Corrigendum: Patchouli alcohol improved diarrhea-predominant irritable bowel syndrome by regulating excitatory neurotransmission in the myenteric plexus of rats.

[This corrects the article DOI: 10.3389/fphar.2022.943119.].

Moxibustion ameliorates visceral hypersensitivity by regulating hypothalamus-spinal cord-colon axis in rats with irritable bowel syndrome with diarrhea. / 基于下丘脑-脊髓-ç»“è‚ è½´æŽ¢è®¨è‰¾ç¸æ”¹å–„è ¹æ³»åž‹è‚ æ˜“æ¿€ç»¼åˆå¾å¤§é¼ å† è„é«˜æ•æ„Ÿçš„ä½œç”¨æœºåˆ¶.

OBJECTIVES: To observe the effect of moxibustion intervention on the hypothalamus-spinal cord-colon axis of rats with irritable bowel syndrome with diarrhea (IBS-D) and explore the mechanism of moxibustion in improving visceral hypersensitivity in rats with IBS-D. METHODS: A total of 36 SD rats were randomly divided into normal, model, and moxibustion groups, with 12 rats in each group. The IBS-D model was established by maternal separation + acetic acid stimulation + chronic restraint. Rats of the moxibustion group received bilateral moxibustion on "Tianshu" (ST25) and "Shangjuxu" (ST37) for 15 min, once a day for 7 consecutive days. The body weight, loose stool rate, and minimum threshold volume of abdominal withdrawal reflex (AWR) were measured before and after moxibustion intervention, respectively. The histopathological changes in the colon tissue were observed after HE staining. The number of colonic mucosal mast cells (MCs) was measured by toluidine blue staining. The activation of MCs was determined by tryptase positive expression level and examined by immunohistochemical staining. The content, protein and mRNA expression levels and positive expression levels of corticotropin releasing factor (CRF), substance P (SP), and calcitonin gene-related peptide (CGRP) in the hypothalamus, spinal cord and colon tissues were measured by ELISA, Western blot, real-time fluorescent quantitative PCR and immunofluorescence staining, respectively. RESULTS: Compared with the normal group, the loose stool rate was increased (P<0.01)；the body weight and minimum threshold volume of AWR were decreased (P<0.01)；the inflammatory infiltration of colon tissues was obvious；the number of MCs and positive expression level of tryptase in the colon tissue were increased (P<0.01)；the contents, positive expression le-vels, protein and mRNA expression levels of CRF, SP and CGRP in the hypothalamus, spinal cord and colon tissues were increased (P<0.01, P<0.05) in the model group. After the intervention, compared with the model group, all these indicators showed opposite trends (P<0.01, P<0.05) in the moxibustion group. CONCLUSIONS: Moxibustion can improve visceral hypersensitivity in rats with IBS-D, and its mechanism may be related to regulating the hypothalamic-spinal-colon axis to reduce the release of CRF, SP and CGRP, and thus to inhibite MC in colon tissue.

Cognition of abdominal pain and abdominal discomfort in Chinese patients with irritable bowel syndrome with diarrhea.

BACKGROUND: In Asia, the proportion of patients with irritable bowel syndrome (IBS) with abdominal discomfort alone is significantly higher than that in western countries. The purposes of this study are to understand the cognition of abdominal pain and abdominal discomfort in Chinese patients with IBS and to compare the clinical characteristics of patients with abdominal pain alone and with abdominal discomfort alone. METHODS: Patients with IBS with diarrhea (IBS-D) who met the Rome III diagnostic criteria and had episodes of at least one day/week were consecutively enrolled. The cognition of abdominal pain and abdominal discomfort were investigated through face-to-face unstructured interview. Patients were divided into a pain group and a discomfort group according to the cognition interviews, then the characteristics and severity of symptoms (IBS symptom severity scale, IBS-SSS), IBS quality of life (IBS-QOL) and psychological state were compared between groups. RESULTS: A total of 88 patients with IBS-D were enrolled. Most of the patients with self-reported abdominal pain described their pain as spasm/cramping; patients with self-reported abdominal discomfort had as many as 24 different descriptions of discomfort. Most patients having abdominal pain and discomfort could accurately distinguish the two symptoms. The degree of abdominal pain in the pain group was higher than abdominal discomfort in the discomfort group (P = 0.002). There was no significant difference in IBS-SSS, extra-intestinal pain, IBS-QOL, and psychological state between the two groups. CONCLUSIONS: For Chinese patients with IBS-D, abdominal pain and abdominal discomfort are two different symptoms, but they have similar clinical features. TRIAL REGISTRATION: ChiCTR, ChiCTR1900028082. Registered 11 December 2019 - Retrospectively registered, http://www.chictr.org.cn .

