Tryptophan-kynurenine metabolism: a link between the gut and brain for depression in inflammatory bowel disease.

Inflammatory bowel disease (IBD), which mainly includes ulcerative colitis (UC) and Crohn's disease (CD), is a group of chronic bowel diseases that are characterized by abdominal pain, diarrhea, and bloody stools. IBD is strongly associated with depression, and its patients have a higher incidence of depression than the general population. Depression also adversely affects the quality of life and disease prognosis of patients with IBD. The tryptophan-kynurenine metabolic pathway degrades more than 90% of tryptophan (TRP) throughout the body, with indoleamine 2,3-dioxygenase (IDO), the key metabolic enzyme, being activated in the inflammatory environment. A series of metabolites of the pathway are neurologically active, among which kynerunic acid (KYNA) and quinolinic acid (QUIN) are molecules of great interest in recent studies on the mechanisms of inflammation-induced depression. In this review, the relationship between depression in IBD and the tryptophan-kynurenine metabolic pathway is overviewed in the light of recent publications.

Moxibustion treatment for diarrhea-predominant irritable bowel syndrome: study protocol for a randomized controlled trial.

BACKGROUND: Irritable bowel syndrome (IBS) is a worldwide disease with high morbidity. The effect of current treatment with Western medicine is not satisfactory. Although moxibustion treatment is widely used for gastrointestinal diseases, randomized controlled trials on the use of this treatment for IBS are limited. This study aims to evaluate the clinical efficacy and safety of moxibustion treatment in patients with diarrhea-predominant irritable bowel syndrome (IBS-D). METHODS/DESIGN: A multi-center, randomized, single-blind and placebo-controlled trial is employed. 104 cases will be divided into two groups: (1) a mild-warm moxibustion group in which moxa stick is 3-5 cm away from acupuncture points and the skin temperature is maintained at 43 ± 1 °C; and (2) a placebo moxibustion group in which moxa stick is 8-10 cm away from acupuncture points and the skin temperature is maintained at 37 ± 1 °C. Moxibustion is performed on bilateral ST25 and ST36 in the two groups for 30 min each time, three times a week for 6 weeks. The patients are followed up at the 12th and 18th weeks. Adequate relief is used as a primary outcome measure; IBS symptom severity score, Bristol stool form scale, IBS quality-of-life questionnaire, and hospital anxiety and depression scale are used as secondary outcome measures. DISCUSSION: This study aims to demonstrate the safety and efficacy of moxibustion treatment for IBS-D, which may validate moxibustion as an effective therapy for treating IBS-D. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT02421627 (8 April 2015).

Brain regions involved in moxibustion-induced analgesia in irritable bowel syndrome with diarrhea: a functional magnetic resonance imaging study.

BACKGROUND: Moxibustion is one of the most commonly used therapies in acupuncture practice, and is demonstrated to be beneficial for patients with diarrhea from irritable bowel syndrome (D-IBS). But its mechanism remains unclear. Because visceral hypersensitivity in IBS patients has been documented by evaluation of perceived stimulations through functional magnetic resonance imaging (fMRI) studies, we focused on observing brain imaging changes in D-IBS patients during rectal balloon distention before and after moxibustion in order to reveal its possible central mechanism and further evaluate its effect. METHODS: This clinical trial is registered under the number: ChiCTR-TRC-10000887. Eighty D-IBS patients were randomly divided into a moxibustion and sham moxibustion group (control group) for a 4-week treatment. Fifteen patients in moxibustion group and thirteen patients in control group completed two fMRI scans during a 50 and 100 ml rectal balloon distention before and after treatment. Rectal pain were obtained with a scan test. Birmingham IBS Symptom Scale and IBS Quality of Life (QOL) Scale were used to evaluate therapeutic effect. RESULTS: After treatment, the decrease in Birmingham IBS Symptom Scale and IBS QOL Scale scores in moxibustion group was significantly greater than that of control group (P < 0.01). The defecation urge threshold and the pain perception threshold of moxibustion group was also significantly higher after treatment than that of control group (P < 0.01). The decrease in pain score during the 100 ml rectal balloon distention in moxibustion group was significantly greater than that of control group (P < 0.05). There was no definite activated center during the 50 ml rectal distention in either group before treatment. After treatment, the prefrontal cortex (PFC) was affected in moxibustion group, while the PFC and the anterior cingulated cortex (ACC) were affected in control group. During the 100 ml distention before treatment in both groups, the PFC and ACC were activated. After treatment, they disappeared in moxibustion group but remained in control group. CONCLUSIONS: Moxibustion can improve symptoms and quality of life in D-IBS patients. It can also decrease rectal sensitivity. The activation of PFC and ACC during a 100 ml rectal distention disappeared after moxibustion treatment.

Probiotics for inflammatory bowel disease: Is there sufficient evidence?

