Therapeutic potential of gene therapy for gastrointestinal diseases: Advancements and future perspectives.

Advancements in understanding the pathogenesis mechanisms underlying gastrointestinal diseases, encompassing inflammatory bowel disease, gastrointestinal cancer, and gastroesophageal reflux disease, have led to the identification of numerous novel therapeutic targets. These discoveries have opened up exciting possibilities for developing gene therapy strategies to treat gastrointestinal diseases. These strategies include gene replacement, gene enhancement, gene overexpression, gene function blocking, and transgenic somatic cell transplantation. In this review, we introduce the important gene therapy targets and targeted delivery systems within the field of gastroenterology. Furthermore, we provide a comprehensive overview of recent progress in gene therapy related to gastrointestinal disorders and shed light on the application of innovative gene-editing technologies in treating these conditions. These developments are fueling a revolution in the management of gastrointestinal diseases. Ultimately, we discuss the current challenges (particularly regarding safety, oral efficacy, and cost) and explore potential future directions for implementing gene therapy in the clinical settings for gastrointestinal diseases.

Application of Nanoparticles in the Diagnosis of Gastrointestinal Diseases: A Complete Future Perspective.

The diagnosis of gastrointestinal (GI) diseases currently relies primarily on invasive procedures like digestive endoscopy. However, these procedures can cause discomfort, respiratory issues, and bacterial infections in patients, both during and after the examination. In recent years, nanomedicine has emerged as a promising field, providing significant advancements in diagnostic techniques. Nanoprobes, in particular, offer distinct advantages, such as high specificity and sensitivity in detecting GI diseases. Integration of nanoprobes with advanced imaging techniques, such as nuclear magnetic resonance, optical fluorescence imaging, tomography, and optical correlation tomography, has significantly enhanced the detection capabilities for GI tumors and inflammatory bowel disease (IBD). This synergy enables early diagnosis and precise staging of GI disorders. Among the nanoparticles investigated for clinical applications, superparamagnetic iron oxide, quantum dots, single carbon nanotubes, and nanocages have emerged as extensively studied and utilized agents. This review aimed to provide insights into the potential applications of nanoparticles in modern imaging techniques, with a specific focus on their role in facilitating early and specific diagnosis of a range of GI disorders, including IBD and colorectal cancer (CRC). Additionally, we discussed the challenges associated with the implementation of nanotechnology-based GI diagnostics and explored future prospects for translation in this promising field.

Exploring the efficacy of herbal medicinal products as oral therapy for inflammatory bowel disease.

Inflammatory bowel disease (IBD) encompasses a collection of idiopathic diseases characterized by chronic inflammation in the gastrointestinal (GI) tract. Patients diagnosed with IBD often experience necessitate long-term pharmacological interventions. Among the multitude of administration routes available for treating IBD, oral administration has gained significant popularity owing to its convenience and widespread utilization. In recent years, there has been extensive evaluation of the efficacy of orally administered herbal medicinal products and their extracts as a means of treating IBD. Consequently, substantial evidence has emerged, supporting their effectiveness in IBD treatment. This review aimed to provide a comprehensive summary of recent studies evaluating the effects of herbal medicinal products in the treatment of IBD. We delved into the regulatory role of these products in modulating immunity and maintaining the integrity of the intestinal epithelial barrier. Additionally, we examined their impact on antioxidant activity, anti-inflammatory properties, and the modulation of intestinal flora. By exploring these aspects, we aimed to emphasize the significant advantages associated with the use of oral herbal medicinal products in the treatment of IBD. Of particular note, this review introduced the concept of herbal plant-derived exosome-like nanoparticles (PDENs) as the active ingredient in herbal medicinal products for the treatment of IBD. The inclusion of PDENs offers distinct advantages, including enhanced tissue penetration and improved physical and chemical stability. These unique attributes not only demonstrate the potential of PDENs but also pave the way for the modernization of herbal medicinal products in IBD treatment.

Edible exosome-like nanoparticles from portulaca oleracea L mitigate DSS-induced colitis via facilitating double-positive CD4+CD8+T cells expansion.