Vitamin D Deficiency (VDD) and Benefits of Supplementation in Veterans with IBS-D.

Many veterans deployed to Gulf War areas suffer from persistent chronic diarrhea that is disabling and affects their quality of life. The causes for this condition have eluded investigators until recently and recent literature has shed light on the effect of vitamin D on the brain-gut axis. This study focused on determining clinical causes contributing to diarrhea and assessed whether reversing the identified causes, specifically vitamin D deficiency (VDD), could reduce the incidence of diarrhea in Gulf War veterans (GWVs). All patients completed a workup that included serologies (IBD, celiac), routine laboratory tests (CBC, chemistry panels, TSH, T4, CRP), cultures for enteric pathogens (C diff, bacteria, viruses, small intestinal bacterial overgrowth (SIBO)), and upper and lower endoscopies with histology and a trial of cholestyramine to exclude choleretic diarrhea and rifaximin for dysbiosis. A total of 4221 veterans were screened for chronic diarrhea, yielding 105 GWVs, of which 69 GWVs had irritable bowel syndrome with diarrhea (IBS-D). Paired t-tests demonstrated that all GWVs had VDD (t-11.62, df68 and sig(2-tailed) 0.0001) (defined as a vitamin D level less than 30 ng/mL with normal ranges of 30-100 ng/mL) but no positive serologies, inflammatory markers, abnormal endoscopies, cultures, or histology to explain their persistent diarrhea. There was no correlation with age, BMI, or inflammation. Some zip codes had a higher frequency of GWVs with VDD, but the number of deployments had no impact. Treatment with vitamin D supplementation (3000-5000 units), given in the morning, based on weight, reduced the number of bowel movements per day (p < 0.0001) without causing hypercalcemia. We suggest that VDD is important in the etiology of IBS-D in GWVs and that vitamin D supplementation significantly reduces diarrhea.

Single-dose Pharmacokinetics of Eluxadoline in Healthy Participants With Normal Renal Function and Participants With Renal Impairment.

Eluxadoline is approved for the treatment of diarrhea-predominant irritable bowel syndrome in the United States. The impact of renal impairment on the pharmacokinetic (PK) parameters of eluxadoline is currently unknown. This phase 1, open-label, parallel-group study evaluated the PK and safety profile of eluxadoline in 8 participants with renal impairment and 8 matched healthy controls. Of the participants with renal impairment, 2 had severe renal impairment (estimated glomerular filtration rate [eGFR] <30 mL/min/1.73 m2 ) and 6 had end-stage renal disease while not yet on dialysis (eGFR <15 mL/min/1.73 m2 ). The primary objective was to assess plasma and urine PKs, and plasma protein binding of eluxadoline. In participants with renal impairment, mean plasma concentrations of eluxadoline were consistently higher compared with matched healthy controls: 1.4-fold higher for mean maximum plasma concentration (Cmax ) and 2.2-fold higher for mean area under the plasma concentration-time curve from time 0 to time t. The median time to Cmax was 2.5 hours in both groups. Although eluxadoline is a locally acting drug with low oral bioavailability, because of the increased systemic exposure in participants with renal impairment as a cautionary measure the lower approved dose of 75 mg twice daily is recommended for individuals with severe renal impairment and end-stage renal disease while not yet on dialysis. Eluxadoline 100 mg single dose was well tolerated in participants with renal impairment and matched healthy controls.

Patchouli alcohol improved diarrhea-predominant irritable bowel syndrome by regulating excitatory neurotransmission in the myenteric plexus of rats.

Background and Purpose: Irritable bowel syndrome (IBS) is usually associated with chronic gastrointestinal disorders. Its most common subtype is accompanied with diarrhea (IBS-D). The enteric nervous system (ENS) modulates major gastrointestinal motility and functions whose aberration may induce IBS-D. The enteric neurons are susceptible to long-term neurotransmitter level alterations. The patchouli alcohol (PA), extracted from Pogostemonis Herba, has been reported to regulate neurotransmitter release in the ENS, while its effectiveness against IBS-D and the underlying mechanism remain unknown. Experimental Approach: In this study, we established an IBS-D model in rats through chronic restraint stress. We administered the rats with 5, 10, and 20 mg/kg of PA for intestinal and visceral examinations. The longitudinal muscle myenteric plexus (LMMP) neurons were further immunohistochemically stained for quantitative, morphological, and neurotransmitters analyses. Key Results: We found that PA decreased visceral sensitivity, diarrhea symptoms and intestinal transit in the IBS-D rats. Meanwhile, 10 and 20 mg/kg of PA significantly reduced the proportion of excitatory LMMP neurons in the distal colon, decreased the number of acetylcholine (Ach)- and substance P (SP)-positive neurons in the distal colon and restored the levels of Ach and SP in the IBS-D rats. Conclusion and Implications: These findings indicated that PA modulated LMMP excitatory neuron activities, improved intestinal motility and alleviated IBS-induced diarrheal symptoms, suggesting the potential therapeutic efficacy of PA against IBS-D.

