Alpha-defensin 1 is a small antimicrobial peptide that acts as the first line of defense against pathogens. It is induced following microbial cues and inflammatory signals in neutrophils and Paneth cells in the small intestine, which suggests that it plays a role in microbial homeostasis in the gut. The gut microbial products also serve as ligands for the aryl hydrocarbon receptor (AhR), an environmental sensor. In the current study, we investigated if there is any crosstalk between AhR and alpha-defensin 1. Interestingly, we found a positive correlation between AhR and alpha-defensin 1 protein levels in ileal tissues from active Crohn's' (CD) patients and epithelial cells (IECs) from multiple models of murine colitis. In vitro downregulation of AhR led to inhibition of α-defensin 1, while activation of AhR induced α-defensin 1 in IECs. AhR directly targeted the dioxin response element 3 (DRE3) region on the α-defensin 1 promoter in IECs. AhR-mediated induction of α-defensin 1 in colitis mice reversed the gut microbial dysbiosis and alleviated colitis. Our data identify a novel signaling pathway in which AhR acts as a transcription factor for α-defensin 1, leading to regulation of homeostasis between gut microbiota, intestinal mucosa, and mucosal immunity.

Free Fatty Acid Receptor 2 (FFA2), also known as GPR43, is a receptor activated by short-chain fatty acids (SCFAs) with fewer than six carbons in their aliphatic chains. This receptor is expressed in immune cells, adipose tissue, the gastrointestinal tract, and pancreatic islet cells, where it plays a crucial role in the modulation of inflammation, lipid metabolism, insulin secretion, and appetite regulation. Extensive research has been conducted to elucidate the structural attributes and physiological functions of FFA2. Furthermore, several synthetic agonists have been developed for FFA2 that can preferentially activate certain G-proteins, demonstrating potential pharmacological advantages in both in vivo and in vitro studies. Herein, we review the structure and physiological functions of FFA2 and its synthetic ligands, discussing the structural basis of FFA2's biased signaling and the potential role of biased ligands targeting this receptor in the treatment of metabolic and neurodegenerative diseases.

Bovine viral diarrhea virus (BVDV) is a globally prevalent pathogen causing severe detriment to the cattle industry. Vertical infection occurring before the development of the fetal adaptive immune response, before 125 days of gestation, results in an immunotolerant, persistently infected (PI) calf. It was hypothesized that epigenetic alterations observed in the splenic tissue of PI fetuses at gestational day 245 would persist into the postnatal period. White blood cell DNA from five PI and five control heifers at 4 months of age was subjected to reduced representation bisulfite sequencing and interpreted within the context of complete blood count and flow cytometry data herein. Analysis revealed 8367 differentially methylated sites contained within genes associated with the immune and cardiac system, as well as hematopoiesis. Differences observed in the complete blood counts of PI heifers include increased monocytes, microcytic anemia, and elevated platelets with decreased mean platelet volume. Flow cytometry revealed increased classical monocytes, B cells, and CD4+/CD8B+ and CD25+/CD127- T cells, as well as decreased γδ+, CD4+, and CD4-/CD8B- T cells. Investigation of the PI methylome provides a new perspective on the mechanisms of pathologies and provides potential biomarkers for the rapid identification of PI cattle.

Gut microbiota and their metabolites play a significant role in inflammatory bowel disease. Here, we attempted to determine the anti-inflammatory role of the probiotic Clostridium. butyricum (CB) in inflammatory bowel disease and identify the exact immune mechanism. The clinical significance of Clostridiales and CB was explored in patients with ulcerative colitis. The inflammation-suppressive role of CB was evaluated in mice with DSS-induced colitis. 16S rRNA sequencing was performed to assess changes in the gut microbiota. Altered transcription levels were detected by RNA sequencing. Flow cytometry was performed to assess the frequency of IgA responses to gut microbiota. Clostridiales and CB were depleted in ulcerative colitis. Oral gavage with CB significantly suppressed weight loss and colon shortening in the dextran sulfate sodium-induced colitis mouse model. Intestinal barrier injury was reversed and the gut microbiota was restored upon treatment with CB administration. The mucosal immune response to gut microbiota was reversed upon treatment with CB. CB conditional medium was more effective than heat-killed CB in alleviating inflammation. Mechanistically, retinol metabolism and retinoic acid levels were higher in groups treated with CB and butyrate. CB and the metabolite butyrate exerted a suppressive role on the abundance of Immunoglobulin A-coated gut microbiota by inhibiting retinoic acid synthesis. In summary, CB protects against inflammation and intestinal barrier injury by producing anti-inflammatory metabolites that can regulate the mucosal immune response to gut microbiota by increasing retinoic acid levels in the colon.