Plant-derived exosome-like nanoparticles (PDENs) have been paid great attention in the treatment of ulcerative colitis (UC). As a proof of concept, we isolated and identified Portulaca oleracea L-derived exosome-like nanoparticles (PELNs) from edible Portulaca oleracea L, which exhibited desirable nano-size (~ 160 nm) and a negative zeta potential value (-31.4 mV). Oral administration of PELNs effectively suppressed the expressions of pro-inflammatory cytokines (TNF-α, IL-6, IL-12, and IL-1ß) and myeloperoxidase (MPO), increased levels of the anti-inflammatory cytokine (IL-10), and alleviated acute colitis in dextran sulfate sodium (DSS)-induced C57 mice and IL-10-/- mice. Notably, PELNs exhibited excellent stability and safety within the gastrointestinal tract and displayed specific targeting to inflamed sites in the colons of mice. Mechanistically, oral administration of PELNs played a crucial role in maintaining the diversity and balance of gut microbiota. Furthermore, PELNs treatment enhanced Lactobacillus reuteri growth and elevated indole derivative levels, which might activate the aryl-hydrocarbon receptor (AhR) in conventional CD4+ T cells. This activation downregulated Zbtb7b expression, leading to the reprogramming of conventional CD4+ T cells into double-positive CD4+CD8+T cells (DP CD4+CD8+ T cells). In conclusion, our findings highlighted the potential of orally administered PELNs as a novel, natural, and colon-targeted agent, offering a promising therapeutic approach for managing UC. Schematic illustration of therapeutic effects of oral Portulaca oleracea L -derived natural exosome-like nanoparticles (PELNs) on UC. PELNs treatment enhanced Lactobacillus reuteri growth and elevated indole derivative levels, which activate the aryl-hydrocarbon receptor (AhR) in conventional CD4+ T cells leading to downregulate the expression of Zbtb7b, reprogram of conventional CD4+ T cells into double-positive CD4+CD8+T cells (DP CD4+CD8+ T cells), and decrease the levels of pro-inflammatory cytokines.

Plant-derived exosomal nanoparticles: potential therapeutic for inflammatory bowel disease.

Inflammatory bowel disease (IBD), encompassing Crohn's disease and ulcerative colitis, is a chronic autoimmune disorder characterized by inflammation. However, currently available disease-modifying anti-IBD drugs exhibit limited efficacy in IBD therapy. Furthermore, existing therapeutic approaches provide only partial relief from IBD symptoms and are associated with certain side effects. In recent years, a novel category of nanoscale membrane vesicles, known as plant-derived exosome-like nanoparticles (PDENs), has been identified in edible plants. These PDENs are abundant in bioactive lipids, proteins, microRNAs, and other pharmacologically active compounds. Notably, PDENs possess immunomodulatory, antitumor, regenerative, and anti-inflammatory properties, making them particularly promising for the treatment of intestinal diseases. Moreover, PDENs can be engineered as targeted delivery systems for the efficient transport of chemical or nucleic acid drugs to the site of intestinal inflammation. In the present study, we provided an overview of PDENs, including their biogenesis, extraction, purification, and construction strategies, and elucidated their physiological functions and therapeutic effects on IBD. Additionally, we summarized the applications and potential of PDENs in IBD treatment while highlighting the future directions and challenges in the field of emerging nanotherapeutics for IBD therapy.

Extracellular Vesicles: The Next Generation Theranostic Nanomedicine for Inflammatory Bowel Disease.

The recent rapid development in the field of extracellular vesicles (EVs) based nanotechnology has provided unprecedented opportunities for nanomedicine platforms. As natural nanocarriers, EVs such as exosomes, exosome-like nanoparticles and outer membrane vesicles (OMVs), have unique structure/composition/morphology characteristics, and show excellent physical and chemical/biochemical properties, making them a new generation of theranostic nanomedicine. Here, we reviewed the characteristics of EVs from the perspective of their formation and biological function in inflammatory bowel disease (IBD). Moreover, EVs can crucially participate in the interaction and communication of intestinal epithelial cells (IECs)-immune cells-gut microbiota to regulate immune response, intestinal inflammation and intestinal homeostasis. Interestingly, based on current representative examples in the field of exosomes and exosome-like nanoparticles for IBD treatment, it is shown that plant, milk, and cells-derived exosomes and exosome-like nanoparticles can exert a therapeutic effect through their components, such as proteins, nucleic acid, and lipids. Moreover, several drug loading methods and target modification of exosomes are used to improve their therapeutic capability. We also discussed the application of exosomes and exosome-like nanoparticles in the treatment of IBD. In this review, we aim to better and more clearly clarify the underlying mechanisms of the EVs in the pathogenesis of IBD, and provide directions of exosomes and exosome-like nanoparticles mediated for IBD treatment.