MicroRNA-16 inhibits the TLR4/NF-κB pathway and maintains tight junction integrity in irritable bowel syndrome with diarrhea.

Irritable bowel syndrome with diarrhea (IBS-D) is a chronic and relapsing inflammatory disorder in which pathogenesis has been shown to be in part the result of miRNA-mediated signaling. Here, we investigated the alleviatory role of miR-16 in IBS-D. First, we established an IBS-D mouse model using colonic instillation of acetic acid and developed an IBS-D cell model using lipopolysaccharide exposure. The experimental data demonstrated that miR-16 was underexpressed in the serum of IBS-D patients, as well as in the colorectal tissues of IBS-D mouse models and lipopolysaccharide-exposed intestinal epithelial cells. Next, miR-16 and TLR4 were overexpressed or inhibited to characterize their roles in the viability and apoptosis of intestinal epithelial cells, inflammation, and epithelial tight junction. We found that miR-16 overexpression increased the viability of intestinal epithelial cells, maintained tight junction integrity, and inhibited cell apoptosis and inflammation. We showed that miR-16 targeted TLR4 and inhibited the TLR4/NF-κB signaling pathway. Additionally, inhibition of NF-κB suppressed the long noncoding RNA XIST, thereby promoting enterocyte viability, inhibiting apoptosis and cytokine production, and maintaining tight junction integrity. In vivo experiments further verified the alleviatory effect of miR-16 on IBS-D symptoms in mice. Taken together, we conclude that miR-16 downregulates XIST through the TLR4/NF-κB pathway, thereby relieving IBS-D. This study suggests that miR-16 may represent a potential target for therapeutic intervention against IBS-D.

External therapy of traditional Chinese medicine for treating irritable bowel syndrome with diarrhea: A systematic review and meta-analysis.

Background: Irritable bowel syndrome with diarrhea (IBS-D) is a chronic functional gastrointestinal disorder that has a significant impact on quality of life, work productivity, and healthcare resources. External therapy of traditional Chinese medicine (TCM) has positive effects on IBS-D and is simple, convenient, and low-cost. This study aimed to systematically evaluate the efficacy and safety of external therapy of TCM for IBS-D. Methods: This study was conducted according to Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. The PubMed, Embase, Cochrane Library, Web of Science, China National Knowledge Infrastructure (CNKI), Chinese Scientific Journals (VIP), Wan Fang, and Chinese Biomedical (CBM) databases were electronically searched to collect randomized controlled trials comparing external therapy of TCM with Western medicine for IBS-D from inception to 31 December 2021. Two authors independently screened, extracted, and assessed the selected studies. The Jadad scale and Cochrane Collaboration Risk of Bias tool were used to evaluate study quality. The certainty of evidence was assessed using the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE). The meta-analysis was performed using the Review Manager software (version 5.3). Results: Twenty-one studies involving 1,862 subjects were included. Acupuncture and moxibustion were the most commonly used external therapies. The meta-analysis showed that based on total effective rate with moderate certainty of evidence (n = 21 studies, n = 1,862 participants, RR = 1.25, 95% CI [1.2, 1.31], I2 = 0%, P < 0.00001), clinical cure rate with low certainty of evidence (n = 17 studies, n = 1,502 participants, RR = 1.66, 95% CI [1.4, 1.96], I2 = 1%, P < 0.00001), recurrence rate with very low certainty of evidence (n = 5 studies, n = 260 participants, RR = 0.44, 95% CI [0.34, 0.58], I2 = 0%, P < 0.00001), total symptom score (MD = -4.9, 95% CI [-7.34, -2.47]), and IBS severity scoring system score (IBS-SSS) with moderate certainty of evidence (MD = -52.72, 95% CI [-63.9, -41.53]), the experimental group had significant advantages compared with the control group. The sensitivity analysis further confirmed the robustness of the primary outcomes. The improvement in quality of life associated with IBS (IBS-QOL) was superior in the experimental group compared to the control group, and the difference was statistically significant; however, the clinical heterogeneity was strong. The inverted funnel plot of the included studies indicated a potential publication bias. Conclusion: External therapy of TCM for IBS-D alleviated abdominal symptoms, improved clinical effectiveness, and reduced recurrence with great safety. However, because of the limitations of publication bias in trials, more rigorous studies with a clinical design are necessary for further verification of the outcomes. Systematic Review Registration: [https://www.crd.york.ac.uk/PROSPERO/], identifier [CRD42020222993].