Persistent intestinal inflammation is a major contributor to various diseases, including digestive disorders, immune dysregulation, and cancer. The NF-κB signaling pathway is pivotal in the inflammatory response of intestinal cells, regulating the secretion of inflammatory factors, mediating signal transduction, and activating receptors. In colitis, NF-κB signaling and its effector molecules are excessively activated by various stimuli, leading to overexpression of inflammatory mediators and immune regulators. Colitis, an inflammation of the intestinal mucosa, underlies many intestinal diseases, with increasing incidence. Traditional treatments such as glucocorticoids and nonsteroidal antiinflammatory drugs have significant limitations and side effects. Pogostemon cablin, a traditional Chinese medicine and food, is widely used in food, spices, and pharmaceuticals. Studies have demonstrated its positive therapeutic effects on intestinal inflammation, primarily through regulation of the NF-κB signaling pathway. Moreover, P. cablin and its active components exhibit pharmacological activities such as antiapoptotic, antioxidant, and antitumor effects. This review summarizes the original research on treating intestinal mucosal inflammation via NF-κB signaling regulation using P. cablin and its active components, providing new insights for colitis treatment.

Gastrointestinal (GI) disease/dysfunction persists in people living with HIV (PLWH) receiving suppressive combination anti-retroviral therapy (ART) leading to epithelial barrier breakdown, microbial translocation and systemic inflammation that can drive non-AIDS associated comorbidities. Although epigenetic mechanisms are predicted to drive GI dysfunction, they remain unknown and unaddressed in HIV/SIV infection. The present study investigated genome-wide changes in DNA methylation, and gene expression exclusively in colon epithelial cells (CE) in response to simian immunodeficiency virus infection (SIV) and long-term low-dose delta-9-tetrahydrocannabinol (THC).

Using reduced-representation bisulfite sequencing, we characterized DNA methylation changes in colonic epithelium (CE) of uninfected controls (n=5) and SIV-infected rhesus macaques (RMs) administered vehicle (VEH/SIV; n=7) or THC (THC/SIV; n=6). Intact jejunum resection segments (~5cm) were collected from sixteen ART treated SIV-infected RMs [(VEH/SIV/ART; n=8) and (THC/SIV/ART; n=8)] to confirm protein expression data identified in the colon of ART-naïve SIV-infected RMs. Transcriptomics data was used to confirm expression of differentially methylated genes. Protein expression of differentially methylated genes and their downstream targets was assessed using Immunofluorescence followed by HALO quantification.

SIV infection in ART-naïve RMs induced marked hypomethylation throughout promoter-associated CpG islands (paCGIs) in genes related to inflammatory response (NLRP6, cGAS), cellular adhesion (PCDH17, CDH7) and proliferation (WIF1, SFRP1, TERT, and HAND2) in CEs. Moreover, low-dose THC reduced NLRP6 protein expression in CE by hypermethylating the NLRP6 paCGI and blocked polyI:C induced NLRP6 upregulation in vitro. In ART suppressed SIV-infected RMs, significant NLRP6 protein upregulation during acute infection was unaffected by long-term ART administration during chronic infection despite successful plasma and tissue viral suppression. In this group, NLRP6 protein upregulation was associated with significantly increased expression of necroptosis-driving proteins; phosphorylated-RIPK3(Ser199), phosphorylated-MLKL(Thr357/Ser358), and HMGB1. Most strikingly, adding ART to THC-treated SIV-infected RMs effectively reduced NLRP6 and necroptosis-driving protein expression to pre-infection levels.

We conclude that DNA hypomethylation-assisted NLRP6 upregulation can lead to its constitutively high expression resulting in the activation of necroptosis signaling via the RIPK3/p-MLKL pathway that can eventually drive intestinal epithelial loss/death. From a clinical standpoint, low-dose phytocannabinoids in combination with ART could safely and successfully reduce/reverse persistent GI inflammatory responses via modulating DNA methylation.

Background/Objectives: This study aims to identify genetic variants associated with early-onset inflammatory bowel disease (IBD) and to improve diagnostic and therapeutic approaches. In selected monogenic IBD cases, treatment included colchicine, interleukin-1 inhibitors, and hematopoietic stem cell transplantation. Methods: This study included patients with early-onset IBD, defined as IBD diagnosed before the age of 10, who were under follow-up at the Department of Pediatric Gastroenterology, Hacettepe University, and agreed to participate between December 2018 and April 2021. Whole-exome sequencing (WES) was performed prospectively in patients without a prior diagnosis of monogenic disease, while clinical and laboratory data were reviewed retrospectively. Identified variants were evaluated for pathogenicity using standard bioinformatics tools. Results: A total of 47 patients were enrolled, including 33 boys (70.2%) and 14 girls (29.8%). The median age at symptom onset was 36 months (IQR: 10-72), and the median age at diagnosis was 3.7 years (IQR: 1.5-7.6). Crohn's disease was diagnosed in 53.2% (n = 25), ulcerative colitis in 38.3% (n = 18), and unclassified IBD in 8.5% (n = 4). Monogenic IBD was identified in 36.2% (n = 17) of patients, including nine with Familial Mediterranean Fever and others with glycogen storage disease type 1b (n = 2), XIAP deficiency, chronic granulomatous disease, DOCK8 deficiency, IL10 receptor alpha defect, LRBA deficiency, and NFKB2 deficiency (n = 1 each). A novel SLC29A3 gene variant (c.480_481delTGinsCA, p.V161I) (transcript ID: ENST00000479577.2) was identified in 76.6% (n = 36) of patients. Conclusions: This study underscores the importance of genetic variants in early-onset IBD, particularly MEFV and the novel NFKB2. The frequent detection of the SLC29A3 variant may suggest its potential involvement in the pathogenesis of the disease.

