Dextran Sulfate Sodium Research Articles

Lactobacillus johnsonii colonizing in mice intestine contributes to control the gut barrier function via regeneration of the crypt in DSS‐treated mice

AbstractBackgroundUnbalanced gut microbiota is considered to cause dysfunction of the gut barrier function. Lactobacillus johnsonii MG, isolated from mouse feces as gut associating lactobacilli, enhanced gut barrier function in Caco‐2 cells via interaction with JAM‐2 in tight junctions. In this study, the anti‐inflammatory effects of L. johnsonii MG were investigated in a colitis mouse model developed by treating mice with 3% dextran sulfate sodium (DSS) for 9 days.ResultsMG treatment of colitis mice resulted in fast recovery of the body weight and showed significant improvement in the disease activity index and histopathological scores. The histomorphological score increased by DSS treatment was significantly improved in the MG‐treated group. In the intestine, the expression of Ocln, Zo1, Itga6, Lama3, and Jam2 genes, which are involved in tight junction functions, were significantly upregulated in MG‐treated colitis mice. In the microflora analysis, the abundance of Ruminococcaceae, Bacteroides, and Lachnospiraceae were reduced in DSS‐treated mice and recovered by MG treatment.ConclusionWe reported the potential of L. johnsonii MG in the regeneration of crypts and integrity of matrix proteins in the gut of mice with colitis through its association with tight junctions. The experimental results provide new insights into the probiotic effect of tight junction associating L. johnsonii MG.

2′-Fucosyllactose alleviate immune checkpoint blockade-associated colitis by reshaping gut microbiota and activating AHR pathway

Immune checkpoint blockade (ICB) therapeutics are highly effective in cancer immunotherapy, but gastrointestinal toxicity limited the application. Intestinal microbiota plays a crucial role in ICB-associated colitis. 2′-Fucosyllactose (2′FL) is most abundance prebiotic in human milk that can reshape gut microbiota and exert immune regulatory effect. The study aimed to determine the effects of 2′FL on ICB-associated colitis and to uncover the mediating mechanism. ICB-associated colitis was induced by the ipilimumab and dextran sulfate sodium. Oral administration of 2′FL (0.6 g/(kg∙day)) ameliorated ICB-induced colitis by enhancing regulatory T cells (Treg) and the M2/M1 ratio of macrophages in colon. 2′FL treatment also increased the expression of tight junction proteins (zonula occludens-1 (ZO-1) and mucin 2 (MUC2)) and antioxidant stress indicators (superoxide dismutase (SOD) and catalase (CAT)). In addition, administration of 2′FL increased the abundance of Bifidobacterium and Lactobacillus, and elevated the levels of microbial metabolites, such as indole-3-lactic acid (ILA), which activated the aryl hydrocarbon receptor ligands (AHR) pathway. The protective effect of 2′FL was abolished upon depletion of gut microbiota, and ILA treatment partially simulated the protective effect of 2′FL. Notably, 2′FL did not exhibit inhibition of antitumor immunity. These findings suggest that 2′FL could serve as a potential protective strategy for ICB-associated colitis by modulating the intestinal microbiota and bacterial metabolites.

Cucurbitacin IIb alleviates colitis via regulating gut microbial composition and metabolites

Cucurbitacin IIb, a member of the triterpenoid family, exerts beneficial effects on intestinal diseases, including enteritis and bacillary dysentery. However, its effects and mechanisms of action on colitis have not yet been explored. In this study, we used a mouse model of dextran sulfate sodium (DSS)-induced colitis and explored the effects of cucurbitacin IIb on colitis symptoms, inflammatory responses, microbiota, and metabolite profiles. The results showed that cucurbitacin IIb alleviated colitis symptoms including body weight loss, an increase in the disease activity index, and elevated levels of myeloperoxidase and eosinophil peroxidase content. Additionally, it ameliorated intestinal morphology impairment, reduced the phosphorylation of NFκB protein, and mitigated accumulation of pro-inflammatory cytokines IL-6 and IL-1β. Furthermore, cucurbitacin IIb alleviated alterations in gut microbial composition and metabolites in DSS-treated mice. However, antibiotic treatment diminishes the beneficial effects of cucurbitacin IIb on colitis. We further found that transplantation of fresh feces or heat-inactivated feces from mice treated with cucurbitacin IIb to DSS-treated mice alleviated colitis, similar to the effects of cucurbitacin IIb. Collectively, our results suggest that cucurbitacin IIb exerted anti-inflammatory effects in colitis by regulating the microbiota composition and metabolites, thereby alleviating colitis symptoms.

