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Annals of Translational Medicine Mar 2022Functional constipation (FC) is a common gastrointestinal (GI) disorder characterized by symptoms of constipation without a clear physiologic or anatomic cause. Gut...
BACKGROUND
Functional constipation (FC) is a common gastrointestinal (GI) disorder characterized by symptoms of constipation without a clear physiologic or anatomic cause. Gut microbiome dysbiosis has been postulated to be a factor in the development of FC, and treatment with probiotic regimens, including strains of , has demonstrated efficacy in managing symptoms. To further understand the role of in GI health, we conducted an animal study and a randomized, double-blind, placebo-controlled clinical trial to evaluate the effect of a specific sub-strain, Lp3a, on FC.
METHODS
For the animal study, male Kunming mice were treated with doses of Lp3a ranging from 0.67 to 2.00 g/kg or an equivalent amount of placebo for 15 days prior to the induction of constipation via 20 mL/kg of 25% diphenoxylate solution. GI motility parameters including intestinal motion and stool amount were then assessed. In the human study, 120 patients with FC were randomized to treatment [ Lp3a; 2×1.0×10 (colony forming units; CFU) ×7 days] or control groups (n=60 each). The primary endpoint was survey information on FC signs/symptoms. Participants and observers were blinded to group allocation. A subset of 20 Lp3a treated patients underwent pre- and post-treatment 16 s ribosomal ribonucleic acid (rRNA) gene sequencing. Whole genome sequencing (WGS) of Lp3a was also performed.
RESULTS
Lp3a-treated mice showed significantly improved intestinal motion, reduced time to first defecation, and increased stool amounts. Similarly, patients in the treatment group (n=59) reported significant improvements in FC signs/symptoms compared to controls (n=58; all P<0.05). Although 16 s rRNA sequencing revealed no significant variations between pre- and post-treatment samples, WGS of Lp3a itself revealed several biological pathways that may underlie the relief of FC symptoms in animals and humans, including methane and fatty acid metabolism and bile acid biosynthesis.
CONCLUSIONS
We found that the use of the novel probiotic sub-strain, Lp3a, led to clinically significant improvements in FC in both mice and humans, and identified the potential biological mechanisms underlying this activity.
PubMed: 35434041
DOI: 10.21037/atm-22-458 -
Bioinformatics and Biology Insights 2019Diarrhoeal disease kills about 1.5 million human beings per year across the continents. The enterotoxigenic (ETEC) pathotype has been noted as a major cause of...
Diarrhoeal disease kills about 1.5 million human beings per year across the continents. The enterotoxigenic (ETEC) pathotype has been noted as a major cause of diarrheal disease in human and livestock. The aim of this study is to identify broad-spectrum molecular targets in bacteria and broad-spectrum lead compounds (functional inhibitors) with high efficacy and no significant adverse implication on human systems, in relevance to diarrhea therapy through computational approaches which include phylogenetics, target prediction, molecular docking, and molecular flexibility dynamic simulations. Three molecular target genes, , and , which code for uridine diphosphate--acetylglucosamine-1-carboxyvinyltransferase, 1-deoxy-D-xylulose-5-phosphate reductoisomerase, and deoxyribonucleic acid polymerase III alpha subunit, respectively, were found to be highly conserved in 7 diarrhea-causing microbes. In addition, 21 potential compounds identified showed varied degree of affinity to these enzymes. At free energy cutoff of -8.0 kcal/mol, the highest effective molecular target was DNA polymerase III alpha subunit (PDB ID: 4JOM) followed by UDP--acetylglucosamine-1-carboxyvinyltransferase (PDB ID: 5UJS), and 1-deoxy-D-xylulose-5-phosphate reductoisomerase (PDB ID: 1ONN), while the highest effective lead compound was -coeleneterazine followed by amphotericin B, MMV010576, MMV687800, MMV028694, azithromycin, and diphenoxylate. The flexibility dynamics of DNA polymerase III alpha subunit unraveled the atomic fluctuation which potentially implicated Asp593 as unstable active site amino acid residue. In conclusion, bacteria gene or its protein is a highly promising molecular target for the next generation of antibacterial drugs of the class of -coeleneterazine.