ROS-responsive thioketal-linked alginate/chitosan carriers for irritable bowel syndrome with diarrhea therapy.

A colon-specific carrier that can protect drugs from the destruction in the gastrointestinal tract is critical for treating irritable bowel syndrome with diarrhea (IBS-D). In this study, chitosan was cross-linked by the thioketal (TK) bond to serve as a ROS-sensitive core of microspheres. Then the chitosan core was coated with an alginate shell. The alginate/chitosan microspheres can protect puerarin against the destruction and elimination in the gastrointestinal tract and release puerarin at the lesion sites in large quantities. The microspheres were characterized using differential scanning calorimetry, Fourier-transform infrared spectroscopy, and scanning electron microscopy. The swelling study showed that microspheres would shrink in an acidic environment. The in vitro release analysis indicated that little puerarin was released at gastric pH but burst release was observed in simulated colonic fluid containing H2O2. Fluorescent tracer revealed that the fluorescence of microspheres lasted up to 30 h in the colon, which was beneficial to prolong the action time between puerarin and colon. The in vivo studies indicated that puerarin-loaded microspheres are more effective in the treatment of IBS-D than free puerarin. Altogether, the ROS-responsive alginate/chitosan microspheres may be a promising strategy for IBS-D.

Acupuncture and related therapies for the anxiety and depression in irritable bowel syndrome with diarrhea (IBS-D): A network meta-analysis of randomized controlled trials.

Objective: A growing number of clinical studies have suggested the value of acupuncture-related therapies for patients with irritable bowel syndrome with diarrhea (IBS-D), and the patient's mental state plays an important role, but there are many types of acupuncture-related therapies involved. This study aimed to evaluate the mental status, efficacy and safety of the different acupuncture-related therapies for IBS-D patients. Methods: We searched seven databases to collect randomized controlled trials of acupuncture-related therapies for IBS-D. After independent literature screening and data extraction, the quality of the final included literature was evaluated. Hamilton anxiety rating scale (HAMA), hamilton depression rating scale (HAMD), self-rating anxiety scale (SAS), and self-rating depression scale (SDS) was used as the primary outcome indicator. And the network meta-analysis (NMA) was performed by using Revman 5.4, Stata 15.0 and WinBUGS 1.4.3 software, and the surface under the cumulative ranking curve was conducted to rank the included interventions. Results: We analyzed 24 eligible studies with 1,885 patients, involving eight types of acupuncture and related therapies along with comprehensive therapies. The NMA result shows that: for SAS scores, combined therapies were more efficacious than anti-diarrheal or antispasmodic (western medicine, WM) (SMD: -8.92; 95% CI: -15.30, -2.47); for SDS scores, combined therapies were more efficacious than WM (SMD: -8.45; 95% CI: -15.50, -1.41). For HAMA scores, moxibustion (MOX) was more efficacious than placebo (SMD: -8.66; 95% CI: -16.64, -0.38). For HAMD scores, MOX was more efficacious than all other included interventions. For response rate, MOX was more efficacious than the following interventions: acupuncture (ACU) (SMD:0.29; 95% CI:0.08,0.93), Chinese herb medicine (CH) (SMD:0.09; 95% CI:0.02,0.36), combined therapies (SMD:0.23; 95% CI:0.06, 0.85), electroacupuncture (EA) (SMD:0.06; 95% CI:0.01,0.33), warm acupuncture (WA) (SMD:22.16; 95% CI:3.53,148.10), WM (SMD:15.59; 95% CI:4.68,61.21), and placebo (SMD:9.80; 95% CI:2.90,45.51). Combined therapies were more efficacious than the following interventions: CH (SMD:0.39; 95% CI:0.19,0.80), WA (SMD:4.96; 95% CI:1.30,21.62), and WM (SMD:3.62; 95% CI:2.35,5.66). The comprehensive ranking results show that MOX, ACU, combined therapies, and EA had high SUCRA rankings involving different outcome indicators. Conclusion: MOX, ACU, combined therapies, and EA better alleviate anxiety and depression among IBS-D patients, and with a higher safety level, may be the optimal therapies. In addition, combining acupuncture-related treatments and other therapies also delivers a higher global benefit level. Systematic review registration: [https://www.crd.york.ac.uk/], identifier [CRD42022364560].

[Effect of Gegen Qinlian Decoction on gut microbiota of irritable bowel syndrome with diarrhea rats].