Evaluation Recovery of Ulcerative Colitis with a Lactobacillus Cocktail Derived from Traditional Dairy Products: In vivo Study.

This investigation investigates the anti-inflammatory and fibrinolytic effects of a cocktail of probiotics derived from traditional dairy products in a murine model of ulcerative colitis (UC). A mix of newly isolated probiotics containing L. plantarum, L. brevis, L. delbrueckii, and L. helveticus was characterized and orally administered to inbred eight-week-old C57BL/6 male mice (n = 6). Clinical symptoms, pathohistological changes, and inflammatory and fibrosis markers were analyzed in the existence and absence of probiotics in colitis mice. Dairy lactobacillus probiotics potently attenuated colitis symptoms by decreasing dextran sulfate sodium (DSS)-induced body weight loss, colon shortening, rectal bleeding, and rectal prolapse. Consistently, a cocktail of probiotics could significantly improve histopathological grading by suppressing crypt loss, mucosal damage, and inflammation scores in colitis tissues. Moreover, the mix of probiotics suppressed pro-inflammatory genes including interleukin (IL)-1β, IL-6, tumor necrosis factor-alpha (TNF-α), and interferon-gamma (IFN-γ), and increased anti-oxidant markers and activity such as superoxide dismutase and catalase in colon tissue. Furthermore, compared to the no-treated group, the administration of probiotics reduced fibrosis by decreasing collagen deposition in tissue sections and down-regulating levels of pro-fibrotic genes including alpha-actin-2 (Acta2), collagen (Col) 1a1, and Col 1a2 in colitis tissue homogenates. The results show the newly isolated cocktail of probiotics elicits a potent protective effect on UC symptoms in mice model. Further study on these probiotics is required to fully explore their effectiveness, strength, and safety considerations.

Protective Effect of Rosavin Against Intestinal Epithelial Injury in Colitis Mice and Intestinal Organoids.

Rhodiola species have been utilized as functional foods in Asia and Europe for promoting health. Research has demonstrated that Rhodiola has the potential to alleviate inflammatory bowel disease (IBD) in animal models. However, the specific active components and the underlying mechanism for ameliorating intestinal damage remain unclear. This study aims to explore the relieving effect of Rosavin (Rov), a known active constituent of Rhodiola, in IBD and the regulatory mechanisms. The therapeutic effect of Rov was evaluated using a murine model of acute colitis induced by dextran sulfate sodium salt (DSS). Inflammatory cytokines and neutrophil activation markers were measured by corresponding kits. Immunohistochemistry, immunofluorescence, TUNEL, and EdU assays were applied to investigate the tight conjunction proteins expression, epithelial marker expression, number of apoptotic cells, and epithelial proliferation, respectively. The protection effect of Rov on gut epithelial injury was assessed using TNF-α-induced intestinal organoids. Additinally, RNA sequencing was applied to observe the genetic alteration profile in these intestinal organoids. Oral administration of Rov significantly attenuated weight loss and restored colon length in mice. Notably, Rov treatment led to decreased levels of pro-inflammatory cytokines and neutrophil activation markers while increasing anti-inflammatory factors. Importantly, Rov restored intestinal despair by increasing the number of Lgr5+ stem cells, Lyz1+ Paneth cells and Muc2+ goblet cells in intestines of colitis mice, displaying reduced epithelial apoptosis and recovered barrier function. In TNF-α-induced intestinal organoids, Rov facilitated epithelial cell differentiation and protected against TNF-α-induced damage. RNA sequencing revealed upregulation in the gene expression associated with epithelial cells (including Lgr5+, Lyz1+ and Muc2+ cells) proliferation and defensin secretion, unveiling the protective mechanisms of Rov on the intestinal epithelial barrier. Rov holds potential as a natural prophylactic agent against IBD, with its protective action on the intestinal epithelium being crucial for its therapeutic efficacy.

