Disease clearance in ulcerative colitis: A new therapeutic target for the future.

Advancements in murine modeling systems for ulcerative colitis have diversified our understanding of the pathophysiological factors involved in disease onset and progression. This has fueled the identification of molecular targets, resulting in a rapidly expanding therapeutic armamentarium. Subsequently, management strategies have evolved from symptomatic resolution to well-defined objective endpoints, including clinical remission, endoscopic remission and mucosal healing. While the incorporation of these assessment modalities has permitted targeted intervention in the context of a natural disease history and the prevention of complications, studies have consistently depicted discrepancies associated with ascertaining disease status through clinical and endoscopic measures. Current recommendations lack consideration of histological healing. The simultaneous achievement of clinical, endoscopic, and histologic remission has not been fully investigated. This has laid the groundwork for a novel therapeutic outcome termed disease clearance (DC). This article summarizes the concept of DC and its current evidence.

Stored white tea ameliorates DSS-induced ulcerative colitis in mice by modulating the composition of the gut microbiota and intestinal metabolites.

Changes in the chemical composition of white tea during storage have been studied extensively; however, whether such chemical changes impact the efficacy of white tea in ameliorating colitis remains unclear. In this study, we compared the effects of new (2021 WP) and 10-year-old (2011 WP) white tea on 3% dextrose sodium sulfate (DSS)-induced ulcerative colitis in mice by gavaging mice with the extracts at 200 mg kg-1 day-1. Chemical composition analysis showed that the levels of 50 compounds, such as flavanols, dimeric catechins, and amino acids, were significantly lower in the 2011 WP extract than in the 2021 WP extract, whereas the contents of 21 compounds, such as N-ethyl-2-pyrrolidinone-substituted flavan-3-ols, theobromine, and (-)-epigallocatechin-3-(3''-O-methyl) gallate, were significantly higher. Results of the animal experiments showed that 2011 WP ameliorated the pathological symptoms of colitis, which was superior to the activity of 2021 WP, and this effect was likely enhanced based on the decreasing of the relative abundance of the g_bacteroides and g_Escherichia-Shigella flora in mice with colitis and promoting the conversion of primary bile acids to secondary bile acids in the colon. These results will facilitate the development of novel functional products from white tea.

Ferric citrate-induced colonic mucosal damage associated with oxidative stress, inflammation responses, apoptosis, and the changes of gut microbial composition.

Ferric citrate (FC) has been used as an iron fortifier and nutritional supplement, which is reported to induce colitis in rats, however the underlying mechanism remains to be elucidated. We performed a 16-week study of FC in male healthy C57BL/6 mice (nine-month-old) with oral administration of Ctr (0.9 % NaCl), 1.25 % FC (71 mg/kg/bw), 2.5 % FC (143 mg/kg/bw) and 5 % FC (286 mg/kg/bw). FC-exposure resulted in colon iron accumulation, histological alteration and reduce antioxidant enzyme activities, such as glutathione (GSH), glutathione peroxidase (GSH-Px), superoxide dismutase (SOD) and total antioxidant capacity (T-AOC), together with enhanced lipid peroxidation level, including malondialdehyde (MDA) level and 4-Hydroxynonenal (4-HNE) protein expression. Exposure to FC was associated with upregulated levels of the interleukin (IL)- 6, IL-1ß, IL-18, IL-8 and tumor necrosis factor α (TNF-α), while down-regulated levels of IL-4 and IL-10. Exposure to FC was positively associated with the mRNA and protein expressions of cysteine-aspartic proteases (Caspase)- 9, Caspase-3, Bcl-2-associated X protein (Bax), while negatively associated with B-cell lymphoma 2 (Bcl2) in mitochondrial apoptosis signaling pathway. FC-exposure changed the diversity and composition of gut microbes. Additionally, the serum lipopolysaccharide (LPS) contents increased in FC-exposed groups when compared with the control group, while the expression of colonic tight junction proteins (TJPs), such as Claudin-1 and Occludin were decreased. These findings indicate that the colonic mucosal injury induced by FC-exposure are associated with oxidative stress generation, inflammation response and cell apoptosis, as well as the changes in gut microbes diversity and composition.

Oral exposure to Ag or TiO2 nanoparticles perturbed gut transcriptome and microbiota in a mouse model of ulcerative colitis.