This study aims to explore the effect of Gegen Qinlian Decoction on gut microbiota of irritable bowel syndrome with diarrhea(IBS-D) rats. A total of 36 male SD rats were randomly classified into the control group, model group, rifaximin group(150 mg·kg~(-1)), and high-dose(8.125 g·kg~(-1)), medium-dose(4.062 5 g·kg~(-1)) and low-dose(2.031 3 g·kg~(-1)) Gegen Qinlian Decoction groups with the random number table method, 6 in each group. After modeling, rats were treated for 8 days. The general state, bristol stool chart(BSC) score, and the minimum volume threshold for abdominal withdrawal reflex were recorded. Pathological changes of colon tissues were observed based on hematoxylin and eosin(HE) staining, and gut microbiota was analyzed based on 16 S rRNA sequencing. Compared with the model group, rifaximin group and high-dose and medium-dose Gegen Qinlian Decoction groups showed low BSC score(P<0.01) and high minimum volume threshold for abdominal lifting(P<0.05). HE staining showed that Gegen Qinlian Decoction could relieve intestinal inflammation. 16 S rRNA sequencing suggested obvious variation of gut microbiota in IBS-D rats. Gegen Qinlian Decoction significantly raised the richness index and diversity index of gut microbiota, regulated the number of the flora, and improved alpha diversity and beta diversity. Species composition of gut microbiota and LEfSe analysis showed that Gegen Qinlian Decoction could significantly increase the ratio of Bacteroidota to Firmicutes, elevate the abundance of probiotics such as Clostridia and Lachnospirales, and reduce the abundance of conditional pathogens such as Bacteroidales, and Prevotellaceae. PICRUSt2 analysis indicated that Gegen Qinlian Decoction was mainly related to multiple metabolic pathways such as carbohydrate metabolism and amino acid metabolism. In summary, Gegen Qinlian Decoction can significantly reduce visceral hypersensitivity of IBS-D rats, alleviate intestinal inflammation, and relieve clinical symptoms such as diarrhea. The mechanism is the likelihood that it regulates the composition and structure of gut microbiota and improves its metabolic pathway as well.

An exploration on the correlation between dietary fiber intake and intestinal barrier function in patients with diarrhea-predominant irritable bowel syndrome / 中华临床营养杂志

Objective:To explore the correlation between dietary fiber intake and intestinal barrier function in patients with irritable bowel syndrome with diarrhea (IBS-D).Methods:IBS-D patients were recruited from May 2019 to October 2019 at the clinic of gastroenterology department in China-Japan Friendship Hospital and healthy controls (HCs) were recruited by advertisement. Clinical manifestations, psychological status and quality of life were assessed using standardized questionnaires. A food frequency questionnaire was used to assess dietary habits in the preceding year. Serum diamine oxidase (DAO) was measured via ELISA.Results:64 IBS-D patients and 35 HCs were enrolled, with no significant difference in sex ratio, age and BMI between the two groups. Second to health concern, food avoidance was the dominant impacting factor for quality of life in IBS-D patients. The intake frequency of dietary fiber was decreased in IBS-D patients, and the intake frequencies of dietary fiber-rich foods were significantly lower in IBS-D patients ( P < 0.01 for tubers, P = 0.002 for vegetables, P = 0.019 for fruits and P = 0.045 for legumes). On the other hand, the intake frequencies of processed meat ( P < 0.01), greasy food ( P = 0.009), barbecued food ( P = 0.002) and animal offal ( P = 0.003) were significantly higher in IBS-D patients compared with HCs, indicating the increased intake frequency of fat. Multivariate logistic regression showed that tubers might reduce the risk of IBS-D ( OR = 0.409,95% CI: 0.232 to 0.722, P = 0.002). The frequency of abdominal pain was positively associated with the intake frequency of greasy food in IBS-D patients. Serum DAO was measured in 37 IBS-D patients and 27 HCs. IBS-D patients had significantly higher serum DAO than HCs ( 77.0 [55.3, 100.6] μg/L vs 42.5 [28.0, 58.2] μg/L, P < 0.01). Among all the participants with serum DAO test results, the level of DAO was negatively associated with the intake frequencies of tubers, vegetables and fruits while positively associated with the intake frequencies of processed meat and barbecued food. Conclusions:Food avoidance was an important impacting factor for quality of life in IBS-D patients. IBS-D patients might have insufficient dietary fiber intake and excessive fat intake. Tubers could possibly reduce the risk of IBS-D. The decreased intake frequency of dietary fiber might have a role in intestinal barrier dysfunction in IBS-D patients.

Activation of KCNQ (KV7) K+ channels in enteric neurons inhibits epithelial Cl- secretion in mouse distal colon.