PubMed: 31695343
DOI: 10.1177/1177932219884297 -
Drug, Healthcare and Patient Safety 2019The U.S. Food and Drug Administration Adverse Event Reporting System (FAERS), contains information on adverse drug events and medication error reports submitted to the...
BACKGROUND
The U.S. Food and Drug Administration Adverse Event Reporting System (FAERS), contains information on adverse drug events and medication error reports submitted to the FDA through the MedWatch program. A significant number of adverse events reported in the FAERS database have been for opioid use. The objective of this study was to determine the frequency counts and associated deaths of opioid drug names in the FAERS database.
METHODS
Drug data were obtained from the DRUG and OUTCOME files in the database. Drugs identified included: morphine, fentanyl, oxycodone, hydrocodone, tramadol, hydromorphone, methadone, codeine, oxymorphone, meperidine, propoxyphene, diphenoxylate, and heroin. Frequency counts and concomitant deaths of opioid drug names were determined via the MySQL database management system.
RESULTS
Fifteen different opioid drugs identified in the FAERS database were associated with ADEs, including death, and 3 drugs (oxycodone, hydrocodone, fentanyl) accounted for more than half of the reports. The highest frequency count value was 158,181 for oxycodone, which represents approximately 20.2% of the frequency counts for the opioids. The lowest frequency count value was 2,161 for dextromethorphan, which represents approximately 0.3% of the total. The opioid with the highest proportion of deaths to drug count was heroin (71.8%), followed by dextromethorphan (55.6%), methadone (37.2%), morphine (26.8%), and propoxyphene (23.7%).
CONCLUSION
The FAERS database represents an important source for detection and reporting of adverse drug events (ADEs), in particular the opioids and related drugs. It remains a challenge to estimate the true incidence of ADEs for this class of drugs in the general population.
PubMed: 31695510
DOI: 10.2147/DHPS.S214771 -
Digestive Diseases and Sciences Sep 2022Slow transit constipation (STC) is caused by intestinal peristalsis dysfunction and is closely associated with disturbance of the intestinal microecological balance....
BACKGROUND
Slow transit constipation (STC) is caused by intestinal peristalsis dysfunction and is closely associated with disturbance of the intestinal microecological balance. Bacillus subtilis plays a positive role in the treatment of STC, but its mechanism needs to be further explored.
AIMS
The purpose of the present study was to explore the effects and mechanism of B. subtilis on the pathophysiology of STC.
METHODS
A STC mouse model was established with compound diphenoxylate, following which B. subtilis was used to treat STC. The effects and possible mechanism of B. subtilis on STC were investigated by assessing intestinal motility, histology of the colon, release of 5-HT in enterochromaffin cells (ECs) and the TGR5/TRPA1 pathway. Moreover, LC-MS targeted metabolomics was used to analyze the regulation of Bacillus subtilis on bile acid metabolisms in STC mice.
RESULTS
Bacillus subtilis significantly increased 24 h defecations, fecal moisture and intestinal transport rate of STC mice, improved pathological damage of the colon and showed protective effects on the intestinal tract. The release of 5-HT from ECs and the bile acid receptor TGR5/TRPA1 pathway were significantly increased in STC mice treated with B. subtilis. In addition, the metabolomics results showed that the bile acid contents of STC mice were significantly decreased, and B. subtilis could increase the bile acid composition and content of STC mice.
CONCLUSION
Bacillus subtilis regulates intestinal peristalsis of STC by promoting the release of 5-HT from ECs through bile acid metabolism and its receptor TGR5 pathway and plays a positive role in the treatment of STC.
Topics: Animals; Bacillus subtilis; Bile Acids and Salts; Constipation; Mice; Peristalsis; Serotonin
PubMed: 34797444
DOI: 10.1007/s10620-021-07308-4 -
The Manufacturing Process of Kiwifruit Fruit Powder with High Dietary Fiber and Its Laxative Effect.Molecules (Basel, Switzerland) Oct 2019Kiwifruit is rich in vitamins, minerals, dietary fiber and other functional components, and it has long been used as a functional food to treat intestinal ailments such...