Inflammatory bowel disease (IBD) refers to chronic inflammatory disorders of the gut. Ulcerative colitis (UC) and Crohn's disease (CD) are two subtypes of IBD. Evidence suggests that the intestinal microbiota plays a role in the pathogenesis of IBD, so probiotics have garnered a lot of interest as a potential treatment or prevention for IBD. However, clinical evidence of the efficacy of probiotics is still debatable. We performed a literature review. An advanced search considered clinical studies on probiotic for IBD from inception to 2023 in PubMed, Embase, Cochrane Library, and Web of Science. In the treatment of UC with probiotics, only Escherichia coli Nissle 1917 for maintenance treatment of UC in remission, and Bifidobacterium and VSL#3 for induction of remission in patients with mild to moderately active UC have shown strong evidence. Currently, there are no definitive conclusions regarding the effectiveness of probiotics in CD. The mechanism of probiotic treatment for IBD may be related to reducing oxidative stress, repairing the intestinal barrier, regulating intestinal flora balance, and modulating intestinal immune response. Differences in the benefits of probiotics between CD and UC may be attributable to the different lesion extent and immune-mediated pathophysiology. More robust randomized clinical trials are required to validate the efficacy and safety of diverse probiotic strains in IBD.

Acupuncture and moxibustion for irritable bowel syndrome: An umbrella systematic review.

BACKGROUND: Irritable bowel syndrome (IBS) is a functional bowel disease characterized by abdominal pain or discomfort associated with altered bowel habits. Several clinical studies have demonstrated the effectiveness of acupuncture and moxibustion for IBS. Many systematic reviews of acupuncture and moxibustion for IBS have been published in recent years, but their results are not entirely consistent. OBJECTIVE: To evaluate the methodological, reporting, and evidence quality of systematic reviews of acupuncture and moxibustion for IBS. SEARCH STRATEGY: Systematic reviews of acupuncture and moxibustion for IBS published before February 20, 2023 were searched in eight databases: PubMed, Embase, Cochrane Library, Web of Science, China National Knowledge Infrastructure, Wanfang Data, VIP Database for Chinese Technical Periodicals, and China Biology Medicine. The keywords used for literature search were acupuncture, moxibustion, systematic review, meta-analysis, and irritable bowel syndrome. INCLUSION CRITERIA: Systematic reviews and meta-analyses of randomized controlled trials of acupuncture and moxibustion for IBS were included. DATA EXTRACTION AND ANALYSIS: Relevant information was independently extracted by two investigators. The A MeaSurement Tool to Assess systematic Reviews 2 (AMSTAR 2), Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA 2020), and Grading of Recommendations Assessment, Development and Evaluation (GRADE) were used to evaluate the methodological quality, reporting quality and evidence quality, respectively. RESULTS: A total of 342 studies were retrieved and 15 systematic reviews were included. The results of AMSTAR 2 showed low methodological quality in 2 studies and very low methodological quality in the remaining 13 studies, with main issues being failure to register a protocol, incomplete search strategy, not providing a list of excluded studies, incomplete consideration of the risk of bias in the included studies, and a failure to assess the publication bias. The results of PRISMA 2020 showed seriously deficient reporting quality of 2 studies, somewhat deficient reporting quality of 12 studies, and relatively complete reporting quality of 1 study, with the main problems being lack of a complete search strategy, non-availability of a list of excluded studies with justification for their exclusion, not conducting heterogeneity and sensitivity analyses, not evaluating the credibility of the evidence, and not registering the protocol. The results of GRADE showed that the quality of the evidence is low or very low. CONCLUSION: Most included systematic reviews interpreted findings to suggest that acupuncture and moxibustion have benefits for IBS. However, there is a need to improve the methodological, reporting and evidence quality of the systematic reviews. Larger, multicenter, rigorously designed randomized controlled trials and high-quality systematic reviews are required to obtain more robust evidence. PLEASE CITE THIS ARTICLE AS: Ma YY, Hao Z, Chen ZY, Shen YX, Liu HR, Wu HG, Bao CH. Acupuncture and moxibustion for irritable bowel syndrome: An umbrella systematic review. J Integr Med. 2024; 22(1): 22-31.

Moxibustion inhibits apoptosis and tumor necrosis factor-alpha/tumor necrosis factor receptor 1 in the colonic epithelium of Crohn's disease model rats.

