Cancer, influenced by genetics and the environment, involves anoikis, a cell death mechanism upon extracellular matrix detachment crucial for metastasis. Understanding this relationship is key for therapy. We analyze cancer and anoikis trends using bibliometrics.

A search was conducted from Web of Science Core, PubMed, Scopus and non-English databases such as the CNKI (inception- 21 December 2024). Data analysis employed Microsoft Excel, VOSviewer, CiteSpace, R software, and the online platform (https://bibliometric.com/).

2510 publications were retrieved, with a significant increase in the last decade. China led, the University of Texas system was productive, and the Oncogene Journal was popular. Breast, and colorectal cancers were frequently studied. Among them, representative tumor-related mechanisms were identified, commonalities such as (EMT, ECM, autophagy) and respective specific mechanisms were summarized.

This bibliometric analysis highlights rapid advances in anoikis research in cancer, emphasizing EMT and FAK pathways' translational potential, guiding targeted therapies, and improving cancer treatment outcomes.

Ulcerative colitis is an idiopathic, chronic inflammatory disorder. The disruption of intestinal epithelial barrier caused by excessive apoptosis of intestinal epithelial cells is a pivotal factor in the etiology and pathology. The mitochondrial pathway is the most significant apoptosis mode of intestinal epithelial cells, which was regulated by the mitochondrial permeability transition pore(mPTP). However, the precise mechanism remains elusive. As a crucial molecule in combating stress and maintaining mitochondrial homeostasis, the heat shock protein 75(HSP75) may play a vital role in regulating the openness of the mPTP. In our research, we ascertained that HSP75 was significantly diminished in the intestinal mucosal of UC patients and experimental colitis mice, concomitantly with the disruption of intestinal epithelial barrier. Furthermore, a negative correlation between HSP75 and the openness of mPTP, mitochondrial-driven apoptosis, and disruption of intestinal epithelial barrier has been demonstrated in vivo and vitro. Secondly, HSP75 level is negatively correlated with the expression of ANT, VDAC, and PiC, which considered to be the components of mPTP. However, the CypD is unaffected by HSP75. Finally, HSP75 altered the synthesis of ANT, VDAC, PiC and the acetylation modification of ANT, but there is no direct interaction between HSP75 and mPTP component proteins. In conclusion, the present study demonstrated that HSP75 significantly decreased in the intestinal mucosa of UC, and preliminarily revealed a novel mechanism of HSP75 regulating the synthesis and openness of mPTP in the intestinal epithelial cells(IECs) of UC, suggesting that the targeted intestinal mucosa supplementation of HSP75 is anticipated to reverse the pathological process.

Microplastic (1 μm - 5 mm) and nanoplastic (<1 μm) pollution is a heightening global challenge affecting the environment and the health of living creatures within. As primary precursors for plastic manufacturing, microplastics predominantly get into the environment through plastic product degradation and integrate into water, food chain and consumer products leading to potential health consequences. The mammalian system is equipped with several blood-tissue barriers with exclusive tight junctions that selectively regulate material transfer and protect vulnerable and functionally important organs. Nonetheless, emerging evidence indicates microplastics interact, traverse and compromise the integrity of these complex barriers. This review summarises the known and potential impact of microplastics on human health, focusing on specific organ barrier breaches. Evidence of microplastic traversal and deposition in distal mammalian organs are discussed. We further highlight current challenges facing both researchers and clinicians and provide an outlook for expanding our understanding of the impact of microplastic on health.

Human intestinal epithelial cells (IECs) play an important role in maintaining gut homeostasis by producing antimicrobial peptides (AMPs). Bacillus subtilis, a commensal bacterium, is considered a probiotic. Although its protective effects on intestinal health are widely reported, the key component of B. subtilis responsible for its beneficial effects remains elusive. In this study, we tried to identify the key molecules responsible for B. subtilis-induced AMPs and their molecular mechanisms in a human IEC line, Caco-2. B. subtilis increased human beta defensin (HBD)-2 mRNA expression in a dose- and time-dependent manner. Among the B. subtilis microbe-associated molecular patterns, lipoprotein (LPP) substantially increased the mRNA expression and protein production of HBD-2, whereas lipoteichoic acid and peptidoglycan did not show such effects. Those results were confirmed in primary human IECs. In addition, both LPP recognition and HBD-2 secretion mainly took place on the apical side of fully differentiated and polarized Caco-2 cells through Toll-like receptor 2-mediated JNK/p38 MAP kinase/AP-1 and NF-κB pathways. HBD-2 efficiently inhibited the growth of the intestinal pathogens Staphylococcus aureus and Bacillus cereus. Furthermore, LPPs pre-incubated with lipase or proteinase K decreased LPP-induced HBD-2 expression, suggesting that the lipid and protein moieties of LPP are crucial for HBD-2 expression. Q Exactive Plus mass spectrometry identified 35 B. subtilis LPP candidates within the LPP preparation, and most of them were ABC transporters. Taken together, these results suggest that B. subtilis promotes HBD-2 secretion in human IECs mainly with its LPPs, which might enhance the protection from intestinal pathogens.

The intestinal barrier serves as a boundary between the mucosal immune system in the lamina propria and the external environment of the intestinal lumen, which contains a diverse array of microorganisms and ingested environmental factors, including pathogens, food antigens, toxins, and other foreign substances. This barrier has a central role in regulating the controlled interaction between luminal factors and the intestinal immune system. Disruptions of intestinal epithelial cells, which serve as a physical barrier, or the antimicrobial peptides and mucins they produce, which act as a chemical barrier, can lead to a leaky gut. In this state, the intestinal wall is unable to efficiently separate the intestinal flora and luminal contents from the intestinal immune system. The subsequent activation of the immune system has an important role in the pathogenesis of inflammatory bowel disease, as well as in metabolic dysfunction-associated steatohepatitis, primary sclerosing cholangitis, and colorectal cancer. Dysregulated intestinal barrier integrity has also been described in patients with chronic inflammatory diseases outside the gastrointestinal tract, including rheumatoid arthritis and neurodegenerative disorders. Mechanistic studies of barrier dysfunction have revealed that the subsequent local activation and systemic circulation of activated immune cells and the cytokines they secrete, as well as extracellular vesicles, promote proinflammatory processes within and outside the gastrointestinal tract. In this Review, we summarise these findings and highlight several new therapeutic concepts currently being developed that attempt to control inflammatory processes via direct or indirect modulation of intestinal barrier function.