Transplant conditioning regimens disrupt the intestinal barriers, leading to delayed vascularity and impeded the regenerative process. However, our understanding of the specific mechanisms underlying the use of cellular therapy to accelerate revascularization for intestinal repair is currently limited. To address this knowledge gap, we conducted a longitudinal study to investigate the effects and potential benefits of endothelial progenitor cells (EPCs) infusion on the restoration of intestinal homeostasis in a murine model of bone marrow transplantation (BMT). Our results revealed that the EPCs infusion improved the structure status of the intestine, as demonstrated by a well-preserved crypt structure, longer villi, reduced infiltration of inflammatory cells, and increased expression of ZO-1 and MECA-32. Additionally, EPCs infusion resulted in significantly lower proportions of Tc1 and Th1 cells on day 10, as well as a delayed peak in Tc17 cells on day 20, with no differences compared with BMT group thereafter. Moreover, EPCs infusion enhanced the expression of immune regulatory molecules IL-10, IL-17, IL-18, and NLRP6 on day 15. Mechanistically, EPCs infusion up-regulated phos-ERK1/2 and down-regulated phos-p38 MAPK on day 5 (early transplantation). The richness of intestinal microbiota changed significantly, and Erysipelotrichaceae was identified as the main index to differentiate the BMT and EPC treatments, exhibiting a significant negative correlation with IL-10 and IL-18 in the EPC group. Taken together, this study highlights the protective role of EPCs in post-transplantation intestinal damage, and identifies critical immune cells, signaling pathways, and selectively enriched intestinal microbes contributing to the beneficial effects of EPCs during intestinal repair.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by impairments in social communication and behavior, frequently accompanied by restricted and repetitive patterns of interests or activities. The gut microbiota has been implicated in the etiology of ASD due to its impact on the bidirectional communication pathway known as the gut-brain axis. However, the precise involvement of the gut microbiota in the causation of ASD is unclear. This study critically examines recent evidence to rationalize a probable mechanism in which gut microbiota symbiosis can induce neuroinflammation through intermediator cytokines and metabolites. To develop ASD, loss of the integrity of the intestinal barrier, activation of microglia, and dysregulation of neurotransmitters are caused by neural inflammatory factors. It has emphasized the potential role of neuroinflammatory intermediates linked to gut microbiota alterations in individuals with ASD. Specifically, cytokines like brain-derived neurotrophic factor, calprotectin, eotaxin, and some metabolites and microRNAs have been considered etiological biomarkers. We have also overviewed how probiotic trials may be used as a therapeutic strategy in ASD to reestablish a healthy balance in the gut microbiota. Evidence indicates neuroinflammation induced by dysregulated gut microbiota in ASD, yet there is little clarity based on analysis of the circulating immune profile. It deems the repair of microbiota load would lower inflammatory chaos in the GI tract, correct neuroinflammatory mediators, and modulate the neurotransmitters to attenuate autism. The interaction between the gut and the brain, along with alterations in microbiota and neuroinflammatory biomarkers, serves as a foundational background for understanding the etiology, diagnosis, prognosis, and treatment of autism spectrum disorder.

Oral delivery of probiotics has shown promising effects in modulating the gut microbiota and treating ulcerative colitis (UC). However, the therapeutic efficacy is restricted by gastrointestinal assaults, poor mucosal adhesion, and single therapeutic modality. Here, we developed acid-resistant, gut-environment-responsive composite microparticles based on microfluidic electrospray for the oral codelivery of probiotic [Lactobacillus acidophilus (LA)] biofilm and postbiotics (indole-3-propionic acid). Montmorillonite was selected for supporting biofilm formation due to its cation-exchange capability and clearly defined biosafety. The montmorillonite-LA biofilm was effectively protected by the microparticles and markedly improved the intestinal retention. Upon oral administration, the composite microparticles notably alleviated colitis in mice, including reducing the inflammatory response, improving intestinal barrier function, and modulating the gut microbiota. Consequently, the composite microparticles show high potential for enhancing probiotic delivery efficacy and present a promising strategy for UC treatment.