FGF20 modulates gut microbiota to mitigate dextran sodium sulfate-induced ulcerative colitis in mouse models

Ulcerative colitis (UC), a prevalent form of inflammatory bowel disease (IBD), presents a significant clinical challenge due to the lack of optimal therapeutic strategies. Emerging evidence suggests that fibroblast growth factor 20 (FGF20) may play a crucial role in mitigating UC symptoms, though the mechanistic underpinnings remain elusive. In this study, a mouse model of UC was established using dextran sodium sulfate (DSS) to investigate the potential role of FGF20. Our findings revealed a marked reduction in FGF20 expression in the serum and colonic tissues of DSS-treated mice. Furthermore, FGF20 knockout did not exacerbate colonic damage in these mice. Conversely, overexpression of FGF20 via adeno-associated virus (AAV) significantly alleviated UC-associated symptoms. This alleviation was evidenced by attenuated intestinal shortening, mitigated weight loss, increased colonic goblet cell density and crypt formation, reduced inflammation severity and inflammatory cell infiltration, and enhanced expression of tight junction and mucin proteins. Moreover, FGF20 significantly ameliorated the dysbiosis of gut microbiota in DSS-treated mice by increasing the abundance of beneficial bacteria and decreasing the abundance of harmful bacteria. The beneficial effects of FGF20 were notably attenuated following gut microbiota depletion with an antibiotic regimen. Fecal microbiota transplantation experiments further supported the critical role of gut microbiota in mediating the effects of FGF20 on DSS-treated mice. In conclusion, these findings highlight the potential involvement of gut microbiota in the therapeutic effects of FGF20 in UC.

Metagenomic analysis of rats with diarrhea treated with mixed probiotics: response to consecutive and alternate-hour supplementation.

Diarrhea is the leading contributory factor of sickness and mortality among children under five and an economic burden for families. This study aimed to investigate the effects of mixed probiotics supplementation at different times (consecutive and alternate-hour) on intestinal microecology in Sprague-Dawley (SD) rats with acute diarrhea. A total of 40 SD rats were randomly assigned to four groups, including the control group, model group, probiotic group A, and probiotic group B. An acute diarrhea model was induced by administration of 5% dextran sulfate sodium. Rats in probiotic group A and probiotic group B were fed with Clostridium butyricum (C. butyricum), Bifidobacterium infantis (B. infantis), and Saccharomyces boulardii (S. boulardii) for a total of 7 days. Probiotic group A was fed with all probiotics simultaneously. Probiotic group B was fed with C. butyricum and B. infantis simultaneously, and then after a 2-hour interval, with S. boulardii. Metagenomic next-generation sequencing was used to analyze the fecal samples from every rat. The metagenomic sequencing used in this experiment was used to evaluate the effect of probiotics on the composition as well as function of the gut microbiota in order to gain a deeper comprehension of probiotic-host interactions on health and disease. The structure of the gut microbiota in probiotic group A showed significant changes. Compared to the model group, the abundance of some beneficial bacteria had increased, including Actinobacteria (P=0.048), Lactobacillus (P=0.050), and Lactobacillus johnsonii (P=0.042), and many opportunistic pathogenic bacteria has decreased, such as Ruminococcus (P=0.001). Compared to the control group, the abundance of some beneficial bacteria had increased, including Fusobacteria (P=0.02) and Phascolarium (P=0.002), and there was a reduction in the abundance of many opportunistic pathogenic bacteria such as Roseburia (P=0.03), Lachnoclosterium (P=0.009), and Oscillibacter_sp_1-3 (P=0.002). In addition, metagenomic analysis showed that as well as an up-regulation of glycoside hydrolase expression, amino acid and inorganic ion transport, and metabolism-related pathways, there was a down-regulation of cell motility. Simultaneous administration of probiotics may have more positive implications in improving the gut microbiota of acute diarrhea rats.