Resveratrol (trans-3,4',5-trihydroxystilbene, RES) is a stilbenoid naturally present in a variety of plants. Although there are several reports about its anti-fatigue activity, its impact on intensive exercise-induced fatigue and the underlying mechanisms are yet not well understood. In the present study, we established a swimming exercise protocol in mice that is similar to the fatigue condition induced by a long period of intensive exercise and explored the effect of RES on fatigue and the mechanisms from the perspective of intestinal injury and gut microbiota. The results revealed that RES significantly prolonged exhaustive swimming time in fatigued mice and improved the serum indexes associated with fatigue, including serum glucose, lactic acid (LA), urea nitrogen (BUN), lactate dehydrogenase (LDH), creatine kinase (CK), catalase (CAT), glutathione peroxidase (GSH-Px), and glycogen storage in liver and muscle. Meanwhile, RES increased the expressions of ZO-1, Occludin, and Claudin-1, thereby enhancing intestinal barrier integrity and inhibiting mRNA expressions of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and interleukin-1β (IL-1β) in the colon, thereby improving the pathological injury in the colon. Importantly, RES modified gut microbiota dysbiosis by increasing the diversity of gut microbiota, regulating microbiota associated with inflammation and fatty acid metabolism at the phylum (Bacteroidetes and Firmicutes), family (Erysipelotrichaceae, Enterobacteriaceae, and Prevotellaceae), and genus (Brevundimonas diminuta, Coprobacillus, Megasphaera, and Lactobacillus) levels, respectively. The results supplemented the anti-fatigue mechanism for RES from the perspective of intestinal injury and gut microbiota. The detailed mechanisms and associated metabonomics analysis remain for further study.

Ulcerative colitis (UC) is a chronic inflammatory bowel disease characterized by impaired intestinal mucosal barrier function, leading to persistent inflammation and tissue damage. Current therapies often fail to address barrier dysfunction, highlighting the need for innovative treatments. This study developed a novel therapeutic strategy by combining decellularized porcine small intestinal submucosa (D-SIS) with fibroblast growth factor 20 (FGF-20) to promote mucosal repair and restore barrier integrity in a TNBS-induced colitis rat model. The D-SIS-based hydrogel, supplemented with hyaluronic acid (HA), was designed to enhance FGF-20 stability and enable sustained drug release. Results showed that the FGF-20-loaded hydrogel (MAF) exhibited excellent rheological properties, erosion resistance, and controlled drug release, making it suitable for rectal administration. In vitro cell experiments demonstrated that MAF enhanced Caco-2 cell proliferation, migration, and tight junction protein expression, restoring epithelial barrier integrity. In the colitis model, MAF significantly reduced disease activity index (DAI) scores, attenuated inflammation, and restored mucosal morphology. Additionally, MAF promoted goblet cell regeneration, enhanced mucus secretion, and upregulated intestinal stem cell markers, indicating its ability to repair both epithelial and mucus barriers. In conclusion, the MAF hydrogel represents a promising therapeutic approach for UC by combining the regenerative properties of FGF-20 with the bioactive support of D-SIS.

Type III interferons (IFN-λ), which include IFN-λ1 (or interleukin [IL]-29), IFN-λ2 (IL-28A), IFN-λ3 (IL-28B) and IFN-λ4, exert their effects through a unique receptor complex composed of interferon lambda receptor 1 (IFNLR1) and IL-10 receptor subunit beta (IL-10R2). Studies have highlighted their critical role in modulating immune response, particularly in the context of autoimmune diseases, viral infections and cancer. Unlike type I IFNs, which are broadly expressed, IFN-λ displays a more tissue-specific expression pattern, predominantly acting on epithelial cells and certain immune cell types, such as neutrophils and B cells. This specificity allows IFN-λ to play a pivotal role in mucosal immunity, particularly at barrier sites, such as the respiratory and gastrointestinal tracts. Emerging evidence suggests that IFN-λ has a dual role in both enhancing antiviral immunity and regulating inflammation, thus offering a promising therapeutic strategy for diseases like systemic lupus erythematosus, rheumatoid arthritis, asthma and various cancers. However, the precise mechanisms by which IFN-λ influence immune modulation and disease progression remain an area of active investigation. This review aims to provide an overview of the structure, function and signalling pathways of IFN-λ, exploring their role in immune-related diseases and discussing potential avenues for therapeutic intervention.

The development of biosensors that can detect specific analytes continuously, in vivo, in real time has proven difficult due to biofouling, probe degradation and signal drift that often occur in vivo. By drawing inspiration from intestinal mucosa that can protect host cell receptors in the presence of the gut microbiome, we develop a synthetic biosensor that can continuously detect specific target molecules in vivo. The biomimetic multicomponent sensor features the hierarchical nano-bio interface design with three-dimensional bicontinuous nanoporous structure, polymer coating and aptamer switches, balancing small-molecule sensing and surface protection in complex biological environments. Our system is stable for at least 1 month in undiluted serum in vitro or 1 week implanted within the blood vessels of free-moving rats, retaining over 50% baseline signal and reproducible calibration curves. We demonstrate that the implanted system can intravenously track pharmacokinetics in real time even after 4 days of continuous exposure to flowing blood within rat femoral vein. In this way, our work provides a generalizable design foundation for biosensors that can continuously operate in vivo for extended durations.

This comprehensive review delves into the pivotal role of intestinal epithelial cells in the context of various diseases. It provides an in-depth analysis of the diverse types and functions of these cells, explores the influence of multiple signaling pathways on their differentiation, and elucidates their critical roles in a spectrum of diseases. The significance of the gastrointestinal tract in maintaining overall health is extremely important and cannot be exaggerated. This complex and elongated organ acts as a crucial link between the internal and external environments, making it vulnerable to various harmful influences. Preserving the normal structure and function of the gut is essential for well-being. Intestinal epithelial cells serve as the primary defense mechanism within the gastrointestinal tract and play a crucial role in preventing harmful substances from infiltrating the body. As the main components of the digestive system, they not only participate in the absorption and secretion of nutrients and the maintenance of barrier function but also play a pivotal role in immune defense. Therefore, the health of intestinal epithelial cells is of vital importance for overall health.

Efficient and stable animal models of celiac disease (CD) are crucial for CD research, dietary supplementation research, and new drug development. This study aimed to establish CD models by administering gliadin to parental and first-generation mice on a gluten-free diet using two intraperitoneal injection and a combination of sensitization by intraperitoneal injection and gavage. Various indicators, including clinical manifestations, characteristic indicators of CD, inflammatory factors, intestinal barriers, immune cells, and other related indicators, were used to compare different modeling methods. The results showed that all four methods induced varying degrees of CD symptoms in the mice. The analysis revealed that intraperitoneal injection in first-generation mice significantly increased specific IgG and total IgE antibody levels; markedly shortened intestinal villus and crypt hyperplasia in the jejunum; significantly increased pro-inflammatory cytokines IFN-γ, IL-17, IL-15, and TNF-α; and significantly decreased the anti-inflammatory cytokine IL-4. Additionally, immune cells in the spleen and intestinal lymph nodes were severely imbalanced. These results suggest that the intraperitoneal injection model in first-generation mice is more efficient, stable, and significant. This study provides a theoretical basis for the efficient construction of CD models.