Kiwifruit is rich in vitamins, minerals, dietary fiber and other functional components, and it has long been used as a functional food to treat intestinal ailments such as constipation. The current research made full use of the kiwifruit, the juice was prepared by microencapsulation, and the dietary fiber in kiwifruit pomace was modified by enzymatic hydrolysis and grinding, then, the two were mixed to obtain an ultra-micro kiwifruit powder (UKP). In addition, the laxative effect of the UKP was verified by a diphenoxylate induced constipated mice model. The results demonstrated that compared with the raw samples, the retention rate of vitamin C, lutein and catechin in UKP were 83.3%, 81.9% and 88.3%, respectively, thus effectively avoiding the loss of functional components during the processing of kiwifruit. Moreover, α-amylase, protease and the ball milling process effectively reduced the size of dietary fiber in kiwifruit pomace, and its water-holding capacity (WHC), oil-holding capacity (OHC) and swelling capacity (SWC) were enhanced by 1.26, 1.65 and 1.10 times, respectively. Furthermore, to analyze the laxative effect of the UKP, a constipation mice model was established by diphenoxylate treatment (5 mg·kg, i.g.) for the last week, with or without UKP supplementation (2.4 g·kg B.W. per day) for 4 weeks. The results demonstrated that UKP significantly increased feces condition (fecal output and dejecta moisture content, gut transit (the intestinal propulsion rates) and substance P (SP) levels in portal vein plasma, and it decreased the whole gut transit time and mucinogen granules secreted by goblet cell in constipated mice.
Topics: Actinidia; Animals; Constipation; Dietary Fiber; Fruit; Laxatives; Male; Mice; Plant Extracts
PubMed: 31652679
DOI: 10.3390/molecules24213813 -
Biomedicine & Pharmacotherapy =... May 2023Constipation arising from the poor bowel movement is a rife enteric health problem. Shouhui Tongbian Capsule (SHTB) is a traditional Chinese medicine (TCM) which...
Shouhui Tongbian Capsules induce regression of inflammation to improve intestinal barrier in mice with constipation by targeted binding to Prkaa1: With no obvious toxicity.
Constipation arising from the poor bowel movement is a rife enteric health problem. Shouhui Tongbian Capsule (SHTB) is a traditional Chinese medicine (TCM) which effectively improve the symptoms of constipation. However, the mechanism has not been fully evaluated. The purpose of this study was to evaluate the effect of SHTB on the symptoms and intestinal barrier of mice with constipation. Our data showed that SHTB effectively improved the constipation induced by diphenoxylate, which was confirmed by shorter first defecation time, higher internal propulsion rate and fecal water content. Additionally, SHTB improved the intestinal barrier function, which was manifested by inhibiting the leakage of Evans blue in intestinal tissues and increasing the expression of occludin and ZO-1. SHTB inhibited NLRP3 inflammasome signaling pathway and TLR4/NF-κB signaling pathway, reduced the number of proinflammatory cell subsets and increased the number of immunosuppressive cell subsets to relieve inflammation. The photochemically induced reaction coupling system combined with cellular thermal shift assay and central carbon metabolomics technology confirmed that SHTB activated AMPKα through targeted binding to Prkaa1 to regulate Glycolysis/Gluconeogenesis and Pentose Phosphate Pathway, and finally inhibited intestinal inflammation. Finally, no obvious toxicity related to SHTB was found in a repeated drug administration toxicity test for consecutive 13 weeks. Collectively, we reported SHTB as a TCM targeting Prkaa1 for anti-inflammation to improve intestinal barrier in mice with constipation. These findings broaden our knowledge of Prkaa1 as a druggable target protein for inflammation inhibition, and open a new avenue to novel therapy strategy for constipation injury.
Topics: Animals; Mice; Constipation; Inflammation; Intestines; NF-kappa B; Signal Transduction; AMP-Activated Protein Kinases
PubMed: 36906969
DOI: 10.1016/j.biopha.2023.114495 -
Medical Science Monitor : International... Jul 2019BACKGROUND The aim of this study was to evaluate the effects of a new type of dietary fiber - high specific volume polysaccharide (HSVP) - on fecal properties, serum...