Voltage-gated Kv7 (KCNQ family) K+ channels are expressed in many neuronal populations and play an important role in regulating membrane potential by generating a hyperpolarizing K+ current and decreasing cell excitability. However, the role of KV7 channels in the neural regulation of intestinal epithelial Cl- secretion is not known. Cl- secretion in mouse distal colon was measured as a function of short-circuit current (ISC), and pharmacological approaches were used to test the hypothesis that activation of KV7 channels in enteric neurons would inhibit epithelial Cl- secretion. Flupirtine, a nonselective KV7 activator, inhibited basal Cl- secretion in mouse distal colon and abolished or attenuated the effects of drugs that target various components of enteric neurotransmission, including tetrodotoxin (NaV channel blocker), veratridine (NaV channel activator), nicotine (nicotinic acetylcholine receptor agonist), and hexamethonium (nicotinic antagonist). In contrast, flupritine did not block the response to epithelium-targeted agents VIP (endogenous VPAC receptor ligand) or carbachol (nonselective cholinergic agonist). Flupirtine inhibited Cl- secretion in both full-thickness and seromuscular-stripped distal colon (containing the submucosal, but not myenteric plexus) but generated no response in epithelial T84 cell monolayers. KV7.2 and KV7.3 channel proteins were detected by immunofluorescence in whole mount preparations of the submucosa from mouse distal colon. ICA 110381 (KV7.2/7.3 specific activator) inhibited Cl- secretion comparably to flupirtine. We conclude that KV7 channel activators inhibit neurally driven Cl- secretion in the colonic epithelium and may therefore have therapeutic benefit in treating pathologies associated with hyperexcitable enteric nervous system, such as irritable bowel syndrome with diarrhea (IBS-D).

Improvement Effect and Mechanism of Shenling Baizhu Powder on IBS-D Model Mice with Anxiety Based on Intestinal Microecology / 中国药房

OBJECTIVE：To study the improvement effect of Shenling baizhu p owder on irritable bowel syndrome with diarrhea（IBS-D）model mice with anxiety ，and to elucidate its mechanism from the point of view of intestinal microecology. METHODS：C57 BL/6 mice were randomly divided into blank control group ，model group ，Shenling baizhu powder group （3.6 g/kg），with 8 mice in each group. Except for blank control group ，IBS-D model with anxiety was established in model group and Shenling baizhu powder group by giving corticosterone subcutaneously combined with intragastric administration of Folium Sennae decoction and chronic restraint treatment. After modeling ， blank control group and model group were given intragastric administration of normal saline ，and Shenling baizhu powder group was given relevant medicine intragastrically ，for consecutive 4 weeks. After last medication ，loose stools rate ，diarrhea index ，body weight ，sugar water preference percentage ，the times of crosssing open field center area and minimum pain threshold as well as the levels of BDNF in hippocampal tissue and 5-HT in serum were detected in each group. The cecal contents of mice in each group were extracted for microbial DNA extraction and sequencing； the abundance and diversity of intestinal microorganisms were analyzed by Alpha and Beta diversity analysis. RESULTS ： Compared with blank control group ，body weight ，sugar water preference percentage ，the times of crossing open field center area and minimum pain threshold as well as the levels of BDNF in hippocampal tissue ，relative abundance of Firmicutes phylum microorganism in intestine ， relative abundance of Lachnospiraceae_NK4A136_group genus microorganism were decreased significantly （P＜0.05）；loose stools rate，diarrhea index ，serum level of 5-HT，relative abundance of Verrucomicrobia phylum microorganism and relative abundance of Ackermann phylum microorganism were increased significantly （P＜0.05），and there were great differences in the types of intestinal microorganisms. Compared with model group ，body weight ，sugar water preference percentage ，the times of crossing open field center area ，minimum pain threshold ，BDNF level of hippocampus ，relative abundance of Firmicutes phylum microorganism，relative abundance of Lachnospiraceae_NK4A136_group genus microorganism were increased significantly （P＜ 0.05 or P＜0.01）；loose stools rate ，diarrhea index ，serum level of 5-HT，relative abundance of Verrucomicrobia phylum microorganism and relative abundance of Ackermann phylum microorganism were decreased significantly （P＜0.05），and and there were great differences in the types of intestinal microorganisms. CONCLUSION ：Shenling baizhu powder can improve the diarrhea and anxiety behavior of IBS-D model mice with anxiety ，increase the level of BDNF in hippocampus and decrease serum level of 5-HT. Its mechanism may be related to decreasing relative abundance of Verrucomicrobia phylum microorganism and Ackermann phylum microorganism ，increasing the relative abundance of Firmicutes phylum and Lachnospiraceae_NK4A136_group genus microorganism.

