not available (e.g., microbiome and food additives) or are insufficient (e.g., packaging, food cost, shelf-life, macronutrient intake, and appetite stimulation) to judge the benefits versus the risks of UPF avoidance. There are yet other evoked mechanisms in which the preponderance of evidence indicates ingredients in UPFs actually moderate body weight (e.g., low-calorie sweetener use for weight management; beverage consumption as it dilutes energy density; and higher fat content because it reduces glycemic responses). Because avoidance of UPFs holds potential adverse effects (e.g., reduced diet quality, increased risk of food poisoning, and food wastage), it is imprudent to make recommendations regarding their role in diets before causality and plausible mechanisms have been verified.

A critical role for erythropoietin on vagus nerve Schwann cells in intestinal motility

BackgroundDysmotility and postoperative ileus (POI) are frequent major clinical problems post-abdominal surgery. Erythropoietin (EPO) is a multifunctional tissue-protective cytokine that promotes recovery of the intestine in various injury models. While EPO receptors (EPOR) are present in vagal Schwann cells, the role of EPOR in POI recovery is unknown because of the lack of EPOR antagonists or Schwann-cell specific EPOR knockout animals. This study was designed to explore the effect of EPO via EPOR in vagal nerve Schwann cells in a mouse model of POI.ResultsThe structural features of EPOR and its activation by EPO-mediated dimerization were understood using structural analysis. Later, using the Cre-loxP system, we developed a myelin protein zero (Mpz) promoter-driven knockout mouse model of Schwann cell EPOR (MpzCre-EPORflox/flox / Mpz-EPOR-KO) confirmed using PCR and qRT-PCR techniques. We then measured the intestinal transit time (ITT) at baseline and after induction of POI with and without EPO treatment. Although we have previously shown that EPO accelerates functional recovery in POI in wild type mice, EPO treatment did not improve functional recovery of ITT in POI of Mpz-EPOR-KO mice.ConclusionsTo the best of our knowledge, this is the first pre-clinical study to demonstrate a novel mouse model of EPOR specific knock out on Schwan cells with an effect in the gut. We also showed novel beneficial effects of EPO through vagus nerve Schwann cell-EPOR in intestinal dysmotility. Our findings suggest that EPO-EPOR signaling in the vagus nerve after POI is important for the functional recovery of ITT.

Alternate-day fasting induces metabolic and morphofunctional changes in the gastrointestinal tract of male rats.

Alternate-day fasting (ADF) is a nutritional intervention with modulatory and overall protective effects, but its role in the gastrointestinal (GI) tract is still uncertain. The aim of this study was to investigate the influence of ADF on the metabolic patterns and morphofunctional motility of the GI tract in rats. Thirty-two male Wistar rats were allocated into groups: control for 15 days (CON 15, n=8), control for 30 days (CON 30, n=8), ADF for 15 days (ADF 15, n=8), and ADF for 30 days (ADF 30, n=8). Blood glucose, body weight, and food and water consumption were measured. Frequency and amplitude of gastric contractions as well as gastric emptying time, small intestinal transit time, and cecum arrival time were measured. Intestinal histomorphometric, relative weight of organs, lipidogram, and leptin levels were also evaluated. ADF decreased water consumption and food consumption. The weight gain decreased; however, the relative kidney weight increased. ADF triggered an increase in the amplitude of gastric contractions and accelerated gastric emptying. However, small intestinal transit time was delayed in both ADF groups. Total cholesterol, triglycerides, non-HDL cholesterol, and very low-density lipoprotein cholesterol levels decreased, whereas villus height, depth of the crypts and thickness of the circular, and longitudinal muscular layers of intestine increased after ADF. In conclusion, our results showed ADF exert an effect on both metabolism and GI motility and impacts on overall digestive functions.