BACKGROUND: Previous studies have shown that moxibustion on Tianshu (ST25) and Qihai (CV6) is effective for treating Crohn's disease. However, the mechanism of moxibustion has not been clearly elucidated. AIM: The purpose of this study was to investigate the effect of moxibustion on the inhibition of colonic epithelial cell apoptosis and on tumor necrosis factor alpha (TNF-alpha) and tumor necrosis factor receptor TNF receptor-1 (TNFR1) and TNFR2 and to determine the mechanism of its protective effect using Crohn's disease (CD) model rats. METHODS AND RESULTS: The experimental CD rat models were established by the administration of trinitrobenzene sulfonic acid. In the herbs-partitioned moxibustion (HPM) and mild-warm moxibustion (MWM) groups, moxibustion was administered to Tianshu (ST25) and Qihai (CV6) acupoints once daily for 14 days. In the salicylazosulfapyridine (SASP) group, SASP was administered twice daily for 14 days. A normal control (NC) group and a model control (MC) group were also studied. The levels of TNF-alpha and its mRNA, TNFR1 as well as the rate of colonic epithelial cell apoptosis were significantly decreased in the HPM, MWM and SASP groups compared with the MC group. The HPM and MWM groups had lower mRNA expression and lower protein levels of TNF-alpha compared to the SASP group. The HPM and MWM groups exhibited less apoptosis than the SASP group. CONCLUSIONS: Moxibustion may inhibit colonic epithelial cell apoptosis by reducing the high expression of TNF-alpha and TNFR1 to protect the defective colonic epithelial barrier in CD model rats.

Acupuncture and Moxibustion Inhibited Intestinal Epithelial-Mesenchymal Transition in Patients with Crohn's Disease Induced by TGF- ß 1/Smad3/Snail Pathway: A Clinical Trial Study.

OBJECTIVE: To explore whether acupuncture combined with moxibustion could inhibit epithelialmesenchymal transition in Crohn's disease by affecting the transforming growth factor ß 1 (TGF- ß 1)/Smad3/Snail pathway. METHODS: Sixty-three patients with Crohn's disease were randomly divided into an observation group (31 cases) receiving moxibustion at 43 °C combined with acupuncture, and a control group (32 cases) receiving moxibustion at 37 °C combined with sham acupuncture using a random number table. Patients were treated for 12 weeks. Crohn's Disease Activity Index (CDAI) was used to evaluate disease activity. Hematoxylin-eosin staining and transmission electron microscopy were utilized to observe the morphological and ultrastructural changes. Immunohistochemistry was used to detect the expression of transforming growth factor ß 1 (TGF-ß 1), T ß R1, T ß R2, Smad3, Snail, E-cadherin and fibronectin in intestinal mucosal tissues. RESULTS: The decrease of the CDAI score, morphological and ultrastructural changes were more significant in observation group. The expression levels of TGF- ß 1, Tß R2, Smad3, and Snail in the observation group were significantly lower than those before the treatment (P<0.05 or P<0.01). After treatment, the expression levels of TGF-ß 1, TßR2, and Snail in the observation group were significantly lower than those in the control group (all P<0.05); compared with the control group, the expression of fibronectin in the observation group was significantly decreased, and the expression of E-cadherin was significantly increased (all P<0.05). CONCLUSIONS: Moxibustion at 43 °C combined with acupuncture may suppress TGF-ß 1/Smad3/Snail pathway-mediated epithelial-mesenchymal transition of intestinal epithelial cells in Crohn's disease patients by inhibiting the expression levels of TGF-ß 1, Tß R2, Smad3, and Snail. (Registration No. ChiCTR-IIR-16007751).

Moxibustion alleviates depression-like behavior in rats with Crohn's disease by inhibiting the kynurenine pathway metabolism in the gut-brain axis.

Background: Moxibustion is a potential therapy for inflammatory bowel disease-related depression, but its specific mechanism of action is unclear. This study aimed to investigate the molecular mechanism by which moxibustion alleviates depressive behavior in rats with Crohn's disease (CD). Methods: The CD rat model was established with 2,4,6-trinitrobenzenesulfonic acid. Treatment with moxibustion was applied to Tianshu (ST25, bilateral), Qihai (CV6), and Baihui (GV20) acupoints, and the effect of moxibustion was compared with that of the combination of moxibustion plus indoleamine-2,3-dioxygenase 1 (IDO1) inhibitor, 1-methyltryptophan (1-MT). The effects of moxibustion and moxibustion plus 1-MT combination on colonic inflammation and depressive behavior (assessed by forced swimming test, sucrose preference test, and open field test) were investigated. The changes in IDO1, TNF-α, and IL-1ß in rat colon and hippocampus were assessed by Western blot (WB). Gas chromatography-mass spectrometry, immunofluorescence staining, and WB were applied to detect kynurenine pathway (KP) metabolites, hippocampal neuronal activity, and microglia activation, respectively. Results: Both moxibustion and moxibustion plus 1-MT combination significantly alleviated intestinal inflammation and depressive behavior, downregulated the levels of IDO1 in the colon and hippocampus, and inhibited inflammation-inducing factors IL-1ß and TNF-α, as well as the kynurenine/tryptophan (KYN/TRP) ratio of KP metabolites, and upregulated the kynurenic acid (KYNA)/KYN ratio and the KYNA/quinolinic acid (QUIN) ratio in the hippocampus in rats with CD; Hippocampal ionized calcium-binding adaptor molecule-1 (Iba-1), c-fos protein expression, activated microglia, and neuronal activation was also significantly reduced by moxibustion and moxibustion plus 1-MT. The addition of 1-MT did not significantly increase the therapeutic effect of moxibustion. Conclusion: Moxibustion can improve depressive behavior in rats with CD, which may be related to its regulation of KP metabolism in the gut-brain axis and inhibition of hippocampal microglia activation and neuronal activation.