Identification and molecular mechanism of the anti-inflammatory effect of sea cucumber peptides: Network pharmacology, molecular docking and animal experiments

Ulcerative colitis (UC) is a chronic inflammatory bowel disease for which there is currently no efficacious therapeutic drug with fewer side effects. Therefore, the development of approaches for the prevention of UC from natural food sources is urgently needed. In this study, mice were pre-fed with sea cucumber peptides prior to dextran sodium sulfate (DSS) induction. Results showed that sea cucumber peptides decreased pro-inflammatory cytokine (IL-4 and IL-10) levels and remissions of main clinic symptoms in a dose-dependent manner. The composition of peptides was identified, and the anti-inflammatory molecular mechanism was evaluated by silico prediction. The molecular weight of the peptides was 243–1800 Da and composed of 3–18 amino acid residues. Online activity assessment and molecular docking prediction revealed that tripeptides of FGI, FLI, FLL, GFL, GFM, IGF and LDF exhibited strong anti-inflammatory activity. Particularly, LDF showed the highest potency, with a binding energy of −5.37 kJ/mol. Network pharmacology analysis of UC related diseases indicated that active peptides interact with colitis disease targets, primarily proto-oncogene tyrosine-protein kinase Src (SRC), E3 ubiquitin-protein ligase XIAP (XIAP) and angiotensin-converting enzyme (ACE). The results suggest that sea cucumber peptides have potential as a novel nutraceutical option for colitis relief.

In vitro and in vivo effects of pectin‐type polysaccharides isolated from crabapples (Malus prunifolia) on inflammatory colitis models

SummaryThe aim of this study was to investigate the anti‐inflammatory effects of polysaccharides extracted from crabapples (Malus prunifolia; MP) in vitro and in vivo. Crabapples were subjected to hot water extraction to obtain MP‐HW, which was further separated into low (MP‐L) and high molecular weight (MW) (crude polysaccharide; MP‐CP) fractions by ethanol precipitation. Based on MW distribution, general composition, component sugars, and Fourier transform infrared spectroscopy, MP‐CP was identified as a pectin‐type polysaccharide rich in galacturonic acid with an MW of 106.2 kDa. MP‐CP inhibited the production and mRNA expression of proinflammatory factors in an IL‐1β‐treated intestinal epithelial cell model. In addition, MP‐CP significantly alleviated the body weight, disease activity index score, colon length, and spleen weight in mice with dextran sulfate sodium (DSS)‐induced colitis. The MP‐CP‐treated group showed effective regulation of the expression of pro‐ and anti‐inflammatory factors and immunoglobulin A than the DSS‐treated group. Haematoxylin and eosin and Alcian blue staining revealed that MP‐CP alleviated inflammatory manifestations and mucin expression in the intestinal lumen. Collectively, pectin‐type polysaccharides isolated from crabapples may be used as a new functional food and pharmaceutical agent for the prevention and treatment of inflammatory colitis.

Ulva lactuca polysaccharides combined with fecal microbiota transplantation ameliorated dextran sodium sulfate-induced colitis in C57BL/6J mice.

Fecal microbiota transplantation (FMT) of healthy donors improves ulcerative colitis (UC) patients by restoring the balance of the gut microbiota. However, donors vary in microbial diversity and composition, often resulting in weak or even ineffective FMT. Improving the efficacy of FMT through combination treatment has become a promising strategy. Ulva lactuca polysaccharides (ULP) have been found to benefit host health by regulating gut microbiota. The effect of the combination of ULP and FMT in ameliorating UC has not yet been evaluated. The present study found that supplementation with ULP combined with FMT showed better effects in ameliorating UC than supplementation with FMT alone. Results suggested that FMT or ULP combined with FMT alleviated the symptoms of UC in mice, as evidenced by prevention of body weight loss, improvement of disease activity index and protection of the intestinal mucus. Notably, ULP in combination with FMT was more effective than FMT in reducing levels of cytokines and related inflammatory enzymes. In addition, ULP combined with FMT effectively restored the dysbiosis induced by dextran sulfate sodium (DSS) and further enriched probiotics (such as Bifidobacterium). The production of short-chain fatty acids, especially acetic acid, was also significantly enriched by ULP combined with FMT. Supplementation of ULP combined with FMT could significantly ameliorate DSS-induced colitis in mice by inhibiting inflammation and restoring dysbiosis of gut microbiota. These results suggested that ULP combined with FMT has potential application in ameliorating UC. © 2024 Society of Chemical Industry.