Silver (nAg) and titanium dioxide (nTiO2) nanoparticles improve texture, flavour or anti-microbial properties of various food products and packaging materials. Despite their increased oral exposure, their potential toxicities in the dysfunctional intestine are unclear. Here, the effects of ingested nAg or nTiO2 on inflamed colon were revealed in a mouse model of chemical-induced acute ulcerative colitis. Mice (eight/group) were exposed to nAg or nTiO2 by oral gavage for 10 consecutive days. We characterized disease phenotypes, histology, and alterations in colonic transcriptome (RNA sequencing) and gut microbiome (16S sequencing). Oral exposure to nAg caused only minor changes in phenotypic hallmarks of colitic mice but induced extensive responses in gene expression enriching processes of apoptotic cell death and RNA metabolism. Instead, ingested nTiO2 yielded shorter colon, aggravated epithelial hyperplasia and deeper infiltration of inflammatory cells. Both nanoparticles significantly changed the gut microbiota composition, resulting in loss of diversity and increase of potential pathobionts. They also increased colonic mucus and abundance of Akkermansia muciniphila. Overall, nAg and nTiO2 induce dissimilar immunotoxicological changes at the molecular and microbiome level in the context of colon inflammation. The results provide valuable information for evaluation of utilizing metallic nanoparticles in food products for the vulnerable population.

Effect of 17ß-estradiol on the daily pattern of ACE2, ADAM17, TMPRSS2 and estradiol receptor transcription in the lungs and colon of male rats.

Covid-19 progression shows sex-dependent features. It is hypothesized that a better Covid-19 survival rate in females can be attributed to the presence of higher 17ß-estradiol (E2) levels in women than in men. Virus SARS-CoV-2 is enabled to enter the cell with the use of angiotensin converting enzyme 2 (ACE2). The expression of several renin-angiotensin system components has been shown to exert a rhythmic pattern, and a role of the circadian system in their regulation has been implicated. Therefore, the aim of the study is to elucidate possible interference between E2 signalling and the circadian system in the regulation of the expression of ACE2 mRNA and functionally related molecules. E2 was administered at a dosage of 40 µg/kg/day for 7 days to male Wistar rats, and sampling of the lungs and colon was performed during a 24-h cycle. The daily pattern of expression of molecules facilitating SARS-CoV-2 entry into the cell, clock genes and E2 receptors was analysed. As a consequence of E2 administration, a rhythm in ACE2 and TMPRSS2 mRNA expression was observed in the lungs but not in the colon. ADAM17 mRNA expression showed a pronounced rhythmic pattern in both tissues that was not influenced by E2 treatment. ESR1 mRNA expression exerted a rhythmic pattern, which was diminished by E2 treatment. The influence of E2 administration on ESR2 and GPER1 mRNA expression was greater in the lungs than in the colon as a significant rhythm in ESR2 and GPER1 mRNA expression appeared only in the lungs after E2 treatment. E2 administration also increased the amplitude of bmal1 expression in the lungs, which implicates altered functioning of peripheral oscillators in response to E2 treatment. The daily pattern of components of the SARS-CoV-2 entrance pathway and their responsiveness to E2 should be considered in the timing of pharmacological therapy for Covid-19.

Trifolirhizin regulates the balance of Th17/Treg cells and inflammation in the ulcerative colitis mice through inhibiting the TXNIP-mediated activation of NLRP3 inflammasome.

Ulcerative colitis (UC) is a chronic and recurrent autoimmune disease, characterized by recurrence and remission of mucosal inflammation. Although the understanding of the pathogenesis of UC has been improved, effective therapeutic drugs are required for treating patients with UC. In current work, the mouse model of colitis was established. Trifolirhizin was demonstrated to improve symptom in dextran sulfate sodium (DSS)-induced colitis mice. The body weight of mice was elevated, whereas the disease activity index (DAI) was reduced. Moreover, trifolirhizin was involved in inhibition of inflammation and regulation of the balance of T helper 17 (Th 17) cells and regulatory T (Treg) cells in DSS-induced colitis mice. Further, the activation NLRP3 inflammasome was suppressed by trifolirhizin in DSS-induced colitis mice. Trifolirhizin was also identified to regulate AMP-activated protein kinase (AMPK)-thioredoxin-interacting protein (TXNIP) pathway. The trifolirhizin-mediated anti-inflammatory effect was inhibited by suppressing AMPK in DSS-induced UC mice. In summary, the research suggested that administration of trifolirhizin significantly improved the symptoms and the pathological damage in DSS-induced UC mice. Trifolirhizin regulated the balance of Th17/Treg cells and inflammation in the UC mice through inhibiting the TXNIP-mediated activation of NLRP3 inflammasome.