Nanoparticles for oral delivery: targeted therapy for inflammatory bowel disease.

As a group of chronic and idiopathic gastrointestinal (GI) disorders, inflammatory bowel disease (IBD) is characterized by recurrent intestinal mucosal inflammation. Oral administration is critical for the treatment of IBD. Unfortunately, it is difficult to target the bowel located in the GI tract due to multiple physical barriers. The unique physicochemical properties of nanoparticle-based drug delivery systems (DDSs) and their enhanced permeability and retention effects in the inflamed bowel, render nanomedicines to be used to implement precise drug delivery at diseased sites in IBD therapy. In this review, we described the pathophysiological features of IBD, and designed strategies to exploit these features for intestinal targeting. In addition, we introduced the types of currently developed nano-targeted carriers, including synthetic nanoparticle-based and emerging naturally derived nanoparticles (e.g., extracellular vesicles and plant-derived nanoparticles). Moreover, recent developments in targeted oral nanoparticles for IBD therapy were also highlighted. Finally, we presented challenges associated with nanotechnology and potential directions for future IBD treatment.

Altered Pattern of Immunoglobulin A-Targeted Microbiota in Inflammatory Bowel Disease After Fecal Transplantation.

Adaptive immune response to the gut microbiota is one of the main drivers of inflammatory bowel disease (IBD). Under inflammatory conditions, immunoglobulin (Ig)-targeted bacteria are altered. However, changes in Ig-targeted bacteria in Asian patients with IBD with ulcerative colitis (UC) remain unclear. Furthermore, changes in IgA-targeted bacteria in patients with UC treated with fecal microbiota transplantation (FMT) are unclear. Here, we analyzed fecal samples of patients with IBD and patients with UC before and after FMT by flow cytometry. We found that the percentage of IgA/G-coated bacteria can be used to assess the severity of IBD. Besides oral pharyngeal bacteria such as Streptococcus, we hypothesized that Megamonas, Acinetobacter, and, especially, Staphylococcus might play an important role in IBD pathogenesis. Moreover, we evaluated the influence of FMT on IgA-coated bacteria in patients with UC. We found that IgA-bacterial interactions were re-established in human FMT recipients and resembled those in the healthy fecal donors. Additionally, the IgA targeting was not influenced by delivery methods: gastroscopy spraying and colonic transendoscopic enteral tubing (TET). Then, we established an acute dextran sulfate sodium (DSS)-induced mouse model to explore whether FMT intervention would impact IgA/G memory B cell in the intestine. We found that after FMT, both IgA/G memory B cell and the percentage of IgA/G-targeted bacteria were restored to normal levels in DSS mice.

Epigenetic DNA methylation of Zbtb7b regulates the population of double-positive CD4+CD8+ T cells in ulcerative colitis.