Paeoniflorin alleviates DSS-induced ulcerative colitis by suppressing inflammation, oxidative stress, and apoptosis via regulating serum metabolites and inhibiting CDC42/JNK signaling pathway

Ulcerative colitis (UC) poses a threat to human health. The present study attempts to unravel the efficacy and potential mechanisms of paeoniflorin (PF), a naturally sourced active ingredient, for the management of UC. By establishing a DSS (dextran sulphate sodium)-induced experimental rat model of UC, this study found that PF was effective in ameliorating UC symptoms, inhibiting oxidative stress, inflammation and apoptosis, and repairing colonic epithelial damage. In addition, metabolomics revealed that PF may alleviate UC by primarily improving linoleic acid metabolism. Mechanistically, PF inhibited the CDC42/JNK signaling pathway by targeting CDC42. In particular, HuProtTM20K proteomics, molecular docking and MST revealed that PF is a novel CDC42 inhibitor. In LPS-treated Caco-2 cells, PF similarly inhibited oxidative stress, inflammation, and apoptosis and down-regulated the CDC42/JNK signaling pathway. Overall, PF inhibits oxidative stress, inflammation and apoptosis and repairs colonic epithelial damage through modulation of serum metabolites and inhibition of the CDC42/JNK signaling pathway, leading to alleviation of UC.

Epithelial Piezo1 deletion ameliorates intestinal barrier damage by regulating ferroptosis in ulcerative colitis

Ferroptosis, a recently discovered form of regulated cell death, has been implicated in the development of ulcerative colitis (UC). While Piezo1's role in inducing ferroptosis in chondrocytes and pulmonary endothelial cells is documented, its regulatory function in ferroptosis and intestinal epithelial cells in UC remains unclear. To address this, colonic tissue samples from patients with UC were examined, and specific intestinal epithelial Piezo1-deficient (Piezo1ΔIEC) mice were created to investigate Piezo1's role in UC pathogenesis. Elevated epithelial Piezo1 levels were observed in patients with UC, correlating with increased ferroptosis and tight junction (TJ) disruption. In dextran sulfate sodium (DSS)-induced colitis, Piezo1ΔIEC mice exhibited significantly reduced intestinal inflammation and improved gut barrier function compared to wild-type (WT) mice. Moreover, Piezo1 deficiency in colitis mice and lipopolysaccharide (LPS)-stimulated Caco-2 cells led to higher TJ protein levels, reduced lipid peroxidation, enhanced mitochondrial function, and altered expression of ferroptosis-associated proteins. Additionally, erastin, a ferroptosis activator, reversed the protective effect of Piezo1 silencing against LPS-induced ferroptosis in Caco-2 cells. Mechanistically, Piezo1 was found to regulate ferroptosis via the AMPK/mTOR signaling pathway. These findings highlight a novel role for Piezo1 deletion in mitigating ferroptosis in intestinal epithelial cells, suggesting Piezo1 as a potential therapeutic target for UC treatment.

Deficiency in epithelium RAD50 aggravates UC via IL-6-mediated JAK1/2-STAT3 signaling and promotes development of colitis-associated cancer in mice.

Ulcerative colitis (UC) is one of the most important risk factors for developing colitis-associated cancer (CAC). Persistent DNA damage increases CAC risk and has been observed in patients with UC. We aimed to identify the regulatory role of RAD50, a DNA double-strand breaks (DSBs) sensor, in UC progression to CAC. DSBs and RAD50 expression in IBD and CAC cell and mouse models were assessed. Mice with intestinal epithelial RAD50 deletion (RAD50IEC-KO) were used to examine the role of RAD50 in colitis and CAC. Along with the increased γ-H2AX expression in colitis and CAC models, RAD50 expression reduced in human IBD and CAC as well as in mouse models. Furthermore, RAD50IEC-KO sensitizes mice to dextran sulfate sodium (DSS)-induced acute and chronic experimental colitis. RNA-seq analyses revealed that RAD50 activated the cytokine-cytokine receptor response, which was amplified through the JAK-STAT pathway. RAD50 directly interacts with STAT3 and subsequently inhibits its phosphorylation, which may disrupt the IL-6-JAK1/2-STAT3-IL-6 feed-forward loop. Pharmacological STAT3 inhibition relieves colitis in RAD50IEC-KO mice. Severe DSBs, increased cell proliferation, and extended inflammatory response were identified in RAD50-deficienct cells, which promoted azoxymethane (AOM)-DSS-induced colon tumor development in RAD50IEC-KO mice. RAD50 exerts anti-IL-6-related inflammatory effects in colitis and suppresses CAC. Increasing RAD50 level in colon tissues may be promising for treating patients with UC and CAC.