Mild moxibustion for Irritable Bowel Syndrome with Diarrhea (IBS-D): A randomized controlled trial.

ETHNOPHARMACOLOGICAL RELEVANCE: Moxibustion therapy is a traditional Chinese medicine external treatment method, which involves crushing dried herb Artemisia argyi H. Lév. & Vanio and rolling it into a long cigarette-like strip, igniting it and using its warmth to stimulate specific acupuncture points for a certain period of time. It is often used in Asia to treat various diseases, especially abdominal pain. Clinical reports suggest that acupuncture and moxibustion are the effective treatment for Irritable Bowel Syndrome with Diarrhea (IBS-D). However, there is no placebo-controlled study to prove its safety and efficacy. OBJECTIVE: To evaluate the effects of mild moxibustion (MM) for the treatment of irritable bowel syndrome with diarrhea (IBS-D) through comparisons with those of placebo moxibustion. PATIENTS AND METHODS: This was a single-site, randomized controlled trial was conducted at Shanghai Research Institute of Acupuncture and Meridian in China and enrolled 76 participants who met the Rome IV diagnostic criteria for IBS-D between May 2017 and December 2019. 76 participants were randomized to either mild moxibustion (MM) or placebo moxibustion group (PM) in a 1:1 ratio. 18 sessions of MM or PM were implemented over the course of 6 weeks (3 times per week). The primary outcome was adequate relief after 6 weeks of treatment. RESULTS: Of 76 patients with IBS-D who were randomized (38 in the MM group and 38 in the PM group) were included in the intention-to-treat (ITT) analysis set. After treatment at week 6, the response rate was significantly higher in the MM group than the PM group (81.58% vs. 36.84%) with an estimated difference of 44.74 (95% CI, 23.46 to 66.02, P < 0.001). No participant reported severe adverse effects. CONCLUSION: The findings suggest that mild moxibustion may be more effective than placebo moxibustion for the treatment of IBS-D, with effects lasting up to 12 weeks. TRIAL REGISTRATION: ChiCTR, ChiCTR2100046852. Registered 29 May 2021 - Retrospectively registered, URL: http://www.chictr.org.cn/showproj.aspx?proj=127000.

Acupuncture improves the symptoms, intestinal microbiota, and inflammation of patients with mild to moderate Crohn's disease: A randomized controlled trial.

BACKGROUND: The efficacy and mechanisms of acupuncture for Crohn's disease (CD) are not well understood. We investigated its effects on symptoms, intestinal microbiota, and circulating inflammatory markers in CD patients. METHODS: This 48-week, randomized, sham controlled, parallel-group clinical trial was performed at a tertiary outpatient clinic in China. From April 2015 to November 2019, 66 patients (mean age 40·4, 62·1% were male, all were Han Chinese) with mild to moderate active CD and unresponsive to drug treatment were enrolled and randomly assigned equally to an acupuncture group or a sham group. The treatment group received 3 sessions of acupuncture plus moxibustion per week for 12 weeks and a follow-up of 36 weeks. Clinicaltrials.gov: NCT02559037. FINDINGS: At week 12, the clinical remission rate (the primary outcome) and clinical response rate of acupuncture group were significantly higher than that of sham group, with a difference of 42·4% (95% CI: 20·1%-64·0%) and 45·5% (95% CI: 24·0%-66·9%), respectively, both of which maintained at week 48. The acupuncture group had significantly lower CD activity index and C-reactive protein level at week 12, which maintained at 36-week follow-up. The CD endoscopic index of severity, histopathological score, and recurrence rate at week 48 were significantly lower in acupuncture group. The number of operational taxonomic unit of intestinal microbiota and relative abundance of Faecalibacterium prausnitzii and Roseburia faecis were increased. Plasma diamine oxidase, lipopolysaccharide, and Th1/Th17 related cytokines were decreased in 12-week after acupuncture. INTERPRETATION: Acupuncture was effective in inducing and maintaining remission in patients with active CD, which was associated with increased abundance of intestinal anti-inflammatory bacteria, enhanced intestinal barrier, and regulation of circulating Th1/Th17-related cytokines. FUNDING: National Key Basic Research Program of China (2015CB554500 and 2009CB522900), Shanghai Rising-Star Program (19QA1408100).

Long-term effect of moxibustion on irritable bowel syndrome with diarrhea: a randomized clinical trial.