Ubiquitin ligases play pivotal roles in the regulation of NLR family pyrin domain containing 3 (NLRP3) inflammasome activation, a critical process in innate immunity and inflammatory responses. This review explores the intricate mechanisms by which various E3 ubiquitin ligases exert both positive and negative influences on NLRP3 inflammasome activity through diverse post-translational modifications. Negative regulation of NLRP3 inflammasome assembly is mediated by several E3 ligases, including F-box and leucine-rich repeat protein 2 (FBXL2), tripartite motif-containing protein 31 (TRIM31), and Casitas B-lineage lymphoma b (Cbl-b), which induce K48-linked ubiquitination of NLRP3, targeting it for proteasomal degradation. Membrane-associated RING-CH 7 (MARCH7) similarly promotes K48-linked ubiquitination leading to autophagic degradation, while RING finger protein (RNF125) induces K63-linked ubiquitination to modulate NLRP3 function. Ariadne homolog 2 (ARIH2) targets the nucleotide-binding domain (NBD) domain of NLRP3, inhibiting its activation, and tripartite motif-containing protein (TRIM65) employs dual K48 and K63-linked ubiquitination to suppress inflammasome assembly. Conversely, Pellino2 exemplifies a positive regulator, promoting NLRP3 inflammasome activation through K63-linked ubiquitination. Additionally, ubiquitin ligases influence other components critical for inflammasome function. TNF receptor-associated factor 3 (TRAF3) mediates K63 polyubiquitination of apoptosis-associated speck-like protein containing a CARD (ASC), facilitating its degradation, while E3 ligases regulate caspase-1 activation and DEAH-box helicase 33 (DHX33)-NLRP3 complex formation through specific ubiquitination events. Beyond direct inflammasome regulation, ubiquitin ligases impact broader innate immune signaling pathways, modulating pattern-recognition receptor responses and dendritic cell maturation. Furthermore, they intricately control NOD1/NOD2 signaling through K63-linked polyubiquitination of receptor-interacting protein 2 (RIP2), crucial for nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and mitogen-activated protein kinase (MAPK) activation. Furthermore, we explore how various pathogens, including bacteria, viruses, and parasites, have evolved sophisticated strategies to hijack the host ubiquitination machinery, manipulating NLRP3 inflammasome activation to evade immune responses. This comprehensive analysis provides insights into the molecular mechanisms underlying inflammasome regulation and their implications for inflammatory diseases, offering potential avenues for therapeutic interventions targeting the NLRP3 inflammasome. In conclusion, ubiquitin ligases emerge as key regulators of NLRP3 inflammasome activation, exhibiting a complex array of functions that finely tune immune responses. Understanding these regulatory mechanisms not only sheds light on fundamental aspects of inflammation but also offers potential therapeutic avenues for inflammatory disorders and infectious diseases.

Intestinal protists are detected by the host innate immune system through mechanisms that remain poorly understood. Here, we demonstrate that Tritrichomonas protozoa induce thickening of the colonic mucus in an NLRP6-, ASC-, and caspase-11-dependent manner, consistent with the activation of sentinel goblet cells. Mucus growth is recapitulated with cecal extracts from Tritrichomonas-infected mice but not purified protozoa, suggesting that NLRP6 may detect infection-induced microbial dysbiosis. In agreement, Tritrichomonas infection causes a shift in the microbiota with the expansion of Bacteroides and Prevotella, and untargeted metabolomics reveals a dramatic increase in several classes of metabolites, including sphingolipids. Finally, using a combination of gnotobiotic mice and ex vivo mucus analysis, we demonstrate that wild-type, but not sphingolipid-deficient, B. thetaiotaomicron is sufficient to induce NLRP6-dependent sentinel goblet cell function, with the greatest effect observed in female mice. Thus, we propose that NLRP6 is a sensor of intestinal protozoa infection through monitoring microbial sphingolipids.

Inflammatory bowel disease (IBD) is a chronic, relapsing, and remitting disease characterized by chronic inflammation in the gastrointestinal tract. The exact etiology and pathogenesis of IBD remain elusive. Although ELF-1 has been known to be highly expressed in epithelial cells for past twenty years, little is known about its function in epithelial cells and epithelial-related IBD. Here, we demonstrated that ELF-1 deficiency in mouse lead to exacerbated DSS-induced colitis, marked by inflammation dominated by neutrophil infiltration and activation of IL-17 signaling pathways in various immune cells, including Th17, ILC3, γδT and NKT cells. Bone marrow transfer experiments confirmed ELF-1 deficiency in non-hematopoietic cells intrinsically worsened DSS-induced colitis. On one hand, ELF-1 deficiency enhanced the production of pro-inflammatory chemokines in colonic epithelial cells, leading to extensive infiltration of neutrophils and other immune cells into the colonic mucosal tissue. On the other hand, ELF-1 directly regulated the expression of the Rack1 gene in colonic epithelial tissue, which has been proved to play critical roles in maintaining intestinal homeostasis. Altogether, ELF-1 plays a protective role in colitis by maintaining intestinal epithelium homeostasis.