The small intestine is essential for digestion, nutrient absorption, immune regulation, and microbial balance. Its epithelial lining, containing specialized cells like Paneth and tuft cells, is crucial for maintaining intestinal homeostasis. Paneth cells produce antimicrobial peptides and growth factors that support microbial regulation and intestinal stem cells, while tuft cells act as chemosensors, detecting environmental changes and modulating immune responses. Along with immune cells such as intraepithelial lymphocytes, innate lymphoid cells, T cells, and macrophages, they form a strong defense system that protects the epithelial barrier. Disruptions in this balance contribute to chronic inflammation, microbial dysbiosis, and compromised barrier function-key features of inflammatory bowel disease, celiac disease, and metabolic syndromes. Furthermore, dysfunctions in the small intestine and immune cells are linked to systemic diseases like obesity, diabetes, and autoimmune disorders. Recent research highlights promising therapeutic strategies, including modulation of epithelial and immune cell functions, probiotics, and gene editing to restore gut health and address systemic effects. This review emphasizes the pivotal roles of small intestinal epithelia and immune cells in maintaining intestinal homeostasis, their involvement in disease development, and emerging treatments for intestinal and systemic disorders.

As a persistent gastrointestinal disorder, irritable bowel syndrome (IBS) influences the gut-brain connection, leading to abdominal pain and altered bowel irregularities. Baicalein, a flavonoid extracted from Scutellaria baicalensis, is frequently utilized in anti-inflammatory treatments. This study aimed to explore baicalein's effectiveness in mitigating IBS symptoms triggered by both chronic and acute stress (CAS) and to uncover its fundamental mechanisms.

Sprague-Dawley rats were employed to develop an IBS rat model by inducing CAS for five weeks. Each rat was randomly allocated to one of four experimental groups: model (M), low-dose baicalein (L), high-dose baicalein (H), and control (C). Baicalein was orally administered throughout the experiment. Behavioral assessments were conducted, including forced swimming, marble-burying, intestinal motility, and visceral sensitivity tests. Colonic tissues were collected for histopathological examination, evaluation of oxidative stress (MDA and SOD levels), and analysis of inflammatory cytokines, and ODC1/NF-κB pathway activation using Western blot assay, ELISA, and immunofluorescence.

Baicalein treatment notably ameliorated IBS-like symptoms, such as fecal pellet output and AWR scores, by alleviating stress-induced behavioral changes. Baicalein bolstered antioxidant defenses through boosting SOD activity and lowering MDA levels. Moreover, baicalein inhibited inflammatory responses, targeting IL-6, IL-1β, and TNF-α, while suppressing the expression of ODC1 and restraining NF-κB p65 phosphorylation within the colon. These results indicate that baicalein modulates oxidative stress and inflammation in CAS-associated IBS.

Baicalein demonstrates protection against CAS-induced IBS by diminishing intestinal inflammation, oxidative damage, and visceral hypersensitivity via suppression of the ODC1/NF-κB pathway. These findings underscore baicalein's potential as a therapeutic approach for IBS.

Inflammation suppresses right ventricular (RV) function in pulmonary arterial hypertension (PAH). In particular, we showed GP130 (glycoprotein-130) signaling promotes pathological microtubule remodeling and RV dysfunction in rodent PAH. Emerging data demonstrate the intestinal microbiome regulates systemic inflammation, but the impact of modulating the gut microbiome on the GP130-microtubule axis in RV failure is unknown.

Two weeks following monocrotaline injection, rats were administered daily Lactobacillus rhamnosus (4×107 colony-forming units) via oral gavage for 10 days. Next-generation metagenomics and internal transcribed spacer 2 sequencing delineated fecal bacterial and fungal compositions. SomaScan proteomics measured levels of 7596 serum proteins. RV immunoblots quantified protein abundances. Light or super resolution confocal microscopy assessed RV, lung, and jejunal morphology. Echocardiography and invasive closed-chest pressure-volume loops evaluated PAH severity and RV function. The relationship between Lactobacillus abundance and RV function was assessed in 65 patients with PAH.

Lactobacillus administration restructured both the intestinal micro- and mycobiome. The alteration in the gut ecosystem improved intestinal health as demonstrated by increased jejunal villus length and glycocalyx thickness and diminished intestinal permeability biomarkers. Serum proteomics revealed Lactobacillus modulated systemic inflammation and decreased circulating GP130 ligands. Lactobacillus-mediated suppression of GP130 signaling blunted pathological microtubule remodeling in RV cardiomyocytes. Microtubule-associated phenotypes, including RV cardiomyocyte and nuclear hypertrophy, transverse tubule integrity, and connexin-43 localization, were all corrected with Lactobacillus. These cellular changes manifested as improved RV function despite no significant alteration in PAH severity. Finally, patients with PAH and detectable fecal Lactobacillus had superior RV function despite similar mean pulmonary arterial pressure and pulmonary vascular resistance as compared with those without detectable Lactobacillus.

Lactobacillus supplementation restructures the gut micro/mycobiome, restores intestinal health, dampens systemic inflammation, and reduces GP130 ligands and associated RV cardiomyocyte microtubule remodeling. These data identify a novel microbiome-inflammation-microtubule axis that has therapeutic relevance for RV dysfunction.

Polygonatum cyrtonema polysaccharides (PCP) exhibit ameliorative effects on colitis. However, whether the protective effects of PCP depend on the gut microbiota and how PCP regulates intestinal immune responses to alleviate colitis remain unclear. Therefore, this study investigated the effect of PCP against colitis focusing on the regulation of intestinal immune response. The PCP structure was reclassified as fructan. PCP treatment significantly reduced the symptoms of colitis. PCP restored IgA, ZO-1, Occludin, and MUC2 expression to enhance intestinal barrier function. Oral PCP administration markedly inhibited excessive inflammation-mediated immune response by modulating inflammatory cytokines secretion and Th17/Tregs cell balance and restored gut microbial composition. Interestingly, PCP still had a significant ameliorating effect on intestinal inflammation in colitis mice with gut microbial depletion by antibiotics. In the Caco-2/RAW264.7 co-culture inflammation model, PCP treatment improved the intestinal epithelial barrier function by regulating the inflammatory immune response through signal transduction pathways. Overall, these findings suggested that the alleviating effects of PCP on colitis are independent of gut microbiota, and that PCP can directly modulate the inflammatory immune response and intestinal barrier function, which in turn regulates gut microbiota. These findings will provide new insights into the action mechanism of natural polysaccharides in relieving colitis.