Vinpocetine prevents rotenone-induced Parkinson disease motor and non-motor symptoms through attenuation of oxidative stress, neuroinflammation and α-synuclein expressions in rats

Parkinson’s disease (PD) is a progressive neurodegenerative disease characterized by motor and non-motor symptoms. Epidemiological reports showed a significant association between environmental toxicants-induced gut dysbiosis and PD. Neuroinflammation, mitochondrial dysfunction and decreased cerebral blood flow are hallmarks of PD. This study sought to evaluate the protective ability of vinpocetine (VIN), a neuroprotectant, on rotenone (ROT) (mitochondrial complex I inhibitor) induced PD in rats. Sixty male Sprague Dawley rats were randomly divided into six groups (n = 10) and treated orally as follows; group 1: vehicle (10 ml/kg); group 2: rotenone (10 mg/kg) + vehicle; group 3–5: vinpocetine (5, 10 or 20 mg/kg) + rotenone (10 mg/kg), respectively, or group 6: vinpocetine 20 mg/kg before behavioural assay for motor symptoms (fore-limb hanging test and open field test) and non-motor symptoms (working memory and learning capabilities in Y-maze/Morris water maze tasks, anxiety in hole board test and gut motility with intestinal transit time). Following treatment for 28 days, biochemical assays and immunostaining was performed. We examined the effect of vinpocetine on rotenone-induced oxidative stress and inflammatory markers. The pretreatment of rats with vinpocetine reversed rotenone-induced locomotor deficit, motor incoordination, cognition deficits and gut dysfunction. In addition, rotenone-induced a significant increase in the level of interleukin-6 and tumor necrotic factor-α, oxidative stress markers, cholinergic signalling, gut dysfunction and haematologic dysfunctions which were attenuated by vinpocetine administration. Immunostainings showed that rotenone-induced dopamine neuron loss, microglia reactivity, astrocytes activation, toll-like receptor 4 (TLR4) and α-synuclein (SNCA) expressions which were attenuated by vinpocetine administration. Findings from this study revealed a neuroprotective effect of vinpocetine on rotenone-induced PD through anti-neuroinflammatory and antioxidant mechanisms.

Using cereal to increase dietary fiber intake to the recommended level and the effect of fiber on bowel function in healthy persons consuming North American diets

Background:Dietary fiber intake remains low despite increasing evidence for its health benefits, including laxation. Objective:We aimed to assess the effects of increasing fiber intake on bowel habits and gastrointestinal tolerance in healthy persons consuming a typical Canadian or US diet. Design:Under a randomized crossover design, 23 free-living participants consumed a typical Canadian or US diet (35% fat, 12 g fiber/d) and received 25.0–28.7 g fiber/d from each of 5 breakfast cereals: All-Bran (AB), Bran Buds with Corn (BBC), Bran Buds with Psyllium (BBP), BBC with viscous fiber blend (VFB), or a low-fiber control for 3 wk, with each study arm separated by a washout of ≥1 wk. Seven-day stool collections and a symptom diary were obtained during the last week of each study arm. Results:All study cereals induced significant (P < 0.05) increases in fecal bulk from the control diet at 128 ± 38 g to 199 ± 56, 199 ± 57, 247 ± 87, and 197 ± 63 g with consumption of AB, BBC, BBP, and VFB, respectively; less intestinal transit time; and significantly (P < 0.05) greater bowel movement frequency. Despite the increased activity of the bowel, a positive level of comfort was maintained. BBP was more effective than other cereals in terms of increasing fecal wet weight (P < 0.05). Conclusion:Water-insoluble dietary fibers (ie, AB and BBC) and their mixtures with water-soluble fibers (ie, BBP and VFB) in the form of breakfast cereals (2.5 servings/d) proved to be a practical way of increasing fiber intake to recommended levels, while maintaining a good level of tolerance.

Bifidobacterium bifidum CCFM1163 Alleviated Cathartic Colon by Regulating the Intestinal Barrier and Restoring Enteric Nerves.