Probiotics‐Loaded Selenium Nanoparticles Effectively Alleviated DSS‐Induced Colitis by Scavenging ROS and Remodeling Intestinal Innate Immune and Microbiota

AbstractAlterations in the intestinal microenvironment, including increased levels of reactive oxygen species (ROS), abnormalities in intestinal mucosal immune regulation, and dysbiosis of the intestinal microbiota, are crucial to the development of inflammatory bowel disease (IBD). Herein, an oral colon‐targeting Se‐Probiotic@Alginate bead (BLSe) with ROS‐scavenging ability and gut immune‐microbiota microenvironment remodeling ability is developed using alginate as the primary outer shell encapsulated with probiotics Bacillus licheniformis (BL) and selenium nanoparticles stabilized by yeast glucan (SeNPs). In vitro studies have shown that SeNPs possess antioxidant activity and BLSe exhibits excellent stability in gastric fluids and are released in intestinal fluids. In vivo studies have also shown that BLSe significantly alleviated dextran sulphate sodium (DSS)‐induced colitis in mice by inhibiting colon shortening, enhancing antioxidant activity, reducing pro‐inflammatory cytokine secretion, and protecting the intestinal mucosal barrier. 16S ribosomal RNA sequencing shows that BLSe can remodel the composition of the gut microbiota by improving bacterial diversity and restoring the relative abundance of beneficial bacteria in the colon. Overall, this study advances a promising probiotic‐based nanomedicine for managing IBD.

Deer oil improves ulcerative colitis induced by DSS in mice by regulating the intestinal microbiota and SCFAs metabolism and modulating NF-κB and Nrf2 signaling pathways.

Deer oil (DO), a byproduct of deer meat processing, possesses high nutritional value. This study aims to evaluate the protective effects of DO on dextran sulfate sodium (DSS)-induced ulcerative colitis (UC) in mice and to explore its potential mechanisms of action. DO was found to inhibit weight loss and colon shortening in colitis mice, significantly reduce disease activity index scores, and notably enhance the levels of tight junction proteins in colon tissues, thus improving intestinal barrier function. ELISA results indicated that DO markedly alleviated the mice's oxidative stress and inflammatory responses. Western blot analysis further demonstrated that DO significantly inhibited the phosphorylation of NF-κB while up-regulating the expression levels of Nrf2 and HO-1 proteins. Additionally, DO increased the abundance of beneficial bacteria such as Odoribacter, Blautia, and Muribaculum, reduced the abundance of harmful bacteria such as Bacteroides, Helicobacter, and Escherichia-Shigella, and promoted the production of short-chain fatty acids. Our study provides the first evidence that DO can effectively improve DSS-induced UC in mice. The underlying mechanisms may involve maintaining intestinal barrier function, inhibiting inflammation, alleviating oxidative stress, and modulation of gut microbiota. These findings offer valuable insights for developing DO as an adjunct treatment for UC and as a functional food. © 2024 Society of Chemical Industry.

Isoorientin Alleviates DSS-Treated Acute Colitis in Mice by Regulating Intestinal Epithelial P-Glycoprotein (P-gp) Expression.

Isoorientin (ISO) is a naturally occurring flavonoid with diverse functional properties that mitigate the risk of diseases stemming from oxidation, inflammation, and cancer cell proliferation. P-glycoprotein (P-gp) is a vital component of the intestinal epithelium and may play a role in the onset of intestinal inflammatory conditions, such as inflammatory bowel disease (IBD). Recent studies have suggested that short-chain fatty acids (SCFAs) and secondary bile acids (SBAs) produced by the gut microbiota stimulate the increase of P-gp expression, alleviating excessive inflammation and thereby preservation of intestinal homeostasis. ISO has been shown to improve colon health and modulate the gut microbiota. In this study, we aimed to explore whether ISO can modulate the microbes and their metabolites to influence P-gp expression to alleviate IBD. First, the impact of ISO on dextran sulfate sodium (DSS)-treated colitis in mice was investigated. Second, 16S rRNA gene sequencing was conducted. The present study indicated that ISO mitigated the symptoms and pathological damage associated with DSS-treated colitis in mice. Western blot analysis revealed ISO upregulated P-gp in colon tissues, suggesting the critical role of P-gp protein in intestinal epithelial cells. 16S microbial diversity sequencing revealed ISO restored the richness and variety of intestinal microorganisms in colitis-bearing mice and enriched SCFA-producing bacteria, such as Lachnospiraceae_NK4A136_group. The experiments also revealed that the ISO fecal microbiota transplantation (FMT) inoculation of DSS-treated mice had similarly beneficial results. FMT mice showed a reduction in colitis symptoms, which was more pronounced in ISO-FMT than in CON-FMT mice. Meanwhile, ISO-FMT expanded the abundance of beneficial microorganisms, increased the expression of metabolites, such as SCFAs and total SBAs, and significantly upregulated the expression of P-gp protein. In addition, Spearman's correlation analysis demonstrated a positive correlation between the production of SCFAs and SBAs and the expression of P-gp. The present study identified that ISO increases the expression of P-gp in the intestinal epithelium by regulating intestinal microorganisms and their metabolites, which maintains colonic homeostasis, improves the integrity of the colonic epithelium, and alleviates colitis.