The mammalian gut harbours trillions of commensal bacteria that interact with their hosts through various bioactive molecules1,2. However, the mutualistic strategies that hosts evolve to benefit from these symbiotic relationships are largely unexplored. Here we report that mouse enterocytes secrete apolipoprotein L9a and b (APOL9a/b) in the presence of microbiota. By integrating flow cytometry sorting of APOL9-binding bacterial taxa with 16S ribosomal RNA gene sequencing (APOL9-seq), we identify that APOL9a/b, as well as their human equivalent APOL2, coat gut bacteria belonging to the order of Bacteroidales with a high degree of specificity through commensal ceramide-1-phosphate (Cer1P) lipids. Genetic abolition of ceramide-1-phosphate synthesis pathways in gut-dominant symbiote Bacteroides thetaiotaomicron significantly decreases the binding of APOL9a/b to the bacterium. Instead of lysing the bacterial cells, coating of APOL9a/b induces the production of outer membrane vesicles (OMVs) from the target bacteria. Subsequently, the Bacteroides-elicited outer membrane vesicles enhance the host's interferon-γ signalling to promote major histocompatibility complex class II expression in the intestinal epithelial cells. In mice, the loss of Apol9a/b compromises the gut major histocompatibility complex class II-instructed immune barrier function, leading to early mortality from infection by intestinal pathogens. Our data show how a host-elicited factor benefits gut immunological homeostasis by selectively targeting commensal ceramide molecules.

A mutualistic co-evolution exists between the host and its associated microbiota in the human body. Bacteria establish ecological niches in various tissues of the body, locally influencing their physiology and functions, but also contributing to the well-being of the whole organism through systemic communication with other distant niches (axis). Emerging evidence indicates that when the composition of the microbiota inhabiting the niche changes toward a pathogenic state (dysbiosis) and interactions with the host become unbalanced, diseases may present. In addition, imbalances within a single niche can cause dysbiosis in distant organs. Current research efforts are focused on elucidating the mechanisms leading to dysbiosis, with the goal of restoring tissue homeostasis. In vitro models can provide critical experimental platforms to address this need, by reproducing the niche cyto-architecture and physiology with high fidelity. This review surveys current in in vitro host-microbiota research strategies and provides a roadmap that can guide the field in further developing physiologically relevant in vitro models of ecological niches, thus enabling investigation of the role of the microbiota in human health and diseases. Lastly, given the Food and Drug Administration Modernization Act 2.0, this review highlights emerging in vitro strategies to support the development and validation of new therapies on the market.

This study investigates the effect and underlying mechanism of targeting SLC7A11 in mitigating dextran sulfate sodium (DSS)-induced intestinal inflammation and injury in colitis.

We utilized wild-type and SLC7A11-/+ mice to assess the inflammatory damage in DSS-induced colitis in vivo. In vitro, colon tissues from patients with ulcerative colitis were analyzed to compare SLC7A11 expression between inflamed and non-inflamed regions. Further mechanistic insights were obtained using Caco-2 cells and bone marrow-derived dendritic cells (BMDCs).

In human colon tissues, SLC7A11 expression was significantly elevated in inflamed regions compared to non-inflamed areas, particularly in dendritic cells. In vivo inhibition of SLC7A11 markedly alleviated DSS-induced colitis symptoms. In vitro, suppressing SLC7A11 restored the integrity of the Caco-2 monolayer intestinal epithelial model. Both knockout and inhibition of SLC7A11 enhanced ERK1/2 phosphorylation and increased efferocytosis in BMDCs.

Targeting SLC7A11 augments dendritic cell efferocytosis and preserves intestinal epithelial barrier function, potentially offering a therapeutic avenue for alleviating ulcerative colitis.

The immature gastrointestinal development of infants and young animals made them more vulnerable to stress-related damage, which affected the gut-liver axis and consequently impaired their health and growth. This study used weaned piglets as a model to investigate how dietary sesamin regulated the gut-liver axis and impacted young animal health. We assessed gut-liver tissue morphology, measured key indicators of intestinal barrier damage, mucosal repair, antioxidant and immune pathways in the gut-liver system and serum, and analyzed microbial composition. We further explored the interactions between sesamin and the gut-liver axis through PLS-PM and molecular docking analysis. Results showed that sesamin enhanced intestinal barrier function, reduced liver damage, decreased oxidative stress, promoted anti-inflammatory immune responses, and enriched beneficial microbes, thereby promoting overall growth. Sesamin can enhance the health of young animals by regulating the function of the gut-liver axis.

Inflammatory bowel disease (IBD) is an inflammatory disease of the intestine whose primary pathological presentation is the destruction of the intestinal epithelium. The intestinal epithelium, located between the lumen and lamina propria, transmits luminal microbial signals to the immune cells in the lamina propria, which also modulate the intestinal epithelium. In IBD patients, intestinal epithelial cells (IECs) die dysfunction and the mucosal barrier is disrupted, leading to the recruitment of immune cells and the release of cytokines. In this review, we describe the structure and functions of the intestinal epithelium and mucosal barrier in the physiological state and under IBD conditions, as well as the patterns of epithelial cell death and how immune cells modulate the intestinal epithelium providing a reference for clinical research and drug development of IBD. In addition, according to the targeting of epithelial apoptosis and necroptotic pathways and the regulation of immune cells, we summarized some new methods for the treatment of IBD, such as necroptosis inhibitors, microbiome regulation, which provide potential ideas for the treatment of IBD. This review also describes the potential for integrating AI-driven approaches into innovation in IBD treatments.

Inflammatory Bowel Disease (IBD) is a complex intestinal disorder that typically triggers inflammatory responses, immune dysregulation, and gut microbiota imbalance. Lignoformic acid (LFA) is a lignin-derived compound containing benzene rings and hydroxyl functional groups. It has antioxidant properties and can regulate intestinal pH. This study aimed to investigate the improve effects of LFA on dextran sulfate sodium (DSS)-induced chronic colitis in mice. The results showed that LFA treatment significantly improved body weight and Disease Activity Index (DAI) in mice and alleviated colon damage. In terms of oxidative stress and anti-inflammatory effects, the expression of antioxidant enzymes such as Glutathione Peroxidase (GSH-PX) and Superoxide Dismutase (SOD) was dose-dependently enhanced in DSS-induced mice. LFA reduced the expression of Tumor Necrosis Factor-alpha (TNF-α) by modulating the TLR4/MyD88/NF-κB signaling pathway. Furthermore, LFA dose-dependently increased the abundance of beneficial bacteria, including Akkermansia and Lachnospiraceae, and promoted the production of short-chain fatty acids (SCFAs). These findings suggest that LFA could serve as a therapeutic agent for colitis by enhancing intestinal barrier integrity, regulating inflammation, and restoring gut microbiota balance.