Mucosal-Associated Microbiota Other Than Luminal Microbiota Has a Close Relationship With Diarrhea-Predominant Irritable Bowel Syndrome.

Studies have linked dysbiosis of gut microbiota to irritable bowel syndrome (IBS). However, dysbiosis only referring to structural changes without functional alteration or focusing on luminal microbiota are incomplete. To fully investigate the relationship between gut microbiota and clinical symptoms of Irritable Bowel Syndrome with Diarrhea (IBS-D), fecal samples, and rectal mucosal biopsies were collected from 69 IBS-D patients and 20 healthy controls (HCs) before and during endoscopy without bowel preparation. 16S rRNA genes were amplified and sequenced, and QIIME pipeline was used to process the composition of microbial communities. PICRUSt was used to predict and categorize microbial function. The composition of mucosa-associated microbiota (MAM) was significantly different in IBS-D patients compared to HCs; while no difference in luminal microbiota (LM). MAM, but not LM, was significantly positively correlated with abdominal pain and bloating. A greater number of MAM functional genes changed in IBS-D patients than that of LM compared with HCs. Metabolic alteration in MAM not in LM was related to abdominal pain and bloating. There was a close relationship between the composition and function of MAM and clinical symptoms in IBS-D patients which suggests the important role of MAM in pathogenesis and therapies in IBS-D and it should be highlighted in the future.

Update on Eluxadoline for the Treatment of Irritable Bowel Syndrome with Diarrhea: Patient Selection and Perspectives.

Irritable bowel syndrome (IBS) is a functional gastrointestinal (GI) disorder characterized by chronic abdominal pain associated with changes in bowel habits. It is the most common GI problem seen by gastroenterologists. IBS is a heterogenous disorder encompassing a spectrum of underlying mechanisms and clinical presentations. The pathophysiology of diarrhea-predominant form of IBS (IBS-D) remains poorly understood, and current available therapeutic options for IBS-D are limited. Eluxadoline is a novel, locally acting mixed µ- and κ-opioid receptor agonist and δ-receptor antagonist approved by the Food and Drug Administration (FDA) for treatment of adults with IBS-D. Data from two phase III clinical trials showed that approximately 25-30% of the eluxadoline-treated patients achieved composite clinical response, defined by a reduction of abdominal pain and improvement in stool consistency. Patients who achieve composite response during the first month of therapy were significantly more likely to demonstrate sustained clinical response. The most common adverse events reported with eluxadoline use were constipation, nausea and abdominal pain. The risk of abuse, dependence, or withdrawal is low. Serious adverse events associated with eluxadoline include sphincter of Oddi spasm (SOS) and pancreatitis particularly in patients without a gallbladder. Development of pancreatitis is likely secondary to SOS, but it remains unclear why pancreatitis occurs so quickly after initial doses. This adverse event profile helps guide proper selection of IBS-D patients for eluxadoline use, with important contraindications including absence of a gallbladder, biliary duct obstruction or sphincter of Oddi dysfunction, alcoholism, history of pancreatitis, or structural diseases of the pancreas. With the recent clinical trials demonstrating its efficacy, eluxadoline provides an additional option to the few existing pharmacologic interventions available for IBS-D. In this review, we discuss the drug development, efficacy and safety of eluxadoline, as well as selection criteria for identifying appropriate candidates for this medication.

Pharmacological Therapies and Their Clinical Targets in Irritable Bowel Syndrome With Diarrhea.

Irritable bowel syndrome (IBS) is one of the most common disorders of the gut-brain axis, which affects approximately 4% of the global population. The Rome IV criteria define IBS as chronic or recurrent abdominal pain associated with altered bowel habits. Patients can be categorized in four subtypes: IBS with predominant constipation (IBS-C), predominant diarrhea (IBS-D), mixed bowel habits (IBS-M), and unclassified (IBS-U). IBS is associated with a lower quality of life, reduced work productivity, and high healthcare costs. When comparing subtypes, patients with IBS-D report lower disease related quality of life. Due to the scope of this review, we have solely focused on patients with IBS-D. Choosing the right pharmacological treatment in these patients remains challenging due to the heterogeneous patient population, patients' expectation of the treatment outcome, unavailability of efficacious drugs, and the multifactorial and incompletely understood underlying pathophysiology. Currently, pharmacological treatment options target individual symptoms, such as abdominal pain, altered bowel habits, and bloating. In this review, we aimed to summarize the current and recent pharmacological treatment options in IBS-D, targeting the predominant gastrointestinal symptoms. Additionally, we proposed a pharmacological treatment algorithm which healthcare professionals could use when treating individual patients with IBS-D.