BACKGROUND AND AIMS: Ulcerative colitis (UC) is a heterogeneous disorder with complex pathogenesis. Therefore, in the present study, we aimed to assess genome-wide DNA methylation changes associated explicitly with the pathogenesis of UC. METHODS: DNA methylation changes were identified by comparing UC tissues with healthy controls (HCs) from the GEO databases. The candidate genes were obtained and verified in clinical samples. Moreover, the underlying molecular mechanism related to Zbtb7b in the pathogenesis of UC was explored using the dextran sodium sulfate (DSS)-induced colitis model. RESULTS: Bioinformatic analysis from GEO databases confirmed that Zbtb7b, known as Th-inducing POZ-Kruppel factor (ThPOK), was demethylated in UC tissues. Then, we demonstrated that Zbtb7b was in a hypo-methylation pattern through the DSS-induced colitis model (P = 0.0357), whereas the expression of Zbtb7b at the mRNA and protein levels was significantly up-regulated in the inflamed colonic tissues of UC patients (qRT-PCR, WB, IHC: P < 0.0001, P = 0.0079, P < 0.0001) and DSS-induced colitis model (qRT-PCR, WB, IHC: P < 0.0001, P = 0.0045, P = 0.0004). Moreover, the expression of Zbtb7b was positively associated with the degree of UC activity. Mechanically, over-expression of Zbtb7b might activate the maturation of CD4+T cells (FCM, IF: P = 0.0240, P = 0.0003) and repress the differentiation of double-positive CD4+CD8+T (DP CD4+CD8+T) cells (FCM, IF: P = 0.0247, P = 0.0118), contributing to the production of inflammatory cytokines, such as TNF-α (P = 0.0005, P = 0.0005), IL-17 (P = 0.0014, P = 0.0381), and IFN-γ (P = 0.0016, P = 0.0042), in the serum and colonic tissue of DSS-induced colitis model. CONCLUSIONS: Epigenetic DNA hypo-methylation of Zbtb7b activated the maturation of CD4+T cells and repressed the differentiation of DP CD4+CD8+ T cells, resulting in the production of inflammatory cytokines and colonic inflammation in UC. Therefore, Zbtb7b might be a diagnostic and therapeutic biomarker for UC, and hypo-methylation might affect the biological function of Zbtb7b.

First Application of Fecal Microbiota Transplantation in Adult Asperger Syndrome With Digestive Symptoms-A Case Report.

Asperger syndrome (AS) is a chronic neurodevelopmental disorder. Although all of the clinically diagnosed cases display normal intelligence and speech functions, barriers in social interaction and communication seriously affect mental health and psychological function. In addition to traditional psychological/behavioral training and symptomatic medication, in-depth studies of intestinal microbiota and mental health have indicated that probiotics (e.g., Lactobacillus rhamnosus) can effectively reduce the occurrence of AS. Fecal microbiota transplantation (FMT) is a type of biological therapy that involves the transplant of intestinal microbiota from healthy donors into the patient's gastrointestinal tract to improve the gut microenvironment. In this case report, we describe the first case of adult AS treated with FMT. The patient suffered from diarrhea-predominant irritable bowel syndrome for 6 years with symptoms of diarrhea and abdominal pain. After three rounds of FMT, the diarrhea and abdominal pain were significantly improved. Moreover, the symptoms of AS were also significantly ameliorated. We found that FMT changed the structure of the intestinal microbiota as well as the patient's serum metabolites, and these changes were consistent with the patient's symptoms. The metabolites may affect signaling pathways, as revealed by Kyoto Encyclopedia of Genes and Genomes enrichment analysis. The changes in microbial metabolites following FMT may affect other regions (e.g., the nervous system) via the circulatory system, such that the bacteria-gut-blood-brain axis may be the means through which FMT mitigates AS.

Characterization of short-chain fatty acids in patients with ulcerative colitis: a meta-analysis.