The Importance of Drug Concentration at the Site of Action: Celecoxib and Colon Polyp Prevention as a Case Study.

Celecoxib is among the more potent and better clinically studied, nonsteroidal anti-inflammatory drugs (NSAID) for use as a chemoprevention agent for colorectal cancer. Its use is associated with a 40% to 50% response rate for reduction in adenomatous polyps. However, rare serious cardiovascular effects and even death with celecoxib and other NSAIDs make it important to understand why some patients respond and others do not. Celecoxib is a selective inhibitor of COX-2. Its anticancer mechanism has largely been attributed to the inhibition of COX-2. Celecoxib also shows activity to induce apoptosis in cancer cells not expressing COX-2. This includes activity to upregulate 15-lipoxygenase-1 (15-LOX-1) independent of COX-2 and increase the synthesis of 13-S-hydroxyoctadecadienoic acid (13-S-HODE) from linoleic acid (LA) to downregulate PPAR-δ and induce apoptosis in colorectal cancer models. In examining the effect of celecoxib on 15-LOX-1 for reducing adenomatous polyps in patients with familial adenomatous polyposis (FAP), Yang and colleagues point out the potential importance of drug bioavailability in blood, normal, and neoplastic colorectal tissue in patient response. See related article, p. 217.

Food additive sodium bisulfite induces intracellular imbalance of biothiols levels in NCM460 colonic cells to trigger intestinal inflammation in mice.

Sulfites and other preservatives are considered food additives to prevent pathogen growth in food, and they are generally regarded as safe since the late 1950s. However, the possible effects of sulfites on potential damage to host intestinal tissue remain largely unexplored. Given that endogenous sulfite mainly comes from the metabolism of biothiol, we attempted to clarify the relationship among biothiol levels, gut and food additives sulfite, including sodium bisulfite (NaHSO3), and the possible mechanism of sulfite affecting the intestine. In the present study, the NaHSO3 treatments markedly increased the homocysteine (Hcy) level but decreased the cysteine (Cys) level by promoting the expression of Hcy synthase and inhibiting the activities of cystathionine ß-synthase and cystathionine γ-lyase in NCM460 cells. The level of methionine (Met) was not significantly changed, but NaHSO3 promoted ROS-mediated NF-κB signaling pathway, and increased the expressions of proinflammatory cytokines by regulating the levels of Hcy and Cys in NCM460 cells. Vitamin B6 (VB6) supplementation successfully ameliorated NaHSO3-induced damage in NCM460 cells and the colon of Balb/c mice. Altogether, our study provided valuable insights into the safety evaluation of food preservatives. Besides, VB6 could be used as a promising candidate in novel therapies for sodium bisulfite-induced intestinal inflammation.

Colonic interleukin-22 protects intestinal mucosal barrier and microbiota abundance in severe acute pancreatitis.