The gut microbiota, the complex community of microorganisms that inhabit the gastrointestinal tract, has emerged as a key player in the pathogenesis of neurodegenerative disorders, including Alzheimer's disease (AD). AD is characterized by progressive cognitive decline and neuronal loss, associated with the accumulation of amyloid-β plaques, neurofibrillary tangles, and neuroinflammation in the brain. Increasing evidence suggests that alterations in the composition and function of the gut microbiota, known as dysbiosis, may contribute to the development and progression of AD by modulating neuroinflammation, a chronic and maladaptive immune response in the central nervous system. This review aims to comprehensively analyze the current role of the gut microbiota in regulating neuroinflammation and glial cell function in AD. Its objective is to deepen our understanding of the pathogenesis of AD and to discuss the potential advantages and challenges of using gut microbiota modulation as a novel approach for the diagnosis, treatment, and prevention of AD.

As one part of the innate immune response to external stimuli, chronic inflammation increases the risk of various cancers, and tumor-promoting inflammation is considered one of the enabling characteristics of cancer development. Recently, there has been growing evidence on the role of anti-inflammation therapy in cancer prevention and treatment. And researchers have already achieved several noteworthy outcomes. In the review, we explored the underlying mechanisms by which inflammation affects the occurrence and development of cancer. The pro- or anti-tumor effects of these inflammatory factors such as interleukin, interferon, chemokine, inflammasome, and extracellular matrix are discussed. Since FDA-approved anti-inflammation drugs like aspirin show obvious anti-tumor effects, these drugs have unique advantages due to their relatively fewer side effects with long-term use compared to chemotherapy drugs. The characteristics make them promising candidates for cancer chemoprevention. Overall, this review discusses the role of these inflammatory molecules in carcinogenesis of cancer and new inflammation molecules-directed therapeutic opportunities, ranging from cytokine inhibitors/agonists, inflammasome inhibitors, some inhibitors that have already been or are expected to be applied in clinical practice, as well as recent discoveries of the anti-tumor effect of non-steroidal anti-inflammatory drugs and steroidal anti-inflammatory drugs. The advantages and disadvantages of their application in cancer chemoprevention are also discussed.

Alzheimer's disease (AD), a prevalent neurodegenerative disease, is primarily characterized by progressive neuron loss and memory impairment. NOD-like receptors (NLRs) are crucial for immune regulation and maintaining cellular homeostasis. Recently, NLRs have been identified as important contributors to neuroinflammation, thus presenting a potential approach for reducing inflammation and slowing AD progression.

We use quantitative RT-PCR to detect levels of NLR family members in AD mouse model. Additionally, we use immunofluorescence to detect NLRP3 expressions in microglia surrounding Aβ plaques in AD mouse model and human AD patients.

In this study, we examined the expression of NLR family members in the human AD database, and found increased levels of CIITA, NOD1, NLRC5, NLRP1, NLRP3, NLRP7, NLRP10, NLRP12, and NLRP13 in hippocampus tissue in patients with AD, along with increased levels of NOD1, NLRC5, NLRX1, NLRP3, and NLRP7 levels in frontal cortex tissue. Furthermore, through detecting their levels in AD mouse model, we found that NLRP3 levels were significantly increased. Additionally, we found that NLRP3 expressions were mainly elevated in microglia surrounding Aβ plaques in AD mouse model and human AD patients.

These findings highlight the potential important role of NLRP3 in AD pathology, offering new therapeutic targets and interventions.

Oil supplements have various benefits for metabolism, particularly Sacha inchi oil (SI), which is rich in polyunsaturated fatty acids (PUFAs) such as ω-3 and fat-soluble vitamins. However, the impacts of oil supplements on gut health remain unclear. The aim of this study was to compare the effects of an SI supplement with those of lard oil (LO), known for its high saturated fatty acid content, and a normal diet on gut health in male Sprague Dawley rats for 12 consecutive weeks. Fecal DNA was used to assess gut microbiota diversity and species abundance, diversity, and function prediction. Colon tissue from each rat was examined for colon crypt depth and histology. Rats administered the LO supplement exhibited higher dysbiosis than those administered the SI supplement, with the LO supplement influencing the relative abundance of various bacteria at the genus level. A KEGG analysis was conducted to examine the effects on metabolic pathways, revealing that the SI supplement promoted carbohydrate metabolism while reducing immune system activity. In contrast, the LO supplement increased replication, repair, and translation activities. A histological analysis of the colon tissues showed no significant alterations in crypt depth or lesions in all groups, indicating that neither supplement induced adverse structural changes in the gut. The results of this study suggest that SI supplementation modulates the gut microbiota, thereby enhancing gut health and metabolic function.