Evaluation of a Dual-Acting Antibacterial Agent, TNP-2092, on Gut Microbiota and Potential Application in the Treatment of Gastrointestinal and Liver Disorders.

TNP-2092 is a unique multitargeting drug conjugate with extremely low propensity for development of resistance. The in vitro activity of TNP-2092 against a panel of urease-producing bacteria was similar to that of rifaximin, a locally acting antibiotic approved for the treatment of hepatic encephalopathy, irritable bowel syndrome with diarrhea, and traveler's diarrhea. When given orally, TNP-2092 exhibited low absorption and the majority of compound was recovered in feces as parent. The impact of oral TNP-2092 on gut microbiota was investigated in rats. TNP-2092 was administered to rats by oral gavage for 7 days. Feces samples were collected and analyzed by 16S rRNA sequencing. Although the total amount of bacterial load appeared relatively unchanged before, during, and after treatment, significant changes in the relative abundance of certain gut bacteria at family and genus levels were observed. Some of the changes are known to be associated with improvement of symptoms associated with liver cirrhosis and hepatic encephalopathy. The observed effects of TNP-2092 on gut microbiota in rats were similar to those of rifaximin. In vivo, TNP-2092 demonstrated potent efficacy in a mouse Clostridium difficile infection model, superior to metronidazole and vancomycin, with no relapse observed after treatment. TNP-2092 is currently in clinical development for the treatment of symptoms associated with gastrointestinal and liver disorders.

Effects of Intestinal Dendritic Cells on Th1/Th2 Immune Balance and Visceral Hypersensitivity in Irritable Bowel Syndrome With Diarrhea Rats / 胃肠病学

Background: The etiology and pathogenesis of irritable bowel syndrome (IBS) are not yet clear, and is lack of effective means for its prevention, diagnosis and treatment in clinic. In recent years, more and more studies showed that intestinal local mucosal immune dysfunction plays an important role in the pathogenesis of IBS. Aims: To investigate the role of intestinal dendritic cells (DC) in the imbalance of colonic mucosal Th1/Th2 immune response pathway in IBS with diarrhea (IBS-D) rats and its effect on visceral hypersensitivity. Methods: Forty-five adult SD rats were randomly divided into blank control group, NS control group and model group, and each group consisted of 15 rats. Visceral hypersensitive model was established by acetic acid enema combined with restraint stress. Abdominal withdrawal reflex (AWR) test and fecal characteristics were used to evaluate the visceral sensitivity. Flow cytometry separation technique was used to isolate DC from mesenteric lymph nodes and CD4

Correlation of Anxiety and Structural Factors With Symptoms in Patients With Irritable Bowel Syndrome With Diarrhea / 胃肠病学

Background: Patients with irritable bowel syndrome (IBS) have comorbid anxiety, which influences the severity of IBS symptoms and therapeutic efficacy. Aims: To investigate the intestinal and extra-gastrointestinal symptoms and psychological status of patients with IBS with diarrhea (IBS-D), and to identify the correlation of comorbid anxiety and structural factors with symptoms. Methods: Consecutive patients met the Rome III criteria for IBS-D were enrolled in this study. The IBS symptom questionnaire and Hamilton anxiety scale (HAMA) were completed in a face-to-face manner. Correlations of HAMA and its structural factors with main bowel symptom, defecation symptom, overlapping with gastroesophageal reflux disease and extra-gastrointestinal symptoms were analyzed. Results: A total of 410 IBS-D patients were enrolled, 264 (64.4%) had comorbid anxiety. Compared with patients without anxiety, score of the main bowel symptom and abdominal pain/discomfort after defecation were significantly increased in patients with anxiety, proportions of abdominal bloating, difficulty in stool passage, mucous stool, overlapping with gastroesophageal reflux disease and extra-gastrointestinal symptoms were significantly increased (P<0.05). Psychic anxiety was significantly correlated with main bowel symptom score and degree of improvement of abdominal pain/discomfort after defecation (P<0.05). Somatic anxiety was significantly correlated with degree of pre-defecation abdominal pain/discomfort (P<0.05). No structural factor had significant correlation with bowel movements or stool form either in the symptom episode or in the non-symptom period. HAMA score, psychic anxiety score, somatic anxiety score in patients with abdominal bloating, mucous stool, overlapping with gastroesophageal reflux disease and extra-gastrointestinal symptoms were significantly higher than those in patients without the corresponding symptoms (P<0.05). Conclusions: The comorbid anxiety and structural factors are mainly correlated with degree of abdominal pain/discomfort in IBS-D patients, but not with bowel movements or stool form.