Intestinal barrier dysfunction plays a critical role in the pathophysiology of many diseases including severe acute pancreatitis (SAP). Interleukin-22 (IL-22) is a critical regulator of intestinal epithelial homeostasis. However, the mechanism, origin site, and characteristics of IL-22 in the intestinal barrier dysfunction remains elusive. Studies were conducted in patients with SAP and SAP mice model. SAP mice model was induced by intraductal infusion of 5% taurocholic acid. The level and source of IL-22 were analyzed by flow cytometry. The effect of IL-22 in SAP-associated intestinal injury were examined through knockout of IL-22 (IL-22-/- ) or administration of recombinant IL-22 (rIL-22). IL-22 increased in the early phase of SAP but declined more quickly than that of proinflammatory cytokines, such as IL-6 and TNF-α. CD177+ neutrophils contributed to IL-22 expression in SAP. IL-22 was activated in the colon rather than the small intestine during SAP. Deletion of IL-22 worse the severity of colonic injury, whereas administration of rIL-22 reduced colonic injury. Mechanistically, IL-22 ameliorates the intestinal barrier dysfunction in SAP through decreasing colonic mucosal permeability, upregulation of E-cadherin and ZO-1 expression, activation of pSTAT3/Reg3 pathway and restoration of fecal microbiota abundance. This study revealing that early decreased colonic IL-22 aggravates intestinal mucosal barrier dysfunction and microbiota dysbiosis in SAP. Colonic IL-22 is likely a promising treating target in the early phase of SAP management. Research in context Evidence before this study Intestinal barrier dysfunction plays a critical role in the pathophysiology of severe acute pancreatitis (SAP). Interleukin-22 (IL-22) is a critical regulator of intestinal epithelial homeostasis. However, the mechanism, origin site and characteristics of IL-22 in the intestinal barrier dysfunction remains elusive. Added value of this study Firstly, we determined the dynamic expression profile of IL-22 in SAP and found that IL-22 was mostly activated in the pancreas and colon and decreased earlier than proinflammatory cytokines. CD177+ neutrophils contributed to IL-22 expression in SAP. Furthermore, we found that IL-22 ameliorates intestinal barrier dysfunction in SAP through decreasing colonic mucosal permeability, upregulation of E-cadherin and ZO-1 expression, activation of pSTAT3/Reg3 pathway and restoration of fecal microbiota abundance. Implications of all the available evidence This study highlights the role of colonic injury and colonic IL-22 in SAP. IL-22 is likely a promising treating target in the early phase of SAP management.

A ß-N-acetylhexosaminidase Amuc_2109 from Akkermansia muciniphila protects against dextran sulfate sodium-induced colitis in mice by enhancing intestinal barrier and modulating gut microbiota.

Inflammatory bowel disease (IBD) is associated with the microbial composition of the gut and its metabolites. Akkermansia muciniphila is a probiotic that exerts a significant alleviative or therapeutic effect on host enteritis. This study was designed to determine the protective effect and potential mechanism underlying the secretion of ß-acetylaminohexosidase (Amuc_2109) by A. muciniphila against dextran sulfate sodium (DSS)-induced colitis in mice. C57BL/6 mice were gavaged with Amuc_2109 for 21 days, and during the last seven days of treatment, they drank DSS dissolved in their drinking water to induce colitis. Our results showed that supplementation with Amuc_2109 improved DSS-induced colitis as evidenced by lowered disease activity index (DAI) scores, reduced weight loss, increased colon length, and inhibited oxidative stress. In addition, Amuc_2109 inhibited the overexpression of inflammatory cytokines (TNF-α, IL-1ß, IL-6) and the NLR family pyrin domain containing 3 (NLRP3) inflammasome in DSS-induced colitis. Furthermore, supplementation with Amuc_2109 also restored the mRNA expression of tight junction proteins (ZO-1, occludin, claudin-1). Further analysis of fecal microbial 16S rRNA sequences showed that Amuc_2109 reshaped the intestinal microbiota. While the anti-inflammatory effects of Amuc_2109 were only manifested with the wild-type protein, the anti-inflammatory effects were completely lost after the mutation of its key catalytic amino acids rendered Amuc_2109 inactive. In summary, these findings demonstrate the potential of Amuc_2109, as a therapeutic agent for ulcerative colitis. We posit that it will provide additional assistance in the prevention and treatment of mucus layer-related diseases such as ulcerative colitis.

Isosteviol Sodium Ameliorates Dextran Sodium Sulfate-Induced Chronic Colitis through the Regulation of Metabolic Profiling, Macrophage Polarization, and NF-κB Pathway.

Inflammatory bowel diseases (IBDs) constitute a group of chronic intestinal conditions prominently featuring deranged metabolism. Effective pharmacological treatments for IBDs are lacking. Isosteviol sodium (STV-Na) exhibits anti-inflammatory activity and may offer therapeutic benefits in chronic colitis. However, the associated mechanism remains unclear. This study is aimed at exploring the therapeutic effects of STV-Na against chronic colitis in terms of metabolic reprogramming and macrophage polarization. Results show that STV-Na attenuated weight loss and colonic pathological damage and restored the hematological and biochemical parameters in chronic colitis mice models. STV-Na also restored intestinal permeability by increasing the goblet cell numbers, which was accompanied by lowered plasma lipopolysaccharide and diamine oxidase levels. Metabolomic analysis highlighted 102 candidate biomarkers and 5 vital pathways that may be crucial in the potential pharmacological mechanism of STV-Na in regulating intestinal inflammation and oxidative stress. These pathways were glycerophospholipid metabolism, phenylalanine metabolism, phenylalanine, tyrosine and tryptophan biosynthesis, the pentose phosphate pathway, and phosphonate and phosphinate metabolism. Furthermore, STV-Na significantly decreased M1 macrophage polarization in the spleen and colon. The mRNA and protein levels of IL-1ß, TNF-α, and NF-κB/p65 in colonic tissue from the colitis mice were decreased after the STV-Na treatment. Overall, STV-Na could alleviate chronic colitis by suppressing oxidative stress and inflammation levels, reprogramming the metabolic profile, inhibiting macrophage polarization, and suppressing the NF-κB/p65 signaling pathway. STV-Na remains a promising candidate drug for treating IBDs.