BACKGROUND: Moxibustion is increasingly used for treatment of irritable bowel syndrome (IBS). This study investigated the long-term effects of moxibustion for IBS with diarrhea (IBS-D). METHODS: Patients with IBS-D were assigned to receive moxibustion or sham moxibustion (52 each, 3× per week, 6 weeks) and were followed up to 24 weeks. The acupoints were bilateral ST25 and ST36, body surface temperatures at acupoints were 43°C ± 1°C and 37°C ± 1°C for the moxibustion and sham groups, respectively. Primary outcome was changes in IBS Adequate Relief (IBS-AR) from baseline to 6 weeks. Secondary outcomes included the following: IBS symptom severity scale (IBS-SSS), Bristol stool form scale (BSS), IBS quality of life (IBS-QOL), and Hospital Anxiety and Depression Scale (HADS). RESULTS: Based on an intention-to-treat analysis, the rate of IBS-AR in the moxibustion group was significantly higher than the sham group at 6 weeks (76.9% versus 42.3%; p < 0.001); the mean decrease of total IBS-BSS score in the moxibustion group was lower than that of the sham group (-116.9 versus -61.5; p < 0.001), both of which maintained throughout the follow-up period. Five specific domains of the IBS-SSS were lower in the moxibustion group than the sham, throughout (p < 0.001). At week 6, the rate of reduction >50 points in IBS-SSS of the treatment group was significantly higher than that of the sham (p < 0.001), which persisted throughout the follow-up period. Similar long-lasting improvements were observed in BSS, stool frequency, and stool urgency (p < 0.001). Improvements of IBS-QOL and HADS were comparable between the groups. CONCLUSIONS: Moxibustion treatment benefits the long-term relief of symptoms in IBS-D patients. TRIAL REGISTRATION: Clinical trials.gov (NCT02421627). Registered on 20 April 2015.

Temperature- and pH-triggered reversible transfer of doubly responsive hairy particles between water and a hydrophobic ionic liquid.

This article reports on the synthesis of thermo- and pH-sensitive polymer-brush-grafted silica particles ("hairy" particles) and the study of their phase-transfer behavior between water and a hydrophobic ionic liquid, 1-ethyl-3-methylimidazolium bis(trifluoromethylsulfonyl)amide ([EMIM][TFSA]), in response to temperature and pH changes. The hairy particles were made by the surface-initiated atom transfer radical polymerization of methoxytri(ethylene glycol) methacrylate (TEGMMA) and tert-butyl methacrylate with a molar ratio of 100:11 in the presence of a free initiator and the subsequent removal of tert-butyl groups. The cloud points (CPs) of poly(TEGMMA-co-methacrylic acid), obtained after the treatment of the free polymer with trifluoroacetic acid, in both water and [EMIM][TFSA]-saturated water increased with the increase in pH and can be tuned over a wide temperature range. The hairy particles moved spontaneously from the aqueous phase to the [EMIM][TFSA] phase upon heating at 80 °C and returned to the aqueous layer upon cooling at 10 °C. This process can be repeated many times regardless of whether the pH of the aqueous phase is 2.99, 5.00, or 7.02. UV-vis absorbance measurements showed that the transfer temperature (T(tr)) of hairy particles from water to [EMIM][TFSA] increased with the increase in the pH of the aqueous phase. A linear relationship was observed between the T(tr) of hairy particles and the CP of the corresponding free polymer. By taking advantage of the tunability of the T(tr) of hairy particles, we demonstrated the pH-driven reversible transfer of hairy particles at a fixed temperature by changing the pH of the aqueous phase and multiple phase-transfer processes by controlling both the temperature and pH.

Development of Real-Time PCR Based on A137R Gene for the Detection of African Swine Fever Virus.

African swine fever virus (ASFV) can infect domestic pigs and wild boars and causes huge economic losses in global swine industry. Therefore, early diagnosis of ASFV is important for the control and eradication of African swine fever (ASF). In this study, a SYBR Green-based real-time polymerase chain reaction (PCR) assay targeting the viral encoded A137R gene was established for the detection of ASFV infection. For the evaluation of the established real-time PCR, 34 clinical samples were assessed by both the A137R gene-based real-time PCR and OIE-recommended TaqMan PCR. The results showed that 85.29% (29/34) were detected by A137R gene-based real-time PCR, but only 79.41% (27/34) positive using OIE-recommended TaqMan PCR. Moreover, no cross-reaction with other common swine pathogens was found in the A137R gene-based real-time PCR. These results demonstrated that the established real-time PCR assay in this study showed better performance than the OIE-recommended method in detecting ASFV from clinical samples, which could be applied for control and eradication programs of ASF.

[Effect of acupuncture-moxibustion on negative emotions and plasma tryptophan metabolism in patients with Crohn's disease at active stage].