Intestinal inflammation entails a multifactorial pathophysiology, frequently treated by using anti-inflammatory drugs with severe side effects. At the same time, bioactive compounds present in plant materials and derived residues could contribute to reducing the use of such medications in terms of dosage and treatment length. Thus, the phytochemicals of winery byproducts, mainly represented by (poly)phenols, display significant anti-inflammatory and antioxidant potential. However, the functionality of bioaccessible fractions remains underexplored. This study uncovers the capacity of bioaccessible (poly)phenols of winery byproducts to modulate inflammatory mediators and secondary oxidative stress (OS). After in vitro simulated digestion, bioaccessible (poly)phenols exhibited significant inhibitory capacity of nitric oxide, interleukin (IL)-6, IL-8, and TNF-α production and prevented OS, lowering reactive oxygen species (ROS) resulting from disturbed cell metabolism while preserving the molecular machinery of cells, involving glutathione, catalase, superoxide dismutase, and glutathione peroxidase. The results retrieved suggested the relevance of specific profiles for efficiently preventing inflammation.

Vaccine approaches for controlling Fasciola hepatica present a promising avenue, particularly considering increasing resistance to anthelmintic treatments and concerns over chemical residues. Targeting vaccine candidates that are expressed and secreted during the early infective stage of F. hepatica could offer an effective alternative. This approach aims to inhibit the invasion and migration of juvenile parasites, which have not yet fully developed their immune evasion mechanisms, thereby preventing parasite establishment and development in the host. In this study, we evaluated the host immune response and the protective efficacy of a vaccine cocktail comprising four antigens -KTSPIDP, VGHC1, CRTA, and CAL- in sheep infected with F. hepatica. These parasitic antigens were selected based on a proteomic analysis coupled with an "in vitro" interaction model between newly excysted juvenile worms and mouse intestinal epithelial cell cultures. Despite inducing a strong IgG1 response, vaccination did not reduce liver fluke burden nor faecal egg counts. However, it reduced liver pathology caused by the parasite. Our findings highlight the need for further research into early-stage interactions between F. hepatica and the host. Understanding these interactions could facilitate the progress of vaccines capable of disrupting parasite development and transmission in livestock, potentially reducing the economic and health impacts associated with fasciolosis.

Nanoplastics pollution is a global issue, with the digestive tract being one of the first affected organs, requiring further research on its impact on intestinal health. This study involved orally exposing mice to polystyrene nanoplastics (PS-NPs) at doses of 0.1, 0.5, or 2.5 mg/d for 42 days. The effects on intestinal health were thoroughly assessed via microbiomics, metabolomics, transcriptomics, and molecular biology. Our study demonstrated that the administration of all three doses of PS-NPs resulted in increased colonic permeability, heightened colonic and peripheral inflammation, reduced levels of antimicrobial peptides, and shortened colonic length. These effects may be attributed to a reduction in the abundance of probiotic bacteria, such as Clostridia_UCG-014, Roseburia, and Akkermansia, alongside an increase in the abundance of the pathogenic bacterium Desulfovibrionaceae induced by PS-NPs. Furthermore, we underscored the crucial role of histidine metabolism in PS-NPs-induced colonic injury, characterized by a significant reduction of L-histidine, which is closely related to microbial ecological dysregulation. Corresponding to microbiota deterioration and metabolic dysregulation, transcriptome analysis revealed that PS-NPs may disrupt colonic immune homeostasis by activating the TLR4/MyD88/NF-κB/NLRP3 signaling pathway. In conclusion, this study provided novel insights into the mechanisms by which PS-NPs disrupt intestinal homeostasis through integrated multiomics analysis, revealing critical molecular pathway and providing a scientific basis for future risk assessment of nanoplastics exposure.

Inflammatory Bowel Disease (IBD) is a group of chronic and recurrent inflammatory diseases characterized by prolonged inflammation of the intestinal tract. Although it has been proven that the immune system plays a crucial role in the pathogenesis of IBD, a defective intestinal epithelium is also responsible for chronic inflammation, hence causing an over-activation of the immune response. For this reason, a therapeutic approach that acts by improving impaired intestinal homeostasis could ensure a greater therapeutic efficacy in IBD. Mitogen-activated protein kinases (MAPKs) signaling pathways may be involved in the pathogenesis of IBD. It has been demonstrated that the inhibition of mitogen-activated protein kinase kinase 1 (MEK1) may be a potential treatment against IBD since it may restore the normal epithelial function and reduce apoptosis of intestinal epithelial cells (IECs). New therapeutic strategies are emerging including small molecules such as microRNAs (miRNAs). In this study, we aimed to demonstrate that miR-369-3p was able to modulate the MEK/ERK signaling pathway. As reported by in silico analysis, miR-369-3p was capable of pairing the 3'UTR of the MAP2K1 gene. In vitro analysis demonstrated that mimic transfection with miR-369-3p in epithelial cells downregulated the expression of MEK1, reduced the activation of ERK signaling, and modulated apoptosis of epithelial cells in response to TNF-α. Moreover, miR-369-3p significantly decreased the release of pro-inflammatory cytokine IL-8. These results support the potential of miR-369-3p to prevent apoptosis of IECs, responsible for a persistent inflammatory condition in IBD, highlighting its application value in the treatment of inflammatory disorders.

To elaborate the causal relationships between specific immunocyte phenotypes and male infertility.

Mendelian randomization using genome-wide association study data.

Large cohorts of European ancestry.

731 immunocyte phenotypes or male infertility.

Genetic variants were used as instrumental variables to infer causality, minimizing confounding and bias. The causal associations were assessed using the inverse variance-weighted (IVW) method for primary analysis, and the findings were validated using MR-Egger, Weighted Median, Simple Mode, and Weighted Mode approaches. Additional sensitivity analyses were performed to validate the robustness of the findings.

Our analysis identified significant causal associations between specific immunocyte phenotypes and male infertility. Phenotypes such as naive-mature B cell %lymphocyte (odds ratio [OR] = 1.257) and IgD- CD38dim %B cell (OR = 1.100) were positively associated with increased infertility risk, whereas phenotypes like CD39+ CD8br %T cell (OR = 0.856) and B cells activator of the TNF-α family receptor (BAFF-R) on transitional (OR = 0.833) were negatively associated, suggesting a protective effect. Additionally, reverse MR analysis revealed that male infertility might causally affect certain immunocyte phenotypes, including CD14- CD16+ monocyte %monocyte (OR = 1.049).

This study provides robust evidence for the causal role of specific immunocyte phenotypes in male infertility and highlights the bidirectional relationship between immune function and reproductive health. These findings provide new insights into the immunological factors contributing to male infertility and suggest potential biomarkers and therapeutic targets for future research and clinical interventions.

