International Journal of Nanomedicine
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2023
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IF 8
Xinyu Fan,Jiachen Shi,Ye Liu,Mengqiu Zhang,Min Lu,Ding Qu
Background Berberine (BR) shows promise as a candidate for treating irritable bowel syndrome with diarrhea (IBS-D). However, the undesired physicochemical properties and poor oral absorption limit its clinical translation. A ketogenic diet (KD) can induce intestinal overexpression of cannabidiol (CB) receptors, which may offer a potential target for IBS-D-specific delivery of BR.Methods The microemulsions loaded with BR and decorated with cannabidiol (CBD/BR-MEs) were developed through a one-step emulsion method. The pharmaceutical behaviors of the CBD/BR-MEs were measured using dynamic light scattering and high-performance liquid chromatography. The efficacy of the anti-IBS-D therapy was evaluated by assessing fecal water content, Bristol score, and AWR score. The intestinal permeability were assessed through immunofluorescent staining of CB1 and ZO-1, respectively. The signaling of CREB/BDNF/c-Fos was also studied along with immunofluorescent and immunohistochemical examination of brain sections.Results The CBD/BR-MEs, which had a particle size of approximately 30 nm and a surface density of 2% (wt%) CBD, achieved greater than 80% (wt%) encapsulation efficiency of BR. The pharmacokinetics performance of CBD/BR-MEs was significantly improved in the KD-fed IBS-D rats than the standard diet-fed ones, which is highly related to intestinal expression of CB1 receptors. The treatment with CBD/BR-MEs and KD exhibited evident comprehensive advantages over the other groups in terms of anti-IBS-D efficacy. CBD/BR-MEs and KD synergistically decreased intestinal permeability. Moreover, the treatment with CBD/BR-MEs and KD not only blocked the CREB/BDNF/c-Fos signaling in the brain but also decreased the levels of neurotrophic factors, neurotransmitters, and inflammatory cytokines in the serum of IBS-D model rats.Conclusion Such a design represents the first attempt at IBS-D-targeted drug delivery for improved oral absorption and efficacy through KD-induced target exposure, which holds promising potential for the treatment of IBS-D.
研究领域:
药学
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胃肠病学
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营养科学
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分子生物学
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JOURNAL OF ETHNOPHARMACOLOGY
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2024
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IF 4.8
Sihao Zhang,Danmei Tian,Zixuan Xia,Fengge Yang,Yanhui Chen,Zhihong Yao,Yi He,Xinglong Miao,Guirong Zhou,Xinsheng Yao,Jinshan Tang
Ethnopharmacological relevance Chang-Kang-Fang (CKF), originated from traditional Chinese medicine (TCM) formulas, has been utilized to treat diarrhea predominant irritable bowel syndrome (IBS-D) based on clinical experience. However, the underlying mechanism of CKF for treating IBS-D remains unclear and need further clarification. Aim of the study The objective of this present investigation was to validate the efficacy of CKF on IBS-D model rats and to uncover its potential mechanism for the treatment of IBS-D. Materials and Methods We first established the IBS-D rat model through neonatal maternal separation (NMS) in combination with restraint stress (RS) and the administration of senna decoction via gavage. To confirm the therapeutic effect of CKF on treating IBS-D, abdominal withdrawal reflex (AWR) scores, the quantity of fecal pellets, and the fecal water content (FWC) were measured to evaluate the influence of CKF on visceral hypersensitivity and the severity of diarrhea symptom after the intragastric administration of CKF for 14 days. Subsequently, enzyme linked immunosorbent assay (ELISA) was applied to assess the effect of CKF on neuropeptides substance P (SP) and 5-hydroxytryptamine (5-HT), as well as inflammatory cytokines in serum and in intestinal tissues. Further, colonic pathological changes, the amount of colonic mast cells, and the expression level of occludin in rat colon tissues, were investigated by hematoxylin-eosin (HE) staining, toluidine blue staining, and immunohistochemistry, respectively. To explore the underlying mechanisms, alterations in colonic RNA transcriptomics for the normal, model, and CKF treatment groups were assessed using RNA sequencing (RNA-Seq). Subsequently, quantitative real-time polymerase chain reaction (qRT-PCR), western blot (WB), and immunofluorescence (IF) assays were applied to validate the effect of CKF on predicted pathways in vivo and in vitro . In addition, to elucidate the potential active compounds in CKF, 11 representative components found in CKF were selected, and their anti-inflammation potentials were evaluated using LPS-treated RAW264.7 cell models. Results CKF treatment significantly reduced the number of fecal pellets, attenuated visceral hypersensitivity, and decreased 5-HT and SP concentrations in serum and colon tissues, along with a reduction in colonic mast cell counts, correlating with improved symptoms in IBS-D rats. Meanwhile, CKF treatment reduced the colonic inflammatory cell infiltration, lowered the levels of IL-6, TNF- α , and IL-1 β in serum and colon tissues, and increased the occludin protein expression in colon tissues to improve inflammatory response and colonic barrier function. RNA-Seq, in conjugation with our previous network pharmacology analysis, indicated that CKF might mitigate the symptoms of IBS-D rats by inhibiting the Toll like receptor 4/Nuclear factor kappa-B/NLR family pyrin domain-containing protein 3 (TLR4/NF- κ B/NLRP3) pathway, which was confirmed by WB, IF, and qRT-PCR experiments in vivo and in vitro . Furthermore, coptisine, berberine, hyperoside, epicatechin, and gallic acid present in CKF emerged as potential active components for treating IBS-D, as they demonstrated in vitro anti-inflammatory effects. Conclusion Our findings demonstrate that CKF effectively improves the symptoms of IBS-D rats, potentially through the inhibition of the TLR4/NF- κ B/NLRP3 pathway. Moreover, this study unveils the potential bioactive components in CKF that could be applied in the treatment of IBS-D.