OBJECTIVE: To observe the effect of acupuncture-moxibustion on negative emotions and plasma tryptophan (Trip)-kynurenine (Kyn) metabolism in the patients with Crohn's disease (CD) at the mild and moderate active stage. METHODS: A total of 66 CD patients were randomized into an observation group (33 cases, 1 case dropped off) and a control group (33 cases, 2 cases dropped off). In the observation group, acupuncture was applied in combination with moxibustion. In the control group, the sham-acupuncture was used in combination with sham-moxibustion. In both of the observation group and the control group, acupuncture was applied to Zhongwan (CV 12), Shangjuxu (ST 37), Sanyinjiao (SP 6), Gongsun (SP 4), Hegu (LI 4), Quchi (LI 11), Taixi (KI 3) and Taichong (LR 3), and moxibustion was applied to Tianshu (ST 25) and Zusanli (ST 36). The treatment was given once every two days, 3 times a week, totally for 12 weeks. Separately, before and after treatment, the score of the hospital anxiety-depression scale (HADS) and the score of intestinal core symptoms (degree of abdominal pain and frequency of diarrhea) were observed in the patients of the two groups. The concentration of plasma indoleamine 2,3-dioxygenase 1 (IDO1) and the ratios of Kyn/Trp, QuinA/Kyn, KynA/Kyn and KynA/QuinA were compared between the two groups. RESULTS: Compared with before treatment, the scores of HADS-A and HADS-D in the observation group and the score of HADS-A in the control group were all reduced after treatment (P<0.01, P<0.05). The scores of abdominal pain degree in the two groups and score of diarrhea frequency in the observation group were all reduced after treatment (P<0.001). After treatment, the reducing ranges of the score of HADS-A and the scores of abdominal pain degree and diarrhea frequency in the observation group were all larger than the control group (P<0.01, P<0.05). Compared with before treatment, the plasma IDO1 concentration in the two groups and the ratios of plasma Kyn/Trp and QuinA/Kyn in the observation group were all reduced after treatment (P<0.001, P<0.05, P<0.01), the ratios of plasma KynA/Kyn and KynA/QuinA were increased after treatment in the observation group (P<0.05, P<0.01). After treatment, the changes in IDO1 concentration and the ratios of plasma QuinA/Kyn and KynA/QuinA in the observation were larger than the control group (P≤0.01, P<0.05). In the observation group, the difference in the ratio of plasma KynA/Kyn before and after treatment was negatively related to the improvement value of HADS-D (r =-0.67, P<0.05). After treatment, plasma IDO1 concentration was positively related to HADS-A in the observation group (r =0.65, P<0.05). CONCLUSION: Acupuncture and moxibustion relieve the negative emotions of anxiety and depression in CD patients at mild and moderate active stage, which is probably related to the regulation of plasma Trp-Kyn metabolic pathway.

Altered functional connectivity of the amygdala in Crohn's disease.

Crohn's disease (CD), a chronic inflammatory bowel disease, involved in brain structural and functional changes, including the amygdala. Amygdala is a key structure in the limbic system and its related circuits are implicated in processing of emotion, pain and sensory. However, limited study of the amygdala is elucidated in CD. This study mainly investigated altered functional connectivity (FC) of the amygdala in CD patients during resting-state. Magnetic resonance imaging scans were acquired from 42 CD patients and 35 healthy controls (HCs). Whole amygdala bilaterally were selected as regions of interest (ROIs). Voxel-based morphometry and FC methods were applied to investigate the differences of structure or intrinsic connectivity of the amygdala between the two groups, separately. Pearson correlations were performed to explore relationships between the clinical characteristics and neuroimaging findings in CD patients. Based on the whole amygdala bilaterally as ROIs, compared with HCs, CD patients showed no statistical differences of grey matter destiny but exhibited decreased FC between the amygdala and insula, parahippocampus, as well as anterior middle cingulate cortex/dorsal anterior cingulate cortex. CD patients had negative correlation between the disease duration and amygdala-insula connectivity. In the patient group, patients with higher anxiety or depression scores revealed increased FC of the amygdala with thalamus and orbitofrontal cortex. Our results reveal that aberrant FC of the amygdala may be involved in processing of visceral pain and sensation, and emotion in CD. These findings may further enhance the understanding of neural mechanisms of CD.

P2X3 Receptor in Primary Afferent Neurons Mediates the Relief of Visceral Hypersensitivity by Electroacupuncture in an Irritable Bowel Syndrome Rat Model.