BACKGROUND: Studies investigating the changes in short-chain fatty acids (SCFAs) in patients with ulcerative colitis (UC) have yielded inconsistent results. We performed a meta-analysis of studies that investigated the alterations in different SCFAs among UC patients to assess their role in the development of UC. METHODS: Three databases were searched for relevant studies published as of April 2021. Results are presented as standardized mean difference (SMD) with 95% confidence interval (95% CI). RESULTS: Eleven studies were included in the meta-analysis. Compared to healthy subjects, UC patients had significantly lower concentrations of total SCFAs (SMD = - 0.88, 95%CI - 1.44, - 0.33; P < 0.001), acetate (SMD = - 0.54, 95% CI - 0.91, - 0.17; P = 0.004), propionate, (SMD = - 0.37, 95% CI - 0.66, - 0.07; P = 0.016), and valerate (SMD = - 0.91, 95% CI - 1.45, - 0.38; P < 0.001). On subgroup analysis based on disease status, patients with active UC had reduced concentrations of acetate (SMD = - 1.83, 95% CI - 3.32, - 0.35; P = 0.015), propionate (SMD = - 2.51, 95% CI - 4.41, - 0.61; P = 0.009), and valerate (SMD = - 0.91, 95% CI - 1.45, - 0.38; P < 0.001), while UC patients in remission had similar concentrations with healthy subjects. Patients with active UC had lower butyrate level (SMD = - 2.09, 95% CI - 3.56, - 0.62; P = 0.005) while UC patients in remission had higher butyrate level (SMD = 0.71, 95% CI 0.33, 1.10; P < 0.001) compared with healthy subjects. CONCLUSION: UC patients had significantly decreased concentrations of total SCFAs, acetate, propionate, and valerate compared with healthy subjects. In addition, inconsistent changes of certain special SCFAs were observed in UC patients with different disease status.

Immunology of Inflammatory Bowel Disease: Molecular Mechanisms and Therapeutics.

As a main digestive organ and an important immune organ, the intestine plays a vital role in resisting the invasion of potential pathogens into the body. Intestinal immune dysfunction remains important pathogenesis of inflammatory bowel disease (IBD). In this review, we explained the interactions among symbiotic flora, intestinal epithelial cells, and the immune system, clarified the operating mechanism of the intestinal immune system, and highlighted the immunological pathogenesis of IBD, with a focus on the development of immunotherapy for IBD. In addition, intestinal fibrosis is a significant complication in patients with long-term IBD, and we reviewed the immunological pathogenesis involved in the development of intestinal fibrogenesis and provided novel antifibrotic immunotherapies for IBD.

New Insights Into the Epigenetic Regulation of Inflammatory Bowel Disease.

Inflammatory bowel disease (IBD) is a chronic inflammatory disease of the colonic mucosa. Environmental factors, genetics, intestinal microbiota, and the immune system are all involved in the pathophysiology of IBD. Lately, accumulating evidence has shown that abnormal epigenetic changes in DNA methylation, histone markers, and non-coding RNA expression greatly contribute to the development of the entire disease. Epigenetics regulates many functions, such as maintaining the homeostasis of the intestinal epithelium and regulating the immune system of the immune cells. In the present study, we systematically summarized the latest advances in epigenetic modification of IBD and how epigenetics reveals new mechanisms of IBD. Our present review provided new insights into the pathophysiology of IBD. Moreover, exploring the patterns of DNA methylation and histone modification through epigenetics can not only be used as biomarkers of IBD but also as a new target for therapeutic intervention in IBD patients.

Selection strategy of dextran sulfate sodium-induced acute or chronic colitis mouse models based on gut microbial profile.

BACKGROUND: Dextran sulfate sodium (DSS) replicates ulcerative colitis (UC)-like colitis in murine models. However, the microbial characteristics of DSS-triggered colitis require further clarification. To analyze the changes in gut microbiota associated with DSS-induced acute and chronic colitis. METHODS: Acute colitis was induced in mice by administering 3% DSS for 1 week in the drinking water, and chronic colitis was induced by supplementing drinking water with 2.5% DSS every other week for 5 weeks. Control groups received the same drinking water without DSS supplementation. The histopathological score and length of the colons, and disease activity index (DAI) were evaluated to confirm the presence of experimental colitis. Intestinal microbiota was profiled by 16S rDNA sequencing of cecal content. RESULTS: Mice with both acute and chronic DSS-triggered colitis had significantly higher DAI and colon histopathological scores in contrast to the control groups (P < 0.0001, P < 0.0001), and the colon was remarkably shortened (P < 0.0001, P < 0.0001). The gut microbiota α-diversity was partly downregulated in both acute and chronic colitis groups in contrast to their respective control groups (Pielou index P = 0.0022, P = 0.0649; Shannon index P = 0.0022, P = 0.0931). The reduction in the Pielou and Shannon indices were more obvious in mice with acute colitis (P = 0.0022, P = 0.0043). The relative abundance of Bacteroides and Turicibacter was increased (all P < 0.05), while that of Lachnospiraceae, Ruminococcaceae, Ruminiclostridium, Rikenella, Alistipes, Alloprevotella, and Butyricicoccus was significantly decreased after acute DSS induction (all P < 0.05). The relative abundance of Bacteroides, Akkermansia, Helicobacter, Parabacteroides, Erysipelatoclostridium, Turicibacter and Romboutsia was also markedly increased (all P < 0.05), and that of Lachnospiraceae_NK4A136_group, Alistipes, Enterorhabdus, Prevotellaceae_UCG-001, Butyricicoccus, Ruminiclostridium_6, Muribaculum, Ruminococcaceae_NK4A214_group, Family_XIII_UCG-001 and Flavonifractor was significantly decreased after chronic DSS induction (all P < 0.05). CONCLUSION: DSS-induced acute and chronic colitis demonstrated similar symptoms and histopathological changes. The changes in the gut microbiota of the acute colitis model were closer to that observed in UC. The acute colitis model had greater abundance of SCFAs-producing bacteria and lower α-diversity compared to the chronic colitis model.