BACKGROUND The aim of this study was to evaluate the effects of a new type of dietary fiber - high specific volume polysaccharide (HSVP) - on fecal properties, serum vasoactive intestinal peptide (VIP) concentration, intestinal flora count, and expression of the VIP-cAMP-PKA-AQP3 signaling pathway. MATERIAL AND METHODS Compound diphenoxylate was used in 48 healthy Wistar rats to establish a constipation model. Rats were divided into a normal control group, a constipation model group, an HSVP low-dose group, an HSVP medium-dose group, an HSVP high-dose group, and a fructose control group. We used colony count method, ELISA, WB, and RT-PCR to determine fecal moisture content, fecal hardness, fecal passage time, serum VIP concentration, number of intestinal bacteria, and VIP-cAMP-PKA-AQP3 signal pathway protein expression. RESULTS The constipation model was established successfully. HSVP (the medium dose was 10% and the high dose was 15%) improved fecal moisture content, reduced hardness, shortened fecal emptying time, increased intestinal bacteria, reduced serum VIP concentration, downregulated cAMP and PKAm RNA transcription, reduced protein expression, and reduced intestinal AQP3 expression. CONCLUSIONS HSVP improved constipation, increased the number of intestinal bacteria, and elevated expression of the VIP-cAMP-PKA-AQP3 signaling pathway. The mechanism of HSVP in regulating intestinal water metabolism in constipated rats may occur through the VIP-cAMP-PKA-AQP3 signaling pathway, and be closely related to changes in intestinal bacteria. The important role of the brain-gut-microbiome axis in the pathogenesis of constipation has been confirmed in this study.
Topics: Animals; Aquaporin 3; Constipation; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Dietary Fiber; Feces; Gastrointestinal Microbiome; Gastrointestinal Transit; Hardness; Humidity; Intestines; Polysaccharides; RNA, Messenger; Rats, Wistar; Transcription, Genetic; Treatment Outcome; Vasoactive Intestinal Peptide; Water
PubMed: 31280283
DOI: 10.12659/MSM.916526 -
Beneficial Microbes Feb 2021Probiotics have been reported to be associated with the alleviation of constipation. The aim of this study was to detect and determine the effect of subsp. MN-Gup... (Randomized Controlled Trial)
Randomized Controlled Trial
Probiotics have been reported to be associated with the alleviation of constipation. The aim of this study was to detect and determine the effect of subsp. MN-Gup (MN-Gup) on the alleviation of constipation in BALB/c mice and humans, and to elucidate the mechanisms underlying its effect by measuring changes in the concentration of short-chain fatty acids and the composition of microbes in human faeces. BALB/c mice were given MN-Gup by gavage for 14 days. On the 8 day of this treatment, constipation was induced by the application of diphenoxylate via gavage. The results showed that MN-Gup significantly decreased the first black stool defecation time, and significantly increased black faecal wet weight, black faecal number and the gastric-intestinal transit rate (<0.05), thereby relieving constipation. In humans, a randomised, double-blind, placebo-controlled trial was performed to investigate the effect of MN-Gup in adults with functional constipation. After 4 weeks of intervention with placebo or MN-Gup yogurt, constipation-related symptoms (including defecation frequency, stool consistency, straining and incomplete feeling during defecation) in the constipated subjects were significantly improved in the two groups, but not different between the groups at the end of the intervention. The concentration of acetate increased significantly in the MN-Gup group compared to the placebo group and before ingestion. Significant changes in the composition of gut microbiota were found after intake of MN-Gup yogurt when compared to placebo. The relative abundances of acetate-producing and were significantly increased after intake of MN-Gup yogurt. These results showed that MN-Gup could relieve constipation related to increased acetate-producing and .
Topics: Adult; Animals; Bacteria; Bifidobacterium animalis; Constipation; Defecation; Feces; Female; Gastrointestinal Microbiome; Gastrointestinal Tract; Humans; Male; Mice; Mice, Inbred BALB C; Middle Aged; Probiotics; Yogurt
PubMed: 33308038
DOI: 10.3920/BM2020.0023 -
Advances in Clinical and Experimental... May 2024Liqi Tongbian is a traditional Chinese medicine (TCM) preparation that contains herbs that may treat slow transit constipation (STC). Atractylodes macrocephala,...