Cathartic colon (CC), a type of slow-transit constipation caused by the long-term use of stimulant laxatives, does not have a precise and effective treatment. This study aimed to evaluate the ability of Bifidobacterium bifidum CCFM1163 to relieve CC and to investigate its underlying mechanism. Male C57BL/6J mice were treated with senna extract for 8 weeks, followed by a 2-week treatment with B. bifidum CCFM1163. The results revealed that B. bifidum CCFM1163 effectively alleviated CC symptoms. The possible mechanism of B. bifidum CCFM1163 in relieving CC was analyzed by measuring the intestinal barrier and enteric nervous system (ENS)-related indices and establishing a correlation between each index and gut microbiota. The results indicated that B. bifidum CCFM1163 changed the gut microbiota by significantly increasing the relative abundance of Bifidobacterium, Faecalibaculum, Romboutsia, and Turicibacter as well as the content of short-chain fatty acids, especially propionic acid, in the feces. This increased the expression of tight junction proteins and aquaporin 8, decreased intestinal transit time, increased fecal water content, and relieved CC. In addition, B. bifidum CCFM1163 also increased the relative abundance of Faecalibaculum in feces and the expression of enteric nerve marker proteins to repair the ENS, promote intestinal motility, and relieve constipation.

Solubility and Intestinal Transit Time Limit Calcium Absorption in Rats

Six-week-old male rats were placed on two high calcium regimens: one with calcium carbonate and monobasic calcium phosphate, with calcium content increased via calcium carbonate; and another with calcium phosphate and calcium gluconate, with calcium gluconate the source of increased calcium. Animals fed the gluconate-containing diets absorbed 29% of the ingested calcium over the entire calcium intake range, whereas those fed the calcium carbonate diets absorbed 25% over an intake range of 225 to 450 mg Ca/d, but at calcium intakes above 450 mg Ca/d their absorption reached a plateau at approximately 109 mg/d. Active calcium transport decreased with increased calcium intake in both the calcium carbonate- and calcium gluconate-fed groups. Nonsaturable transport was unchanged as a result of increasing calcium intake and did not differ among the diet groups. Because the absorptive processes were unaffected by the calcium source, events in the lumen must have been responsible for the observed differences. Because phosphate is nearly 18 times more soluble than carbonate, very little calcium of calcium carbonate origin can have been solubilized in the presence of phosphate and this, we conclude, accounts for the limit on calcium absorption observed in diets high in calcium carbonate. Moreover, when intake is expressed as soluble calcium, absorption approaches 50%, the value expected when intestinal transit time (approximately 3 h) is multiplied by 16%/h, the experimental value of nonsaturable absorption.

Aryl hydrocarbon receptor activation affects nitrergic neuronal survival and delays intestinal motility in mice.

Despite progress describing the effects of persistent organic pollutants (POPs) on the central nervous system, the effect of POPs on enteric nervous system (ENS) function remains underexplored. We studied the effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a POP, and a potent aryl hydrocarbon receptor (AHR) ligand, on the ENS and intestinal motility in mice. C57Bl/6J mice treated with TCDD (2.4 µg/kg body weight) for 8 weeks (once per week) exhibited significant delay in intestinal motility as shown by reduced stool frequency, prolonged intestinal transit time, and a persistence of dye in the jejunum compared to control mice with maximal dye retention in the ileum. TCDD significantly increased Cyp1a1 expression, an AHR target gene, and reduced the total number of neurons and affected nitrergic neurons in cells isolated from WT mice, but not Ahr-/- mice. In immortalized fetal enteric neuronal cells, TCDD-induced nuclear translocation of AHR as well as increased Cyp1a1 expression. AHR activation did not affect neuronal proliferation. However, AHR activation resulted in enteric neuronal toxicity, specifically, nitrergic neurons. Our results demonstrate that TCDD adversely affects nitrergic neurons and thereby contributes to delayed intestinal motility. These findings suggest that AHR signaling in the ENS may play a role in modulating TCDD-induced gastrointestinal pathophysiology.