Stachyose has traditionally been considered to exert prebiotic effects primarily through its interaction with gut microbiota. However, this study reveals a novel mechanism by which stachyose alleviates cyclophosphamide (CY)-induced small intestinal mucosa disruption by regulating the intestinal exosomal miRNAs, without relying on the gut microbiota. Specifically, stachyose significantly mitigates CY-caused damage to the intestinal permeability, oxidative stress, and the structure of intestinal villi and crypts in pseudo-germ-free (PGF) mice. The immunofluorescence staining and qPCR analyses show that stachyose treatment restores CY-caused abnormal changes on the levels of tight junction proteins including MUC2, Occludin, Claudin-1, and ZO-1, and pro-inflammatory cytokines including TNF-α, IL-1β, and IL-2. Furthermore, by conducting fecal miRNA transplantation experiment, we further demonstrated that, similar to stachyose, stachyose-shaped intestinal miRNAs protect against CY-induced intestinal mucosal damage in PGF mice. In summary, this study provides new scientific evidence for the direct interaction between nondigestible stachyose and the proximal small intestine. It also opens new avenues for further investigation into the systemic nutritional functions of stachyose, particularly the health benefits of stachyose in the upper gastrointestinal tract.

Curcumin (Cur) has gained considerable recognition because of its anti-inflammatory and antioxidant effects as a bioactive compound, but its water insolubility and low bioaccessibility limit its application in food industry. In this study, Pickering emulsion stabilized by Spanish mackerel protein and pectin complex (SMP/PEC) was prepared to deliver curcumin, and its alleviating effects on DSS-induced ulcerative colitis (UC) were investigated. The emulsions stabilized by SMP/PEC 1:1 inhibited phase separation, had good rheological properties and the emulsions were stable at high temperatures, centrifugation, salt ions, and pH conditions. Meanwhile, the bioaccessibility of Cur loaded in the emulsion was 2.6 times higher than that of free Cur in corn oil. Furthermore, in vivo experiments have demonstrated that Cur loaded Pickering emulsion stabilized by SMP/PEC could enhance the proliferation of goblet cells and the expression of tight junction proteins, and restore the structural integrity of colonic tissues. Additionally, it has been shown to downregulate pro-inflammatory cytokines, such as serum IL-6 and TNF-α, and reduce the levels of MPO, NO, and other biomarkers in colonic tissues. Concurrently, gut microbiota demonstrated that emulsion stabilized by SMP/PEC could regulate the relative abundance of intestinal microorganisms, facilitating the increase of beneficial bacteria and reducing the level of harmful bacteria in the gut. In conclusion, the findings of this study indicated that SPECPE might be a potentially beneficial dietary supplement for the prevention of ulcerative colitis.

Dietary polysaccharides have attracted considerable attention because of their species-specific chemical composition and diverse biological activities. Polysaccharides derived from Houttuynia cordata (HC) exhibit broad pharmacological activities, emphasizing their diverse roles in biological processes. This study investigated the effects of HC-derived polysaccharides on Peyer's patch (PP)-mediated intestinal immune response. The crude polysaccharide (HCP) isolated from HC extract (HCE) was identified as a pectin-type polysaccharide rich in the homogalacturonan (HG) domain, which was further hydrolyzed by endo-polygalacturonase to produce HCPE. In vitro, HCPE significantly enhanced PP-mediated cytokine secretion and bone marrow cell (BMC) proliferation compared with HCP. In vivo, a 4-week treatment with oral HCPE stimulated PP-mediated secretion of hematopoietic growth factors and promoted BMC proliferation. Additionally, HCPE upregulated IgA-associated factors, leading to increased IgA levels in the small intestine, serum, and feces, while also significantly elevating short-chain fatty acid levels, potentially improving the gut environment. To the best of our knowledge, this is the first study to systematically analyze PP-mediated intestinal immunostimulatory activity of HC-derived polysaccharides both in vitro and in vivo. These findings provide valuable insights into the potential of HCPE as an intestinal immunostimulatory agent and establish a foundation for future research on the immunological effects of HC-derived polysaccharides.

Aging-related cognitive impairment has emerged as a major health-threatening factor among the elderly, and cyanidin-3-glucoside (C3G) is a prominent anthocyanin with biological activities, including antioxidant, anti-inflammatory, and alleviation of neurodegeneration. However, the role of C3G in alleviating natural aging-induced cognitive impairment and the underlying mechanisms thereof remain unclear. In this study, experimental methods mainly included biochemical analysis, pathological analysis, immunofluorescence staining, transmission electron microscopy analysis, western blot, as well as the determination of the gut microbiota composition and detection of metabolites. We found that C3G may exert neuroprotective effects and promote brain health by alleviating brain atrophy and neuroinflammation, enhancing brain antioxidant capacity, regulating neurotransmitter expression and hypothalamic-pituitary-adrenal axis activity, and attenuating blood-brain barrier and hippocampal synaptic damage. Furthermore, C3G also promotes gut health by decreasing inflammatory responses and intestinal tissue crypt damage, upregulating the expression of tight junction proteins, and attenuating intestinal damage. Notably, C3G regulated the microbiota composition in different intestinal segments and intestinal mucosa, as well as the metabolic homeostasis of gut microbiota metabolites, such as short-chain fatty acids (SCFAs), amino acids, and bile acids. Substantially increased levels of SCFAs could activate the extracellular signal-regulated kinase (ERK)/cAMP response element-binding protein (CREB)/brain-derived neurotrophic factor (BDNF) signaling pathway by acting on the G protein-coupled receptors. Correlation analysis indicated that increased gut microbiota, such as Faecalibaculum and Bifidobacterium, and elevated SCFAs were positively correlated with behavioral improvement and brain health. In conclusion, our findings reveal that C3G has the potential to improve natural aging-induced cognitive impairment by modulating the gut microbiota and its metabolite SCFAs, thereby activating the ERK/CREB/BDNF pathway.

This study aimed to clarify the role and mechanism of tetrahedral framework nucleic acids (tFNAs) in regulating M2 macrophages to reduce intestinal injury. An intestinal injury model was established by intraperitoneal injection of lipopolysaccharides (LPS) in mice to explore the alleviating effects of tFNAs on intestinal injury. Inflammatory factors were detected by quantitative polymerase chain reaction (qPCR) and enzyme-linked immunosorbent assay (ELISA). The intestinal barrier and permeability were assessed using western blotting and immunohistochemistry. Macrophages in the gut were localised and quantified using immunofluorescence. Western blotting was used to investigate the role and mechanism of tFNAs in regulating macrophages and alleviating inflammation in the injured intestines. These results show that tFNAs attenuated sepsis-induced intestinal injury. tFNAs can also promote the intestinal barrier reconstruction and reduce intestinal permeability. In vivo, tFNAs accelerated the aggregation of M2 macrophages at an early stage of injury and reduced the number of M1 macrophages in the intestine. In addition, tFNAs enhanced the clearance ability of intestinal macrophages. They activated the signalling and transcription activating factor 1(STAT1) and cytokine signalling inhibitory factor 1/3 (SOCS1/3) pathways by increasing the expression of the phagocytic receptor Mertk. These findings indicated that tFNAs can alleviate sepsis-induced intestinal injury by regulating M2 macrophages, providing a new option for treating intestinal injury.