G protein-coupled sphingosine-1-phosphate receptor 1 (S1PR1), a drug target for inflammatory bowel disease (IBD), enables immune cells to egress from lymph nodes, but the treatment increases the risk of immunosuppression. The functional signaling pathway triggered by S1PR1 activation in endothelial cells and its therapeutic application remains unclear. Here, we showed that S1PR1 is highly expressed in endothelial cells of IBD patients and positively correlated with endothelial markers. Gi-biased agonist-SAR247799 activated S1PR1 and reversed pathology in male mouse and organoid IBD models by protecting the integrity of the endothelial barrier without affecting immune cell egress. Cryo-electron microscopy structure of S1PR1-Gi signaling complex bound to SAR247799 with a resolution of 3.47 Å revealed the recognition mode for the biased ligand. With the efficacy of SAR247799 in treating other endothelial dysfunction-associated inflammatory diseases, our study offers mechanistic insights into the Gi-biased S1PR1 agonist and represents a strategy for endothelial dysfunction-associated disease treatment.

Endothelial injury destroys endothelial barrier integrity, triggering organ dysfunction and ultimately resulting in sepsis-related death. Considerable attention has been focused on identifying effective targets for inhibiting damage to endothelial cells to treat endotoxemia-induced septic shock. Global gasdermin D (Gsdmd) deletion reportedly prevents death caused by endotoxemia. However, the role of endothelial GSDMD in endothelial injury and lethality in lipopolysaccharide-induced (LPS-induced) endotoxemia and the underlying regulatory mechanisms are unknown. Here, we show that LPS increases endothelial GSDMD level in aortas and lung microvessels. We demonstrated that endothelial Gsdmd deficiency, but not myeloid cell Gsdmd deletion, protects against endothelial injury and death in mice with endotoxemia or sepsis. In vivo experiments suggested that hepatocyte GSDMD mediated the release of high-mobility group box 1, which subsequently binds to the receptor for advanced glycation end products in endothelial cells to cause systemic vascular injury, ultimately resulting in acute lung injury and lethality in shock driven by endotoxemia or sepsis. Additionally, inhibiting endothelial GSDMD activation via a polypeptide inhibitor alleviated endothelial damage and improved survival in a mouse model of endotoxemia or sepsis. These data suggest that endothelial GSDMD is a viable pharmaceutical target for treating endotoxemia and endotoxemia-induced sepsis.

Mucosa-associated invariant T (MAIT) cells are a large population of unconventional T cells widely distributed in the human gastrointestinal tract. Their homing to the gut is central to maintaining mucosal homeostasis and immunity. This review discusses the potential mechanisms that guide MAIT cells to the intestinal mucosa during homeostasis and inflammation, emphasizing the roles of chemokines, chemokine receptors, and tissue adhesion molecules. The potential influence of the gut microbiota on MAIT cell homing to different regions of the human gut is also discussed. Last, we introduce how organoid technology offers a potentially valuable approach to advance our understanding of MAIT cell tissue homing by providing a more physiologically relevant model that mimics the human gut tissue. These models may enable a detailed investigation of the gut-specific homing mechanisms of MAIT cells. By understanding the regulation of MAIT cell homing to the human gut, potential avenues for therapeutic interventions targeting gut inflammatory conditions such as inflammatory bowel diseases (IBD) may emerge.

Low molecular weight galactomannan (LMGM), a soluble dietary fibre derived from guar gum, is recognized for its prebiotic functions, including promoting the growth of beneficial intestinal bacteria and the production of short-chain fatty acids, but the mechanism of alleviating diarrhea is not fully understood. This study established an acute diarrhea mouse model using senna leaf decoction and evaluated the therapeutic effects of LMGM by monitoring diarrhea scores, loose stool prevalence, intestinal tissue pathology and gene expression, and gut microbiota composition and metabolisms. The results indicated that LMGM significantly reduced diarrhea scores and loose stool prevalence within two hours post-treatment. Hematoxylin and eosin staining and quantitative real-time polymerase chain reaction analysis revealed that LMGM improved intestinal epithelial structure and up-regulated the expression of zonula occludens 1, occludin, mucin 2, aquaporin 3, and aquaporin 4 in ileum, jejunum, and colon tissues. Moreover, LMGM increased the abundance of beneficial bacteria such as Lactobacillaceae and Lachnospiraceae, and decreased Prevotellaceae in the cecum. Furthermore, LMGM promoted short-chain fatty acid production and reduced ammonia nitrogen and skatole concentrations in the intestinal content. The study suggests that LMGM could serve as a functional prebiotic for diarrhea alleviation, potentially by enhancing the intestinal barrier, modulating water transportation, and regulating the microbiota composition.