BACKGROUND
Liqi Tongbian is a traditional Chinese medicine (TCM) preparation that contains herbs that may treat slow transit constipation (STC). Atractylodes macrocephala, Astragalus membranaceus, Fructus aurantii, radish seed, uncooked Polygonum multiflorum, and Agastache rugosa were included in the formula for their unique qualities. The control of water transfer in the colon is greatly influenced by aquaporin 3 (AQP3).
OBJECTIVES
Based on this, the Liqi Tongbian mixture was used to detect the concentrations of aquaporins (AQPs), 5-HT and nitrix oxide synthase 1 (NOS1) in STC rats, and explore its effect, in order to provide a theoretical basis for the remedy of STC with TCM.
MATERIAL AND METHODS
Zhejiang University of Traditional Chinese Medicine provided 32 three-week-old Sprague Dawley rats of SPF-grade. The pairs licensed under SYXK (Zhejiang) 2021-0012 were kept at 20-25°C and humidity of 50-65%. The compound diphenoxylate caused constipation in the control, model, Liqi laxative (LQTB), and mosapride groups. The Liqi laxative rats were administered a mixture of traditional Chinese herbs after modeling, while mosapride was given to the other group. The levels of 5-HT, NOS1 and AQPs were tested in the feces and intestinal tissues.
RESULTS
Comparing the condition of rat feces, it was found that the model group had significantly lower overall bulk, score and particles within 24 h compared to the control group. In comparison to mosapride, LQTB performed better. The model group had higher levels of 5-HT and NOS1 in intestinal tissue, while the LQTB and mosapride groups had decreased levels of these AQPs. LQTB had lower levels of AQP1, AQP3 and AQP4 than mosapride, while the model group had higher levels of these AQPs.
CONCLUSIONS
Liqi Tongbian mixture works better than mosapride in improving constipation symptoms in rats with STC, and its mechanism is related to regulating the level of intestinal AQPs and neurotransmitters.
PubMed: 38819938
DOI: 10.17219/acem/175808 -
The Kaohsiung Journal of Medical... Jun 2024Slow transit constipation (STC) is one of the most common gastrointestinal disorders in children and adults worldwide. Paeoniflorin (PF), a monoterpene glycoside...
Slow transit constipation (STC) is one of the most common gastrointestinal disorders in children and adults worldwide. Paeoniflorin (PF), a monoterpene glycoside compound extracted from the dried root of Paeonia lactiflora, has been found to alleviate STC, but the mechanisms of its effect remain unclear. The present study aimed to investigate the effects and mechanisms of PF on intestinal fluid metabolism and visceral sensitization in rats with compound diphenoxylate-induced STC. Based on the evaluation of the laxative effect, the abdominal withdrawal reflex test, enzyme-linked immunosorbent assay, quantitative real-time polymerase chain reaction, western blot, and immunohistochemistry were used to detect the visceral sensitivity, fluid metabolism-related proteins, and acid-sensitive ion channel 3/extracellular signal-regulated kinase (ASIC3/ERK) pathway-related molecules. PF treatment not only attenuated compound diphenoxylate-induced constipation symptoms and colonic pathological damage in rats but also ameliorated colonic fluid metabolic disorders and visceral sensitization abnormalities, as manifested by increased colonic goblet cell counts and mucin2 protein expression, decreased aquaporin3 protein expression, improved abdominal withdrawal reflex scores, reduced visceral pain threshold, upregulated serum 5-hydroxytryptamine, and downregulated vasoactive intestinal peptide levels. Furthermore, PF activated the colonic ASIC3/ERK pathway in STC rats, and ASIC3 inhibition partially counteracted PF's modulatory effects on intestinal fluid and visceral sensation. In conclusion, PF alleviated impaired intestinal fluid metabolism and abnormal visceral sensitization in STC rats and thus relieved their symptoms through activation of the ASIC3/ERK pathway.
Topics: Animals; Glucosides; Monoterpenes; Acid Sensing Ion Channels; Constipation; Rats; Male; MAP Kinase Signaling System; Rats, Sprague-Dawley; Colon; Gastrointestinal Transit; Aquaporin 3; Serotonin; Visceral Pain
PubMed: 38634140
DOI: 10.1002/kjm2.12829