Cross-Talk Between Butyric Acid and Gut Microbiota in Ulcerative Colitis Following Fecal Microbiota Transplantation.

Fecal microbiota transplantation (FMT) can inhibit the progression of ulcerative colitis (UC). However, how FMT modulates the gut microbiota and which biomarker is valuable for evaluating the efficacy of FMT have not been clarified. This study aimed to determine the changes in the gut microbiota and their relationship with butyric acid following FMT for UC. Fecal microbiota (FM) was isolated from healthy individuals or mice and transplanted into 12 UC patients or colitis mice induced by dextran sulfate sodium (DSS). Their clinical colitis severities were monitored. Their gut microbiota were analyzed by 16S sequencing and bioinformatics. The levels of fecal short-chain fatty acids (SCFAs) from five UC patients with recurrent symptoms after FMT and individual mice were quantified by liquid chromatography-mass spectrometry (LC-MS). The impact of butyric acid on the abundance and diversity of the gut microbiota was tested in vitro. The effect of the combination of butyric acid-producing bacterium and FMT on the clinical responses of 45 UC patients was retrospectively analyzed. Compared with that in the controls, the FMT significantly increased the abundance of butyric acid-producing bacteria and fecal butyric acid levels in UC patients. The FMT significantly increased the α-diversity, changed gut microbial structure, and elevated fecal butyric acid levels in colitis mice. Anaerobic culture with butyrate significantly increased the α-diversity of the gut microbiota from colitis mice and changed their structure. FMT combination with Clostridium butyricum-containing probiotics significantly prolonged the UC remission in the clinic. Therefore, fecal butyric acid level may be a biomarker for evaluating the efficacy of FMT for UC, and addition of butyrate-producing bacteria may prolong the therapeutic effect of FMT on UC by changing the gut microbiota.

Fecal Microbiota Transplantation: A New Therapeutic Attempt from the Gut to the Brain.

Gut dysbacteriosis is closely related to various intestinal and extraintestinal diseases. Fecal microbiota transplantation (FMT) is a biological therapy that entails transferring the gut microbiota from healthy individuals to patients in order to reconstruct the intestinal microflora in the latter. It has been proved to be an effective treatment for recurrent Clostridium difficile infection. Studies show that the gut microbiota plays an important role in the pathophysiology of neurological and psychiatric disorders through the microbiota-gut-brain axis. Therefore, reconstruction of the healthy gut microbiota is a promising new strategy for treating cerebral diseases. We have reviewed the latest research on the role of gut microbiota in different nervous system diseases as well as FMT in the context of its application in neurological, psychiatric, and other nervous system-related diseases (Parkinson's disease, Alzheimer's disease, multiple sclerosis, epilepsy, autism spectrum disorder, bipolar disorder, hepatic encephalopathy, neuropathic pain, etc.).

The effect of different combinations of antibiotic cocktails on mice and selection of animal models for further microbiota research.