Effects and Mechanisms of the Xianhecao-Huanglian Drug Pair on Autophagy-Mediated Intervention in Acute Inflammatory Bowel Disease via the JAK2/STAT3 Pathway

To explore the effects and mechanisms of the Xianhecao-Huanglian drug pair on autophagy-mediated intervention in acute inflammatory bowel disease (IBD) via the JAK2/STAT3 pathway. The study examined the underlying mechanisms of action of Xianhecao (APL) and Huanglian (CR) using a mouse model of dextran sodium sulfate (DSS)-induced acute inflammatory bowel disease (IBD) and in an in vitro model of IBD induced by lipopolysaccharide (LPS). The assessment of the therapeutic efficacy of the Xianhecao-Huanglian drug combination in a mouse model of IBD caused by DSS included the following parameters: Assessment of weight loss or gain. Measurement of the disease activity index (DAI). Assessment of histological damage. Determination of organ index. Measurement of colon length. Ascertain the levels of inflammatory cytokines in the intestinal tissues and serum of mice. Immunohistochemistry (IHC) for the measurement of tight junction protein concentrations in the colon mucosa, including ZO-1, claudin-1, and occludin. Measurement of mucin levels, specifically Mucin 2 (Muc2). Hematoxylin and eosin (HE) staining for the observation of histopathological alterations in colonic tissues. Examining the effect on goblet cells using periodic acid-Schiff (PAS) labeling. Application of Western blot and immunofluorescence techniques for the detection of autophagy-related markers in colonic tissues and proteins associated with the JAK2/STAT3 pathway. A cell inflammation model of IBD was induced through LPS stimulation, and a serum containing the Xianhecao-Huanglian drug pair (referred to as ACHP-DS) was formulated. Cell viability, anti-proinflammatory cytokines, tight junction proteins, mucins, autophagy-related markers, and the JAK2/STAT3 signaling pathway were assessed. The Xianhecao-Huanglian drug pair significantly ameliorated the symptoms and survival quality of acute IBD mice, reducing the disease activity index score, raising MUC2 secretion and tight junction protein expression to improve the integrity of the intestinal barrier, and preserving goblet cell function; thus, protecting the intestines. It effectively restrained triggering the signaling pathway that involves JAK2 and STAT3, leading to the suppression of inflammation and amelioration of colonic inflammation damage. Additionally, it induced autophagy in mouse colonic tissues.The in vitro experiments demonstrated that the Xianhecao-Huanglian drug combination enhanced the viability of LOVO and NCM460 cells when exposed to LPS stimulation. Furthermore, it suppressed the production of inflammatory cytokines such as IL-6, IL-1β, as well as TNF-α, whilst increasing the production of IL-10, ZO-1, along with MUC2. These effects collectively led to the alleviation of inflammation and the restoration of mucosal integrity. The results were consistent with what was shown in the in vivo trial. Moreover, the medication demonstrated effectiveness in reducing JAK2 along with STAT3 phosphorylation levels in the LPS-induced inflammatory model of IBD cells. The intervention with either the Xianhecao-Huanglian drug combination-containing serum or the JAK2/STAT3 pathway inhibitor AG490 reversed the pro-inflammatory effects and increased autophagy levels in the LPS-stimulated cells. The Xianhecao-Huanglian drug combination modulates the JAK2/STAT3 pathway, leading to the induction of autophagy, which serves as an intervention for IBD.