Infections by enteric virus and intestinal inflammation are recognized as a leading cause of deadly gastroenteritis, and NLRP6 and NLRP9b signaling control these infection and inflammation. However, the regulatory mechanisms of the NLRP6 and NLRP9b signaling in enteric viral infection remain unexplored. In this study, we found that the E3 ligase TRIM29 suppressed type III interferon (IFN-λ) and interleukin-18 (IL-18) production by intestinal epithelial cells (IECs) when exposed to polyinosinic:polycytidylic acid (poly I:C) and enteric RNA viruses. Knockout of TRIM29 in IECs was efficient to restrict intestinal inflammation triggered by the enteric RNA viruses, rotavirus in suckling mice, and the encephalomyocarditis virus (EMCV) in adults. This attenuation in inflammation was attributed to the increased production of IFN-λ and IL-18 in the IECs and more recruitment of intraepithelial protective Ly6A+CCR9+CD4+ T cells in small intestines from TRIM29-deficient mice. Mechanistically, TRIM29 promoted K48-linked ubiquitination, leading to the degradation of NLRP6 and NLRP9b, resulting in decreased IFN-λ and IL-18 secretion by IECs. Our findings reveal that enteric viruses utilize TRIM29 to inhibit IFN-λ and inflammasome activation in IECs, thereby facilitating viral-induced intestinal inflammation. This indicates that targeting TRIM29 could offer a promising therapeutic strategy for alleviating gut diseases.

The conversion of primary bile acids to secondary bile acids by the gut microbiota has been implicated in colonic inflammation. This study investigated the role of gut microbiota related bile acid metabolism in colonic inflammation in both patients with inflammatory bowel disease (IBD) and a murine model of dextran sulfate sodium (DSS)-induced colitis.

Bile acids in fecal samples from patients with IBD and DSS-induced colitis mice, with and without antibiotic treatment, were analyzed using ultraperformance liquid chromatography-mass spectrometry (UPLC-MS). The composition of the microbiota in fecal samples from IBD patients and DSS-colitis mice was characterized via Illumina MiSeq sequencing of the bacterial 16S rRNA gene V3-V4 region. Metagenomic profiling further identified metabolism-related gene signatures in stool samples from DSS-colitis mice. Histological analysis, quantitative PCR (qPCR) and Western Blotting were conducted on colonic samples from DSS-induced colitis mice to assess colonic inflammation, mucosal barrier integrity, and associated signaling pathways. The multivariate analysis of bile acids was conducted using Soft Independent Modelling of Class Analogy (SIMCA, Umetrics, Sweden). The relation between the relative abundance of specific phyla/genera and bile acid concentration was assess through Spearman's correlation analyses. Finally, lithocholic acid (LCA), the key bile acid, was administered via gavage to evaluate its effect on colonic inflammation and mucosal barrier integrity.

In patients with IBD, the composition of colonic bile acids and gut microbiota was altered. Moreover, changes in the gut microbiota further modulate the composition of bile acids in the intestine. As the gut microbiota continues to shift, the bile acid profile undergoes additional alterations. The aforementioned alterations were also observed in mice with DSS-induced colitis. The study revealed a correlation between dysbiosis of the gut microbiota and modifications in the profile of colonic bile acids, notably LCA observed in both patients with IBD and mice with DSS-induced colitis. Through multivariate analysis, LCA was identified as the key bile acid that significantly affects colonic inflammation and the integrity of mucosal barrier. Subsequent experiments confirmed that LCA supplementation effectively mitigated the inhibitory effects of gut microbiota on colitis progression in mice, primarily through the activation of the sphingosine-1-phosphate receptor 2 (S1PR2)/NF-κB p65 signaling pathway. Analysis of the microbiome and metagenomic data revealed changes in the gut microbiota, notably an increased abundance of an unclassified genus within the family Prevotellaceae in DSS-induced colitis mice. Furthermore, a positive correlation was observed between the relative abundance of Prevotellaceae and bile acid biosynthesis pathways, as well as colonic LCA level.

These findings suggest that LCA and its positively correlated gut bacteria, Prevotellaceae, are closely associated with intestinal inflammation. Targeting colonic inflammation may involve inhibiting LCA and members of the Prevotellaceae family as potential therapeutic strategies.

The role of gut microbiota in inflammatory disease development and progression has been recognized more recently. Inflammasome-mediated pyroptosis in involved in these diseases. This complex relationship between gut microbiota and inflammasome-mediated pyroptosis provides an important field of research. Bibliometric analysis provides a comprehensive understanding of this relationship, offering valuable insights into emerging research trends.