The gut microbiota is closely related to host health and disease. However, there are no suitable animal models available at present for exploring its functions. We analyzed the effect of 3 different antibiotic cocktails (ABx) via two administration routes on the composition of murine gut microbiota, as well as on the general physiological and metabolic indices. High-throughput 16S rRNA sequencing showed that ABx treatment altered the gut microbiota community structure, and also caused low-degree inflammation in the colon. In addition, ad libitum administration of antibiotics depleted the gut microbiota more effectively compared to direct oral gavage, especially with 3ABx. The ABx treatment also had a significant impact on renal and liver functions, as indicated by the altered serum levels of creatinine, urea, total triglycerides, and total cholesterol. Finally, Spearman's correlation analysis showed that the predominant bacterial genera resulting from ABx intervention, including Lactobacillus, Roseburia, and Candidatus-Saccharimonas, were negatively correlated with renal function indices. Taken together, different antibiotic combinations and interventions deplete the gut microbiota and induce physiological changes in the host. Our findings provide the basis for developing an adaptive animal model for studying gut microbiota. KEY POINTS: • Ad libitum administration of 3ABx can effectively deplete intestinal microbiota. • ABx treatment may have slight effect on renal and liver function. • The levels of urea and creatinine correlated with the growth of Roseburia.

Inhibition of PD-1 Protects against TNBS-Induced Colitis via Alteration of Enteric Microbiota.

METHODS: Colitis was induced in mice using 2,4,6-trinitrobenzene-sulfonic acid (TNBS), and mice were subsequently treated with either a PD-1 inhibitor or 5-amino-salicylic acid (ASA) as a positive control. Body weight, disease activity index (DAI), colon length, and tissue damage were evaluated, and the enteric microbiota was profiled using high-throughput 16S rRNA sequencing of fecal samples from the experimental mice. RESULTS: TNBS caused mice to experience IBD-like symptoms, which were attenuated by the PD-1 inhibitor, as indicated by a decrease in DAI scores (p = 0.0002). Furthermore, in this mouse model of IBD, PD-1 inhibition improved the alpha diversity as well as restored the beta diversity of the enteric microbiome. It also significantly enriched the abundance of short-chain fatty acid- (SCFA-) producing bacteria of the Firmicutes (p < 0.05) and Bacteroidetes (p < 0.05) phyla but depopulated Proteobacteria (p < 0.05). CONCLUSION: PD-1 inhibition can partly mitigate TNBS-induced colitis and restore the enteric microbiota by enriching the abundance of SCFA-producing bacteria.

The roles and interaction of FXR and PPARs in the pathogenesis of nonalcoholic fatty liver disease.

BACKGROUND AND STUDY AIMS: To identify the roles and interaction of farnesoid X receptor (FXR) and peroxisome proliferator activated receptors (PPARs) in Non-alcoholic fatty liver disease (NAFLD) pathogenesis. MATERIAL AND METHODS: 16 C57/BL male FXR knockout (KO) mice and sex- and age-matched C57/BL wild type mice were received either standard rodent chow or high-fat and sucrose diet (Blank control, NAFLD, FXR KO and FXR KO NAFLD) for 8 weeks. After that, all mice were sacrificed. Liver tissues and blood samples were collected for laboratory and RT-PCR examination. RESULTS: NAFLD, FXR KO and FXR KO NAFLD mouse models were successful established. Compared with blank control, FXR and PPAR-α mRNA expression decreased significantly (P < 0.05), PPAR-ß expression increased slightly (P > 0.05), PPAR-γ expression increased significantly in NAFLD (P < 0.05). Slight increased PPAR-α mRNA expression (P > 0.05) and markedly decreased PPAR-ß and PPAR-γ expression (P < 0.05) were found in FXR KO. Compared with FXR KO group, there was a slight increase in PPAR-αand PPAR-ßmRNA expression (P > 0.05) and significant increase in PPAR-γ expression (P < 0.05) in FXR KO NAFLD group. Comparison with NAFLD, PPAR-α mRNA expression increased slightly (P > 0.05), PPAR-ß and PPAR-γ expression decreased significantly (P < 0.05) in FXR KO NAFLD. CONCLUSION: FXR and PPARs interaction may play important roles in NAFLD pathogenesis.