Unravelling Mechanisms of Doxorubicin-Induced Toxicity in 3D Human Intestinal Organoids.

Doxorubicin is widely used in the treatment of different cancers, and its side effects can be severe in many tissues, including the intestines. Symptoms such as diarrhoea and abdominal pain caused by intestinal inflammation lead to the interruption of chemotherapy. Nevertheless, the molecular mechanisms associated with doxorubicin intestinal toxicity have been poorly explored. This study aims to investigate such mechanisms by exposing 3D small intestine and colon organoids to doxorubicin and to evaluate transcriptomic responses in relation to viability and apoptosis as physiological endpoints. The in vitro concentrations and dosing regimens of doxorubicin were selected based on physiologically based pharmacokinetic model simulations of treatment regimens recommended for cancer patients. Cytotoxicity and cell morphology were evaluated as well as gene expression and biological pathways affected by doxorubicin. In both types of organoids, cell cycle, the p53 signalling pathway, and oxidative stress were the most affected pathways. However, significant differences between colon and SI organoids were evident, particularly in essential metabolic pathways. Short time-series expression miner was used to further explore temporal changes in gene profiles, which identified distinct tissue responses. Finally, in silico proteomics revealed important proteins involved in doxorubicin metabolism and cellular processes that were in line with the transcriptomic responses, including cell cycle and senescence, transport of molecules, and mitochondria impairment. This study provides new insight into doxorubicin-induced effects on the gene expression levels in the intestines. Currently, we are exploring the potential use of these data in establishing quantitative systems toxicology models for the prediction of drug-induced gastrointestinal toxicity.

Matrine protects colon mucosal epithelial cells against inflammation and apoptosis via the Janus kinase 2 /signal transducer and activator of transcription 3 pathway.

Ulcerative colitis (UC) is a type of chronic disease of inflammation, and matrine has anti-inflammatory activity. However, it is unclear that whether matrine can alleviate UC. This study aimed to evaluate the effect of matrine on DSS-induced intestinal epithelial cell injury. Cell viability was performed by MTT assay. Then cell apoptosis was analyzed using the TUNEL assay and flow cytometry. The levels of interleukin (IL)-2, IL-6, TNF-α, and IL-1ß were evaluated using qRT-PCR. Myeloperoxidase (MPO) activity was detected using ELISA assay. Nitric oxide (NO) production was detected by the Griess reagent. Bax, cleaved caspase-3, Bcl-2, JAK2, p-JAK2, STAT3, p-STAT3, STAT5, p-STAT5 levels were measured by Western blot. Bax (6A7) was asses using immunoprecipitation and immunofluorescence assays. The results illustrated that cell viability was inhibited as the concentration of DSS increased. Matrine did not affect cell viability at the concentration of 0-2 mg/ml but inhibited cell viability in a time-independent manner. Matrine suppressed the levels of pro-inflammatory factors, MPO activity, NO production, and apoptosis of DSS-stimulated cells. Furthermore, we found that matrine inhibited the levels of p-JAK2/JAK2 and p-STAT3/STAT3 but did not affect p-STAT5/STAT5. AG490 treatment further enhanced the effect of matrine on the apoptosis and pro-inflammatory factor levels in DSS-induced cells. In summary, matrine protected NCM460 cell against injury by inactivating the JAK2/STAT3 pathway. These data suggested for the first time that matrine may effective in treating UC.

Chicoric Acid Prevents Neuroinflammation and Neurodegeneration in a Mouse Parkinson's Disease Model: Immune Response and Transcriptome Profile of the Spleen and Colon.