研究领域:
药理学
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胃肠病学
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传统中药
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分子生物学
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免疫学
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高影响因子
Physiological Reports
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2026
·Vol. 14
·期 11
·e70975
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IF 2.1
Yunxian Wang,Fenglan Chu,Yanhua Gong,Ruihong Guo,Hui Dong
Despite the ubiquitous use of monosodium glutamate (MSG) as a food additive, its specific effects on intestinal health and disease remain largely unclear. Here we found mucosal application of MSG induced an upward intestinal short-circuit current ( I sc ) in the murine ileum, which was significantly reduced by extracellular Cl − , Na + , and Ca 2+ removal. Mechanistically, MSG-induced I sc was significantly attenuated by pharmacological inhibition of key transporters (NCX, SGLT1, NKA) and secretory channels (CaCC, CFTR, IK Ca ). Furthermore, disrupting intracellular Ca 2+ homeostasis via endoplasmic reticulum (ER) chelation or blockade of IP 3 R, RyR, SOCE/CRAC, and VGCC significantly suppressed both the ileal I sc and MSG-stimulated Ca 2+ signaling in IECs. Importantly, MSG triggered a simultaneous elevation in intracellular Ca 2+ and a reduction in Na + , which were abolished by the blockers of NCX and SGLT1. In vivo, MSG-induced Ca 2+ -dependent ion transports were significantly reduced in irritable bowel syndrome with diarrhea (IBS-D) mice. Our findings indicate that MSG drives Ca 2+ -dependent intestinal ion transports through a complex network orchestrated by SGLT1 and NCX under healthy state, which is markedly attenuated in IBS-D. This study provides novel insights into the gastrointestinal impact of dietary MSG in both health and bowel disease.
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高影响因子
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
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2026
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IF 8.7
Li Cui,Rongling Zhong,Wanqiu Peng,Zhenhai Zhang,Zhentao An,Hui Li
Current clinical management of diarrhea-predominant irritable bowel syndrome (IBS-D) faces substantial challenges due to the limited efficacy of existing therapeutic strategies. This study aimed to synthesize and characterize the hyaluronic acid-ethylenediamine-cinnamic acid conjugate (HA-EDA-CA), investigate its oral bioavailability and colonic tissue distribution, and validate its therapeutic potential along with underlying mechanisms of action in IBS-D models. Following oral administration of free CA or HA-EDA-CA, the colon concentration of CA released from the derivative was significantly higher than that of free CA alone. Both free and conjugated forms of CA likely contributed to the therapeutic effects against IBS-D. The IBS-D model was established by a combination of senna decoction administration and physical restraint stress. After HA-EDA-CA intervention, IBS-D model mice showed marked improvements in stool consistency, fecal water content, stool output, body weight, visceral hypersensitivity, and colon length. ELISA results indicated significant reduction in enteric neurotransmitter levels, including 5-hydroxytryptamine, substance P, and vasoactive intestinal peptide, after oral gavage administration of HA-EDA-CA. Additionally, intestinal permeability assessment and immunofluorescence analyse revealed that HA-EDA-CA improved intestinal barrier function. Western blot analysis indicated HA-EDA-CA inhibited 5-hydroxytryptamine signaling pathway. Furthermore, HA-EDA-CA modulated gut microbiota composition. These findings suggested the potential of HA-EDA-CA as a promising therapeutic candidate for IBS-D treatment. Key novelties: (i) First colon-targeted CA-HA conjugate: We developed and characterized the first hyaluronic acid-based conjugate specifically designed for colon-targeted delivery of cinnamic acid. (ii) Multi-mechanism rescue: The conjugate simultaneously restores gut homeostasis by modulating the 5-hydroxytryptamine signaling pathway, enhancing intestinal barrier function, and rebalancing gut microbiota. (iii) Enhanced therapeutic efficacy: HA-EDA-CA demonstrates superior colonic drug accumulation and integrated therapeutic outcomes compared to free cinnamic acid or simple drug mixtures. (iv) Open-source data availability: All relevant data and analysis scripts supporting the findings are publicly accessible to ensure reproducibility and further research.