BACKGROUND: Electroacupuncture (EA) has been confirmed effectiveness in the treatment of irritable bowel syndrome (IBS), and P2X3 receptors in the peripheral and central neurons participate in the acupuncture-mediated relief of the visceral pain in IBS. OBJECTIVE: To reveal the neurobiological mechanism that P2X3 receptor of colonic primary sensory neurons in the dorsal root ganglia of the lumbosacral segment is involved in the alleviation of visceral hypersensitivity by EA in an IBS rat model. METHODS: The IBS chronic visceral pain rat model was established according to the method of Al-Chaer et al. EA at the bilateral He-Mu points, including ST25 and ST37, was conducted for intervention. The behavioral studies, histopathology of colon, electrophysiology, immunofluorescence histochemistry, and real-time polymerase chain reaction assays were used to observe the role of P2X3 receptor in the colon and related DRG in relieving visceral hypersensitivity by EA. RESULTS: EA significantly reduced the behavior scores of the IBS rats under different levels (20, 40, 60, 80 mmHg) of colorectal distention stimulation and downregulated the expression levels of P2X3 receptor protein and mRNA in colon and related DRG of the IBS rats. EA also regulated the electrical properties of the membranes, including the resting membrane potential, rheobase, and action potential of colon-associated DRG neurons in the IBS rats. CONCLUSION: EA can regulate the P2X3 receptor protein and mRNA expression levels in the colon and related DRG of IBS rats with visceral pain and then regulate the excitatory properties of DRG neurons.

Herbs-partitioned moxibustion improves intestinal epithelial tight junctions by upregulating A20 expression in a mouse model of Crohn's disease.

BACKGROUND: To investigate effects moxibustion exerts on A20 expression and regulation of intestinal epithelial tight junctions via the TNF-α-NF-κB-MLCK pathway in Crohn's disease (CD). METHODS: C57BL/6 wild type (WT) and A20IEC-KO mice (48 each) were randomly divided into normal control (NC), model control (MC), mesalazine (MESA) and herbs-partitioned moxibustion (HPM) groups (12 mice per group). An experimental model of CD was established using 2, 4, 6 trinitrobenzene sulfonic acid. MESA and HPM mice were treated with MESA and HPM (at Tianshu (ST25) and Qihai (CV6)), respectively. In HPM group, moxa cones (0.5 cm in diameter and 0.3 cm in height) made of refined mugwort floss were placed on herbal cakes (medicinal formula dispensing [radix] Aconiti praeparata, [cortex] Cinnamomi, etc.) at Tianshu (ST25) and Qihai (CV6) and ignited. The moxa cones were ignited, and two moxa cones were used for each treatment once daily for 10 days. In MESA group, mice were fed MESA, which was prepared at a proportion of 1:0.0026, twice daily for 10 days. RESULTS: Intestinal epithelial ultrastructure of WT HPM mice improved more than A20IEC-KO HPM mice compared to MC mice. WT HPM mice exhibited greater expression of A20 compared with MC mice (P < 0.01). TNF-α, NF-kB p65, MLCK, MLC, TRAF6 and RIP1 levels in A20IEC-KO and WT HPM mice were all decreased compared to MC mice (Pall < 0.01). NF-κB p65、MLCK and TRAF6 levels were increased in A20IEC-KO HPM mice as compared to WT HPM mice (Pall < 0.05). Intestinal epithelial levels of occludin, claudin-1, ZO-1 and F-actin increased in all HPM mice (Pall  < 0.01-0.05), while occludin, claudin-1, and ZO-1 levels were lower in A20 IEC-KO HPM mice (P < 0.05, P < 0.01, P < 0.01). CONCLUSION: HPM downregulates abnormal activation of the TNF-α-NF-κB-MLCK pathway by upregulating expression of A20 in a mouse model of CD, thereby protecting intestinal epithelial tight junctions and repairing the damage CD causes to the intestinal epithelial barrier.

Effect of mild moxibustion on intestinal microbiota and NLRP6 inflammasome signaling in rats with post-inflammatory irritable bowel syndrome.