Garlic supplementation improves intestinal transit time, lipid accumulation product and cardiometabolic indices in subjects with metabolic syndrome: A randomized controlled trial.

Subjects with metabolic syndrome (MetS) are at increased risk for cardiovascular disease (CVD). Altered gut microbiota is involved in the pathogenesis of MetS. It has been hypothesized that garlic can improve intestinal transit time and cardiovascular risks. We investigated the effect of garlic powder supplementation on intestinal transit time, lipid accumulation product (LAP), and cardiometabolic indices in subjects with MetS. A double-blind randomized controlled trial was conducted for 3 months among subjects with MetS. Ninety subjects were randomly assigned to the treatment group (intake of 1,600 mg/d garlic powder) or control group (placebo) using a computer-generated random number table. All participants were asked to follow the common healthy dietary recommendations during follow-up. The primary outcomes included intestinal transit time, LAP, cardiometabolic index (CMI), atherogenic index of plasma (AIP), Castelli risk index I (CRI-I) and Castelli risk index II (CRI-II). Garlic powder compared to the placebo improved intestinal transit time (p=.001), LAP (-21.5 ± 23.4 vs. 0.7 ± 21.5; p < .001), CMI (-0.85 ± 0.8 vs. 0.13 ± 0.8; p < .001), AIP (-0.14 ± 0.1 vs. 0.01 ± 0.1; p < .001), CRI-I (-0.69 ± 0.5 vs. 0.16 ± 0.5; p < .001) and CRI-II (-0.50 ± 0.3 vs. 0.02 ± 0.3; p < .001). Garlic supplementation can improve intestinal transit time, LAP, and cardiometabolic indices.

Physiologically based pharmacokinetic modeling to predict OAT3-mediated drug-drug interactions of meropenem in varying stages of chronic kidney disease

ObjectiveThis study aimed to predict OAT3-mediated meropenem DDIs in varying stages of CKD using physiologically based pharmacokinetic (PBPK) models. MethodsMeropenem DDI model was performed with OAT3 perpetrators probenecid (strong inhibitor), piperacillin (moderate inhibitor) and acyclovir (weak inhibitor). Firstly, whole-body PBPK models were developed for meropenem and piperacillin in healthy adults with PK-Sim®. Then the models were translated to patients with varying stages of CKD by accounting for changes in eGFR, kidney volume, kidney blood flow, hematocrit, gastric emptying time, small intestinal transit time, OAT transport function and non-renal clearance. Subsequently, meropenem DDI model was verified by comparing the model simulation results of the interaction between meropenem and probenecid with the observational data from clinical studies. Finally, pharmacokinetics of meropenem under co-administration of piperacillin and acyclovir were predicted through simulations with the virtual population in varying stages of CKD. ResultsThe developed PBPK models of meropenem and piperacillin adequately described the pharmacokinetic characteristics in healthy adults and in adults with varying stages of CKD. The predicted AUC ratio of meropenem co-administered with probenecid to meropenem given alone was within 1.5-fold of the observed clinical data. The predicted steady-state AUC values of meropenem in healthy adults co-administered with probenecid, piperacillin or acyclovir were 1.593-fold (95% CI, 1.436-1.6244), 1.031-fold (95% CI, 1.017-1.045) and 1.005-fold (95% CI, 1.004-1.005), respectively, as compared to the AUC of meropenem given alone. And all predicted probenecid-meropenem, piperacillin-meropenem and acyclovir-meropenem DDI AUC ratios were decreased in renal impairment. Our presented meropenem DDI model demonstrated that patients with CKD may be less vulnerable to OAT3-mediated DDIs compared with healthy adults. However, further clinical DDI studies are required to verify our prediction results. ConclusionPBPK analysis provided a quantitative basis for guiding the clinical application of meropenem combined with OAT3 inhibitor in varying stages of CKD.