Psidium guajava Seed Oil Reduces the Severity of Colitis Induced by Dextran Sulfate Sodium by Modulating the Intestinal Microbiota and Restoring the Intestinal Barrier.

The oil derived from Psidium guajava seeds (TKSO) exhibits an abundance of diverse unsaturated fatty acids, notably oleic, linoleic, and α-linolenic acids, conferring substantial health advantages in addressing metabolic irregularities and human diseases. This research endeavor focused on elucidating the impacts of TKSO on colonic inflammatory responses and intestinal microbiota alterations in a murine model of colitis induced by dextran sulfate sodium (DSS), demonstrated that substantial supplementation with TKSO reduces the severity of colitis induced by DSS. Furthermore, TKSO effectively attenuated the abundance and expression of proinflammatory mediators while augmenting the expression of tight junction proteins in DSS-challenged mice. Beyond this, TKSO intervention modulated the intestinal microbial composition in DSS-induced colitis mice, specifically by enhancing the relative presence of Lactobacillus, Norank_f_Muribaculaceae, and Lachnospiraceae_NK4A136_group, while concurrently diminishing the abundance of Turicibacter. Additionally, an analysis of short-chain fatty acids (SCFAs) revealed noteworthy elevations in acetic, propionic, isobutyric, and butyric acids, and total SCFAs levels in TKSO-treated mice. In summary, these findings underscore the potential of TKSO to reduce the severity of colitis induced by DSS in mice through intricate modulation of the intestinal microbiota, metabolite profiles, and intestinal barrier repair, thereby presenting a promising avenue for the development of therapeutic strategies against intestinal inflammatory conditions.

Protective effect of walnut active peptide against dextran sulfate sodium-induced colitis in mice based on untargeted metabolomics

Inflammatory bowel disease (IBD) is a chronic condition characterized by inflammation of the digestive tract, whose exact cause remains unknown, and its prevalence is on the rise. This study investigated the effects of a walnut-derived peptide LPLLR (LP-5) on intestinal inflammation and metabolism in IBD mice. Metabolomics revealed that LP-5 regulated the levels of metabolites, such as thalsimidine, fumagillin, and geniposide, and LP-5 could regulate several signaling pathways, such as protein digestion and absorption, aminoacyl-tRNA biosynthesis, and ABC transporters. Additionally, LP-5 alleviated dextran sulfate sodium (DSS)-induced colitis by modulating autophagy and inflammasome pathways. Western blotting demonstrated that LP-5 reduced the expressions of NLRP3, Caspase-1, ASC and IL-1β, and increased the expressions of Beclin-1 and LC3-II/LC3-I, corresponding to activation of the AMPK/mTOR/ULK1 pathway. These findings suggested that LP-5 activated autophagy in vivo to suppress inflammation and modulate metabolic substances, highlighting potential implications for gut health and the development of functional foods containing LP-5.

Hepatic Gα13 ablation shifts region-specific colonic inflammatory status by modulating the bile acid synthetic pathway in mice

Inflammatory bowel disease is defined by inflammation and immune dysregulation. This study investigated the effects of Gα13 liver-specific knockout (LKO) on proximal and distal colons of dextran sodium sulfate (DSS)-induced mice in conjunction with a high-fat diet (HFD). HFD improved body weight gain and disease activity index scores. Gα13LKO exerted no improvement. In the proximal colon, HFD augmented the DSS effect on Il6, which was not observed in Gα13LKO mice. In the distal colon, HFD plus DSS oppositely fortified an increase in Tnfa and Cxcl10 mRNA in Gα13LKO but not WT. Il6 levels remained unchanged. Bioinformatic approaches using Gα13LKO livers displayed bile acid and cholesterol metabolism-related gene sets. Cholic acid and chenodeoxycholic acid levels were increased in the liver of mice treated with DSS, which was reversed by Gα13LKO. Notably, mice treated with DSS showed a reduction in hepatic ABCB11, CYP7B1, CYP7A1, and CYP8B1, which was reversed by Gα13LKO. Overall, feeding HFD augments the effect of DSS on Il6 in the proximal colon of WT, but not Gα13LKO mice, and enhances DSS effect on Tnfa and Cxcl10 in the distal colon of Gα13LKO mice, suggesting site-specific changes in the inflammatory cytokines, potentially resulting from changes in BA synthesis and excretion.