Chicoric acid (CA), a polyphenolic acid compound extracted from chicory and echinacea, possesses antiviral, antioxidative and anti-inflammatory activities. Growing evidence supports the pivotal roles of brain-spleen and brain-gut axes in neurodegenerative diseases, including Parkinson's disease (PD), and the immune response of the spleen and colon is always the active participant in the pathogenesis and development of PD. In this study, we observe that CA prevented dopaminergic neuronal lesions, motor deficits and glial activation in PD mice, along with the increment in striatal brain-derived neurotrophic factor (BDNF), dopamine (DA) and 5-hydroxyindoleacetic acid (5-HT). Furthermore, CA reversed the level of interleukin-17(IL-17), interferon-gamma (IFN-γ) and transforming growth factor-beta (TGF-ß) of PD mice, implicating its regulatory effect on the immunological response of spleen and colon. Transcriptome analysis revealed that 22 genes in the spleen (21 upregulated and 1 downregulated) and 306 genes (190 upregulated and 116 downregulated) in the colon were significantly differentially expressed in CA-pretreated mice. These genes were functionally annotated with GSEA, GO and KEGG pathway enrichment, providing the potential target genes and molecular biological mechanisms for the modulation of CA on the spleen and gut in PD. Remarkably, CA restored some gene expressions to normal level. Our results highlighted that the neuroprotection of CA might be associated with the manipulation of CA on brain-spleen and brain-gut axes in PD.

The Anti-Inflammatory Effect of Acidic Mammalian Chitinase Inhibitor OAT-177 in DSS-Induced Mouse Model of Colitis.

Inflammatory bowel diseases (IBD) are chronic and relapsing gastrointestinal disorders, where a significant proportion of patients are unresponsive or lose response to traditional and currently used therapies. In the current study, we propose a new concept for anti-inflammatory treatment based on a selective acidic mammalian chitinase (AMCase) inhibitor. The functions of chitinases remain unclear, but they have been shown to be implicated in the pathology of various inflammatory disorders regarding the lung (asthma, idiopathic pulmonary fibrosis) and gastrointestinal tract (IBD and colon cancer). The aim of the study is to investigate the impact of AMCase inhibitor (OAT-177) on the dextran sulfate sodium (DSS)-induced models of colitis. In the short-term therapeutic protocol, OAT-177 given intragastrically in a 30 mg/kg dose, twice daily, produced a significant (p < 0.001) anti-inflammatory effect, as shown by the macroscopic score. Additionally, OAT-177 significantly decreased TNF-α mRNA levels and MPO activity compared to DSS-only treated mice. Intraperitoneal administration of OAT-177 at a dose of 50 mg/kg caused statistically relevant reduction of the colon length. In the long-term therapeutic protocol, OAT-177 given intragastrically in a dose of 30 mg/kg, twice daily, significantly improved colon length and body weight compared to DSS-induced colitis. This is the first study proving that AMCase inhibitors may have therapeutic potential in the treatment of IBD.

Deoxycholic Acid Modulates Cell-Junction Gene Expression and Increases Intestinal Barrier Dysfunction.

Diet-related obesity is associated with increased intestinal hyperpermeability. High dietary fat intake causes an increase in colonic bile acids (BAs), particularly deoxycholic acid (DCA). We hypothesize that DCA modulates the gene expression of multiple cell junction pathways and increases intestinal permeability. With a human Caco-2 cell intestinal model, we used cell proliferation, PCR array, biochemical, and immunofluorescent assays to examine the impact of DCA on the integrity of the intestinal barrier and gene expression. The Caco-2 cells were grown in monolayers and challenged with DCA at physiological, sub-mM, concentrations. DCA increased transcellular and paracellular permeability (>20%). Similarly, DCA increased intracellular reactive oxidative species production (>100%) and accompanied a decrease (>40%) in extracellular signal-regulated kinase 1/2 (ERK1/2) signaling pathways. Moreover, the mRNA levels of 23 genes related to the epithelial barrier (tight junction, focal adhesion, gap junction, and adherens junction pathways) were decreased (>40%) in (0.25 mM) DCA-treated Caco-2 cells compared to untreated cells. Finally, we demonstrated that DCA decreased (>58%) the protein content of occludin present at the cellular tight junctions and the nucleus of epithelial cells. Collectively, DCA decreases the gene expression of multiple pathways related to cell junctions and increases permeability in a human intestinal barrier model.