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PHYTOMEDICINE
·
2026
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IF 11.3
Fengge Yang,Danmei Tian,Yuting Zhang,Zixuan Xia,Yunjuan Li,Xinsheng Yao,Yanxia Xiong,Guirong Zhou,Hongwei Liu,Jinshan Tang
CKF ameliorates intestinal dysfunction and neurobehavioral abnormalities in IBS-D mice. • CKF boosts L. johnsonii and tryptophan-derived indoles, notably ILA. • L. johnsonii acts as a psychobiotic for IBS-D and comorbidities. • ILA improves IBS-D intestinal and behavioral deficits mainly via AhR activation. • CKF targets the L. johnsonii -ILA-AhR/IL-22 gut-brain axis. Background Gut dysbiosis contributes to irritable bowel syndrome (IBS) by disrupting intestinal barrier functions and promoting inflammation. Chang‑kang‑fang (CKF), a Chinese herbal formula proven effective for diarrhea‑predominant IBS (IBS‑D) in a phase III trial, is thought to modulate the gut microbiota, yet the underlying mechanism remains unclear. Purpose To elucidate how CKF ameliorates IBS‑D by modulating the gut microbiota. Methods IBS‑D was induced by restraint stress, tail pinch, and senna gavage. Intestinal function, inflammation, and behavior were evaluated. Gut microbiota and metabolites were profiled via 16S rRNA sequencing and metabolomics. FMT confirmed the causal involvement of the microbiota. The key microbe and metabolite were validated in vivo . Mechanistic analyses evaluated intestinal barrier integrity, systemic inflammation, hippocampal blood‑brain barrier (BBB) function, neuroinflammation, and synaptic plasticity. Results CKF alleviated diarrhea, visceral hypersensitivity, inflammation, barrier dysfunction, and anxiety‑ and depression‑like behaviors. These benefits were associated with gut microbiota remodeling, featuring enrichment of Lactobacillus johnsonii and enhanced tryptophan metabolism. FMT confirmed that this microbial remodeling mediates the therapeutic effects of CKF. Supplementation with L. johnsonii or its metabolite indole‑3‑lactic acid (ILA) largely recapitulated these gut-brain benefits via AhR/IL‑22 activation. Mechanistically, CKF‑induced L. johnsonii enrichment activated the ILA-AhR-IL‑22 pathway, which enhanced intestinal and BBB integrity, thereby attenuating systemic and neuroinflammation, and restoring hippocampal synaptic plasticity. Conclusion This study positions CKF as a microbiota‑modulating therapy for IBS‑D that restores gut‑brain homeostasis via the L. johnsonii -ILA-AhR-IL‑22 axis, highlighting L. johnsonii and ILA as potential therapeutics for IBS and its comorbidities. Download: Download high-res image (278KB) Download: Download full-size image Chang-Kang-Fang alleviates IBS-D and comorbid depression by activating the Lactobacillus johnsonii -indole-3-lactic acid-aryl hydrocarbon receptor/interleukin-22 gut-brain axis.
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Nutrients
·
2024
·Vol. 16
·期 22
·3854
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IF 4.8
Yannan Zhang,Sijuan Huang,Shuai Zhang,Zhihui Hao,Jianzhong Shen
Background: Diarrhea-predominant irritable bowel syndrome (IBS-D) is a common chronic functional gastrointestinal disorder that causes diarrheal and intestinal barrier disruptions. Although pomegranate peel extract (PPE) has been reported for the treatment of diarrheal and intestinal inflammation, its effectiveness and mechanisms specifically for the treatment of IBS-D remain unknown. Objectives: This study aimed to explore the therapeutic effect of PPE on IBS-D and elucidate its underlying mechanisms. Methods: A high-fat diet, restraint stress, and senna gavage were combined to establish a rat model mimicking IBS-D, to evaluate the therapeutic effects of PPE. Network pharmacology analysis, serum medicinal chemistry, and transcriptomics were employed to investigate potential downstream signaling pathways. Findings were further validated through molecular docking and Western blot analysis. Results: The findings revealed that PPE significantly improved the symptoms of IBS-D, ameliorated intestinal inflammation, and promoted intestinal barrier function. The target genes in the MAPK and NF-κB signaling pathways were significantly enriched and down-regulated. Molecular docking and Western blot assays were performed to verify that PPE had a high affinity for the protein candidates in these pathways, and significantly down-regulated the expression of p-IκB, p-p65, p-JNK, p-p38, and p-ERK1/2. Conclusions: The present study is the first to demonstrate that PPE alleviates diarrheal and intestinal damage in IBS-D, potentially by inhibiting MAPK and NF-κB signaling pathways. These findings suggest that PPE may provide a novel therapeutic option for IBS-D.
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研究领域:
胃肠病学
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药理学
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分子生物学
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动物模型
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功能基因组学
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高影响因子
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