Resveratrol, a naturally occurring polyphenolic compound found in grapes, berries, and traditional medicinal plants like Polygonum cuspidatum, has been used for centuries in traditional medicine systems for its anti-inflammatory, antioxidant, and cardioprotective properties. Ulcerative colitis (UC), a chronic inflammatory bowel disease, is characterized by intestinal barrier disruption due to excessive colonocyte apoptosis, leading to increased permeability and inflammation. Targeting apoptosis is a critical therapeutic strategy for UC.

This study aims to investigate the therapeutic potential of Resveratrol in ulcerative colitis (UC) by targeting excessive colonocyte apoptosis and intestinal barrier dysfunction. Specifically, we seek to elucidate the mechanisms through which Resveratrol modulates apoptosis-related pathways and evaluate its efficacy in restoring intestinal homeostasis and mitigating UC progression in both in vivo and in vitro models.

We used dextran sulfate sodium (DSS) to induce UC in a mouse model. Colonic damage was assessed through colonic length measurement, histological examination, and immunofluorescence staining. Single-cell sequencing was employed to explore changes in the colonic immune microenvironment and cellular signaling pathways after Resveratrol treatment. In vitro, colonocytes isolated from healthy mouse colonic tissue were exposed to TGF-β to induce apoptosis. DNA fragmentation, mitochondrial membrane potential, and annexin V/propidium iodide staining were used to assess apoptosis. Additionally, we employed an Adeno-Associated Virus system to overexpress MDM2 in the colon and evaluate its protective role in DSS-induced UC.

Resveratrol treatment effectively repaired colonic damage in the UC mouse model by significantly increasing colon length, reducing inflammatory cell infiltration, and mitigating mucosal injury. Single-cell sequencing revealed that Resveratrol primarily targeted colonocytes, decreasing genes related to apoptosis and the P53 pathway. In vitro, Resveratrol reduced DNA fragmentation, apoptotic cell populations, and increased mitochondrial membrane potential in a dose-dependent manner. Furthermore, Resveratrol increased MDM2 expression, inhibiting P53 and downstream pro-apoptotic signaling. Nutlin-3a, an MDM2 inhibitor, reversed the anti-apoptotic effects of Resveratrol. Overexpression of MDM2 in the colon protected against DSS-induced damage.

Resveratrol is an effective treatment for DSS-induced UC, primarily by inhibiting excessive apoptosis in colonocytes through the MDM2/P53/PUMA axis. MDM2 presents a promising therapeutic target for UC treatment.

Inflammatory bowel disease (IBD), encompassing Crohn's disease (CD) and ulcerative colitis (UC), is a multifactorial, immune-mediated condition marked by chronic gastrointestinal inflammation. This condition significantly impairs patients' quality of life and represents a major public health challenge globally. Pathogenesis of IBD arises from complex interplay among genetic predisposition, environmental factors, immune dysregulation, and microbial dysbiosis. Although significant strides have been made in unraveling these mechanisms, existing therapeutic options remain inadequate in addressing the full spectrum of clinical needs, underscoring the urgent demand for innovative strategies. Regenerative medicine has emerged as a promising frontier, offering novel tools for therapeutic development. We briefly consolidated current knowledge on IBD pathogenesis and treatments, emphasized the pivotal potential of human intestinal organoids (including adult stem cell-derived organoids and pluripotent stem cell- derived organoids) as a robust platform for mechanistic studies and treatment exploration. Leveraging this technology, we aim to advance personalized and next-generation therapies for IBD.

Whereas intestinal epithelial barrier dysfunction is implicated in inflammatory bowel disease (IBD), the underlying mechanisms remain elusive. Tumor necrosis factor α stimulated gene 6 (TSG-6) is a secretory protein with anti-inflammatory properties. Our previous research demonstrated TSG-6 can relieve intestinal inflammation and mucosal damage. However, the underlying mechanism and targets remain unclear. This research sought to explore how TSG-6 regulates the intestinal epithelial barrier and its mechanistic role in experimental colitis.

IBD mouse model was generated using dextran sodium sulfate (DSS), with or without intraperitoneal injection of TSG-6(100 µg/kg or 200 µg/kg). The effects of TSG-6 on colonic inflammation and intestinal barrier function were investigated. Label-free quantitative proteomic analysis was performed on intestinal samples to explore the mechanism and therapeutic target of TSG-6. Molecular interactions were determined by co-immunoprecipitation (Co-IP) and immunofluorescence colocalization.

TSG-6 treatment significantly attenuated DSS-induced colitis symptoms and inflammatory cell infiltration. Microarray analysis revealed that TSG-6 decreased pro-inflammatory cytokine levels in colon tissue. TSG-6 restored the intestinal epithelial barrier through the promotion of intestinal epithelial cells (IECs) proliferation and mitigation of tight junctions (TJs) damage. Mechanistically, TSG-6 promoted tuft cells differentiation and increased interleukin-25 (IL-25) levels by directly binding to Pou class 2 homeobox 3(Pou2f3) and up-regulating its expression in the gut.

This study demonstrated TSG-6 as a positive regulator of tuft cells differentiation by interacting with Pou2f3, and the effectiveness of exogenous TSG-6 treatment on maintaining intestinal barrier integrity showed a promising potential for its clinical application.

The inhibitory effects of the tumor necrosis factor-α (TNF-α) antibody infliximab (IFX) on colitis are well established. Since IFX dosing is weight-based and associated with various side effects, there is a growing interest in identifying combination therapies that can enhance its efficacy, particularly in overweight inflammatory bowel disease (IBD) patients, to maximize the anti-inflammatory effect while minimizing the required dose. Our research revealed that overweight IBD patients present decreased vitamin D levels in the intestinal epithelium alongside elevated TNF-α levels. In mice fed a high-fat diet (HFD) for four weeks, treatment with the vitamin D analog palicalcitol (PAL) reduced lipid synthesis and TNF-α production in intestinal epithelial cells (IECs). In a 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced experimental colitis model, PAL treatment mitigated TNF-α-induced damage to the intestinal epithelial barrier and reduced the activation of Th1 and Th17 cells in the lamina propria, thereby reducing colitis development in HFD-fed mice. Notably, the combination of IFX and PAL was more effective than IFX alone in treating colitis in these mice. Overall, our findings suggest that vitamin D inhibits TNF-α production by reducing lipid synthesis in IECs, thereby enhancing IFX therapy in overweight IBD patients.