Multistage-Responsive Nanocomplexes Attenuate Ulcerative Colitis by Improving the Accumulation and Distribution of Oral Nucleic Acid Drugs in the Colon.

Oral gene therapy has emerged as a potential optimal treatment for ulcerative colitis (UC). Nucleic acid drugs possessing versatility can not only inhibit inflammation but realize colon mucosal healing, fulfilling the clinical objective of UC therapy. However, the effective accumulation and distribution of oral nucleic acid drugs in the colon remain a considerable challenge. Furthermore, current delivery systems pay more attention to the accumulation of nucleic acid drugs in the colon, while the distribution of nucleic acid drugs in the colon, which plays a key role in the UC treatment, never catches the attention of researchers. Here, we used miR-320 as a model nucleic acid drug to develop a kind of multistage-responsive nanocomplexes (MSNs) based on polymeric nanocapsules and alginate. MSNs possess the pH responsiveness in the stomach, the enzyme responsiveness in the colonic lumen, and the redox responsiveness in the cytoplasm. In vivo imaging results showed that MSNs reach the colon within 2 h and effectively release miR-320 nanocapsules in the colonic lumen. The nanocapsules can further deliver miR-320 to the submucosal layer and even the muscular layer. Moreover, MSNs decreased the activity of myeloperoxidase and proinflammatory cytokines and exhibited anti-inflammatory activity by inhibiting the phosphorylation of IκBα and AKT, reducing colonic inflammation and enhancing mucosal repair. Therefore, MSNs can successfully alleviate UC by improving the accumulation and distribution of oral nucleic acid drugs in the colon, promoting the clinical translational application of nucleic acid drugs in the treatment of UC.

Microbial enzymes induce colitis by reactivating triclosan in the mouse gastrointestinal tract.

Emerging research supports that triclosan (TCS), an antimicrobial agent found in thousands of consumer products, exacerbates colitis and colitis-associated colorectal tumorigenesis in animal models. While the intestinal toxicities of TCS require the presence of gut microbiota, the molecular mechanisms involved have not been defined. Here we show that intestinal commensal microbes mediate metabolic activation of TCS in the colon and drive its gut toxicology. Using a range of in vitro, ex vivo, and in vivo approaches, we identify specific microbial ß-glucuronidase (GUS) enzymes involved and pinpoint molecular motifs required to metabolically activate TCS in the gut. Finally, we show that targeted inhibition of bacterial GUS enzymes abolishes the colitis-promoting effects of TCS, supporting an essential role of specific microbial proteins in TCS toxicity. Together, our results define a mechanism by which intestinal microbes contribute to the metabolic activation and gut toxicity of TCS, and highlight the importance of considering the contributions of the gut microbiota in evaluating the toxic potential of environmental chemicals.

Metformin ameliorates chronic colitis in a mouse model by regulating interferon-γ-producing lamina propria CD4+ T cells through AMPK activation.

Metformin, a commonly prescribed drug for type 2 diabetes mellitus, has been shown to activate AMP-activated protein kinase (AMPK). Notably, AMPK activation has recently been observed to be associated with anti-inflammatory responses. Metformin is also reported to elicit anti-inflammatory responses in CD4+ T cells, resulting in improvement in experimental chronic inflammatory diseases, such as systemic lupus erythematosus. To investigate the effect of metformin on inflammatory bowel disease (IBD), we developed a T cell-transfer model of chronic colitis in which SCID mice were injected with CD4+ CD45RBhigh T cells to induce colitis. We examined the effects of metformin via in vitro and in vivo experiments on lamina propria (LP) CD4+ T cells. We observed that metformin suppresses the frequency of interferon (IFN) -γ-producing LP CD4+ T cells in vitro, which were regulated by AMPK activation, a process possibly induced by the inhibition of oxidative phosphorylation. Furthermore, we examined the effects of metformin on an in vivo IBD model. Metformin-treated mice showed AMPK activation in LP CD4+ T cells and ameliorated colitis. Our study demonstrates that metformin-induced AMPK activation in mucosal CD4+ T cells contributes to the improvement of IBD by suppressing IFN-γ production. Moreover, our results indicate that AMPK may be a target molecule for the regulation of mucosal immunity and inflammation. Thus, AMPK-activating drugs such as metformin may be potential therapeutic agents for the treatment of IBD.