BACKGROUND: About one-third of refractory irritable bowel syndrome (IBS) cases are caused by gastrointestinal (GI) infection/inflammation, known as post-infectious/post-inflammatory IBS (PI-IBS). Although it is known that intestinal microbiota and host NOD-like receptor family pyrin domain containing 6 (NLRP6) inflammsome signaling are closely related to PI-IBS and moxibustion has a therapeutic effect on PI-IBS, whether moxibustion regulates the intestinal flora and host NLRP6 events in PI-IBS remains unclear. AIM: To examine the regulatory effect of moxibustion on intestinal microbiota and host NLRP6 inflammatory signaling in PI-IBS. METHODS: Sprague-Dawley rats were divided into a normal control group, a model control group, a mild moxibustion group, and a sham mild moxibustion group. PI-IBS rats in the mild moxibustion group were treated with moxibusiton at bilateral Tianshu (ST 25) and Zusanli (ST36) for 7 consecutive days for 10 min each time. The sham group rats were given the same treatment as the mild moxibustion group except the moxa stick was not ignited. Abdominal withdrawal reflex (AWR) score was measured to assess the visceral sensitivity, and colon histopathology and ultrastructure, colonic myeloperoxidase (MPO) activity, and serum C-reactive protein (CRP) level were measured to evaluate low-grade colonic inflammation in rats. The relative abundance of selected intestinal bacteria in rat feces was detected by 16S rDNA PCR and the NLRP6 inflammsome signaling in the colon was detected by immunofluorescence, qRT-PCR, and Western blot. RESULTS: The AWR score was significantly decreased and the low-grade intestinal inflammation reflected by serum CRP and colonic MPO levels was inhibited in the mild moxibustion group compared with the sham group. Mild moxibustion remarkably increased the relative DNA abundances of Lactobacillus, Bifidobacterium, and Faecalibacterium prausnitzii but decreased that of Escherichia coli in the gut of PI-IBS rats. Additionally, mild moxibustion induced mRNA and protein expression of intestine lectin 1 but inhibited the expression of IL-1ß, IL-18, and resistance-like molecule ß by promoting the NLRP6 and reducing the mRNA and protein expression of apoptosis-associated speck-like protein containing CARD (ASC) and cysteinyl-aspartate-specific proteinase 1 (Caspase-1). The relative DNA abundances of Lactobacillus, Bifidobacteria, Faecalibacterium prausnitzii, and Escherichia coli in each group were correlated with the mRNA and protein expression of NLRP6, ASC, and Caspase-1 in the colon. CONCLUSION: These findings indicated that mild moxibustion can relieve low-grade GI inflammation and alleviate visceral hypersensitivity in PI-IBS by regulating intestinal microbes and controlling NLRP6 inflammasome signaling.

Efficacy of electroacupuncture for the treatment of constipation in Parkinson's disease: study protocol for a multicentre randomised controlled trial.

INTRODUCTION: Constipation is one of the most common non-motor symptoms in Parkinson's disease (PD). Acupuncture can have a positive on chronic functional constipation and PD, but its efficacy for the treatment of constipation in PD has not yet been confirmed by high-quality clinical trials. Therefore, this study aims to evaluate the efficacy and safety of electroacupuncture (EA) in the treatment of constipation in PD. METHODS AND ANALYSIS: This study is a multicentre randomised controlled trial. A total of 124 qualified patients with PD and constipation will be randomly divided into the intervention group (62 participants will receive 12 weeks of EA +usual care) or the waitlist control group (62 participants will receive 12 weeks of usual care). EA will be performed three times per week from weeks 1-8, two times per week during weeks 9 and 10, and once a week during weeks 11 and 12. The primary outcome is the change in mean weekly spontaneous bowel movements from baseline to weeks 8 and 9. The secondary outcomes are the changes from baseline in mean weekly bowel movements, mean weekly stool consistency, and mean weekly straining. Other secondary outcomes include the weekly doses of defecation drugs, Visual Analogue Scale for subjective improvements in stool symptoms, Unified Parkinson's Disease Rating Scale, and the time and number of steps required to walk 20 m. Outcomes will be assessed at baseline, week 4, 8, 12 (intervention period); as well as at week 16, 24 (follow-up period). ETHICS AND DISSEMINATION: Ethical approval has been obtained from four local ethics committees. The results of the study will be published in peer-reviewed journals and will be disseminated through national and international conferences. TRIAL REGISTRATION NUMBER: ChiCTR1900021053.

Herbs-Partitioned Moxibustion Combined with Acupuncture Inhibits TGF-ß1-Smad-Snail-Induced Intestinal Epithelial Mesenchymal Transition in Crohn's Disease Model Rats.

Crohn's disease may cause excessive damage and repair in the intestinal epithelium due to its chronic relapsing intestinal inflammation. These factors may initiate the TGF-ß 1-Smad pathway to activate the transcription factor of Snail, and the Snail-mediated pathway promotes the transformation of intestinal epithelial cells to mesenchymal cells, leading to intestinal fibrosis. Acupuncture and moxibustion have been demonstrated to prevent intestinal fibrosis in Crohn's disease. However, it is not clear whether acupuncture and moxibustion can inhibit intestinal epithelial mesenchymal transformation in Crohn's disease by affecting the TGF-ß 1-Smad-Snail pathway. This study indicated that abnormal increased expressions of TGFß1, TßR2, Smad3, and Snail were significantly downregulated by herbs-partitioned moxibustion at Tianshu (ST25) and Qihai (RN6) and acupuncture at Zusanli (ST36) and Shangjuxu (ST37). In addition, protein and mRNA levels of E-cadherin, the epithelial cell marker, were significantly increased. Protein and mRNA levels of fibronectin, the mesenchymal cell marker, were decreased in the intestinal tissue. Moreover, the number of mesenchymal cells in the intestinal mucosa can be reversely transformed to intestinal epithelial cells. Therefore, herbs-partitioned moxibustion combined with acupuncture can prevent intestinal epithelial mesenchymal transition by inhibiting abnormal expression of TGFß1, TßR2, Smad3, and Snail in the TGF-ß1-Smad-Snail pathway in Crohn's disease.