Metabolic dysfunction-associated fatty liver disease (MAFLD) is a complex metabolic disorder characterized by hepatic lipid accumulation and subsequent inflammation. This condition is closely linked to metabolic syndrome and obesity, with its prevalence rising due to sedentary lifestyles and high-calorie diets. The pathogenesis of MAFLD involves multiple factors, including insulin resistance, lipotoxicity, oxidative stress, and inflammatory responses. The gut microbiota plays a crucial role in MAFLD development, with dysbiosis contributing to liver inflammation through various mechanisms, such as enhanced intestinal permeability and the translocation of bacterial products like lipopolysaccharide (LPS). Microbial metabolites, including short-chain fatty acids (SCFAs) and bile acids, influence hepatic function and immune responses, with potential implications for disease progression. Specific gut microbiome signatures have been identified in MAFLD patients, offering potential diagnostic and therapeutic targets. Moreover, gut-derived toxins, such as endotoxins, lipopolysaccharides, trimethylamine-N-oxide and bacterial metabolites, significantly influence liver damage and inflammation, highlighting the complex interplay between the gut microbiome and hepatic health. This review comprehensively examines the complex interplay between the gut microbiota and MAFLD, focusing on underlying pathogenic mechanisms, potential biomarkers, and emerging microbiome-targeted therapeutic strategies for disease management.

Brusatol (BR) is an active compounds isolated from Brucea javanica, a Chinese herbal medicine that is famous for its anti-diarrheal effect. We have previously reported that BR mitigated inflammation in murine ulcerative colitis (UC) models. However, BR's role in intestinal mucosal healing, which is recently established as central strategy for the prevention and treatment of UC, remains unknown. In this study, the ameliorative effect of BR on intestinal mucosal damage was investigated in DSS-induced UC mice. BR significantly alleviated colitis symptoms, improved intestinal barrier function by preventing loss of goblet cells and downregulation of mucins and tight junction proteins, as well as maintained proliferative and apoptotic homeostasis in the colonic epithelium of UC mice. Mechanistically, BR enhanced the level and secretion of IL-22, but inhibited IL-22BP, an inhibitory protein of IL-22, in the blood serum and intestinal tissues of UC mice, as well as in MNK3 cells which is an effective cell model for studying ILC3s. Additionally, BR elevated the expressions of receptors for IL-22 (IL-10R2 and IL-22R1), and activated its downstream STAT3 signaling pathway. Furthermore, the involvement of IL-22 was further investigated by using recombinant IL-22 (rIL-22) and IL-22 antibody (anti-IL-22). BR demonstrated comparable effects with rIL-22 on alleviating intestinal inflammation and repairing intestinal mucosal injury. Treatment with anti-IL-22 abrogated the mucosal protective effects of BR. The present findings shed novel insights into the role of BR in intestinal mucosal healing via activating IL-22/STAT3 signaling pathway in UC.

The gastrointestinal tract is a remarkable example of complex biology, with a constant dialogue between the intestinal epithelium, in close contact with the microbiota, and the immune cells that protect the gut from infection. Organoids have revolutionized our approach to modeling the intestinal cellular compartment and have opened new avenues for unraveling the mechanisms involved in intestinal homeostasis and chronic pathogenesis, such as inflammatory bowel disease. To date, few models have been established to explore the role of the colon, which is, however, the main site of inflammation in ulcerative colitis. Here, we used conditioned media produced by colon organoids from mice or humans (control patients and patients with ulcerative colitis) to investigate the relationship between macrophages and the colon epithelium. We addressed transcriptomic profiles of organoid conditioned media-stimulated bone marrow-derived macrophages and found that these cells exhibited a unique anti-inflammatory signature distinct from that of conventional in vitro IL-4/IL-13 M2-differentiated macrophages. In addition, organoid conditioned media induced a clear CD5 antigen-like-mediated immunoregulatory effect characterized by a significant reduction in lipopolysaccharide-induced inducible nitric oxide synthase expression. In line, organoid conditioned media from human colons inhibited lipopolysaccharide-dependent inflammatory cytokine expression in human monocyte-derived macrophages. Interestingly, the inflammatory marker CD68 was reduced by organoid conditioned media from control patients but not from patients with ulcerative colitis, suggesting epithelial dysfunction in patients with ulcerative colitis. Our results report new regulatory mechanisms in the colon and highlight the importance of developing new in vitro models to better characterize the relationship between the intestinal epithelium and immune mucosal cells.

Inflammatory bowel disease (IBD) is an immune-mediated gastrointestinal disorder that significantly impacts the life quality of people worldwide. Genetic factors play crucial roles in the development of IBD. Tas2rs, members of the G protein-coupled receptor (GPCR) superfamily, are known for their roles in bitter taste perception. However, Tas2rs have also been identified in the gut, where they help sense luminal contents and regulate gastrointestinal hormones. Periodontal Tas2r105 has been shown to modulate innate immunity by interacting with metabolites produced by oral bacteria. In this study, we observed increased Tas2r105 in the inflammatory colons induced by dextran sulfate sodium salt (DSS). We also noted that α-gustducin, the α-subunit of GPCRs, is present in the intestine, and that α-gustducin knockout mice exhibit aggravated colitis. Based on these findings, we hypothesize that Tas2r105 may play a role in immune regulation during IBD pathogenesis. To test this hypothesis, we used Tas2r105 knockout (KO) mice in a colitis model. Our results show that the KO mice had significantly shorter colon length, more severe colon inflammation, and greater destruction of the gut barrier compared with control mice. We also observed increased recruitment of macrophages to the lamina propria mucosa in the KO mice. Microbiological analysis revealed a significant increase in Proteobacteria and Bacteroidota, with a concomitant decrease in Firmicutes after Tas2r105 knockout. Metabolomic analysis showed a significant reduction in lysophosphatidylethanolamine (LPE) levels in the KO mice, which is known to have anti-inflammatory effects. Based on these findings, we speculate that Tas2r105 may help protect the intestine from inflammation by influencing the gut microbiota composition and LPE production.IMPORTANCEIncreased Tas2r105 was detected in the inflamed colon of mice outside the tongue. Tas2r105 deletion aggravated mice colon colitis. Tas2r105 might alleviate mice colitis by downregulating the Proteobacteria and the Bacteroidota abundance in the colon. Lysophosphatidylethanolamine (LPE) might be the key metabolite that mediated the intestinal protection of Tas2r105.