Leveraging data spanning from 2014 to 2023 sourced from the Web of Science Core Collection, our analysis was conducted using advanced tools such as SCImago Graphica, VOSviewer, and CiteSpace software. Visualizations were created using GraphPad Prism software. We explored the nuanced aspects of research hotspots, collaborative networks, and developing trends in this field.

A global bibliometric analysis identified 520 relevant studies spanning 41 countries and 887 institutions. Over the past decade, publication trends have shown consistent growth, with China and the United States leading the research output. Southern Medical University and Nanjing Medical University in China emerged as leading institutions in this filed. Prominent contributors include Jia Sun, Yuan Zhang, Wei Chen, Jing Wang, and Hongtao Liu from China, alongside Eicke Latz from Germany. High-impact journals such as Frontiers in Immunology and Nature Communications have been pivotal in disseminating research in this domain. Keyword analysis highlighted a primary focus on gut microbiota, NLRP3 inflammasome, pyroptosis pathways, and inflammatory diseases, themes that persist in recent studies. Furthermore, burst keyword analysis identified "butyrate" as the sole term currently experiencing a marked increase in research interest.

Research has been deeply focused on the gut microbiota and inflammasome triggered pyroptosis in years. Over the past decade, the exploration of how gut microbiota and NLRP3 or NLRP6 inflammasome-mediated pyroptosis has been an area of interest. Future investigations in this filed may primarily revolve around understanding the correlation between butyrate and NLRP3 inflammasome induced pyroptosis in relation to conditions. However, an in-depth analysis, through studies is crucial to uncover and elucidate the complex mechanisms linking these elements.

The gut microbiota, a dynamic ecosystem of trillions of microorganisms, produces secondary metabolites that profoundly influence host health. Recent research has highlighted the significant role of these metabolites, particularly short-chain fatty acids, indoles, and bile acids, in modulating immune responses, impacting epigenetic mechanisms, and contributing to disease processes. In gastrointestinal (GI) cancers such as colorectal, liver, and gastric cancer, microbial metabolites can drive tumorigenesis by promoting inflammation, DNA damage, and immune evasion. Conversely, these same metabolites hold therapeutic promise, potentially enhancing responses to chemotherapy and immunotherapy and even directly suppressing tumor growth. In addition, gut microbial metabolites play crucial roles in infectious disease susceptibility and resilience, mediating immune pathways that impact pathogen resistance. By consolidating recent insights into the gut microbiota's role in shaping disease and health, this review underscores the therapeutic potential of targeting microbiome-derived metabolites for treating GI cancers and infectious diseases and calls for further research into microbiome-based interventions.

Inflammasomes are multi-protein complexes that assemble within the cytoplasm of mammalian cells in response to pathogen-associated molecular patterns (PAMPs) or damage-associated molecular patterns (DAMPs), driving the secretion of the pro-inflammatory cytokines IL-1β and IL-18, and pyroptosis. The best-characterized inflammasome complexes are the NLRP3, NAIP-NLRC4, NLRP1, AIM2, and Pyrin canonical caspase-1-containing inflammasomes, and the caspase-11 non-canonical inflammasome. Newer inflammasome sensor proteins have been identified, including NLRP6, NLRP7, NLRP9, NLRP10, NLRP11, NLRP12, CARD8, and MxA. These inflammasome sensors can sense PAMPs from bacteria, viruses and protozoa, or DAMPs in the form of mitochondrial damage, ROS, stress and heme. The mechanisms of action, physiological relevance, consequences in human diseases, and avenues for therapeutic intervention for these novel inflammasomes are beginning to be realized. Here, we discuss these emerging inflammasome complexes and their putative activation mechanisms, molecular and signaling pathways, and physiological roles in health and disease.

Inflammation drives pathology in many human diseases for which there are no disease-modifying drugs. Inflammasomes are signalling platforms that can induce pathological inflammation and tissue damage, having potential as an exciting new class of drug targets. Small-molecule inhibitors of the NLRP3 inflammasome that are now in clinical trials have demonstrated proof of concept that inflammasomes are druggable, and so drug development programmes are now focusing on other key inflammasome molecules. In this Review, we describe the potential of inflammasome components as candidate drug targets and the novel inflammasome inhibitors that are being developed. We discuss how the signalling biology of inflammasomes offers mechanistic insights for therapeutic targeting. We also discuss the major scientific and technical challenges associated with drugging these molecules during preclinical development and clinical trials.

Exercise can effectively prevent and treat depression and anxiety, with gut microbiota playing a crucial role in this process. Studies have shown that exercise can influence the diversity and composition of gut microbiota, which in turn affects depression through immune, endocrine, and neural pathways in the gut-brain axis. The effectiveness of exercise varies based on its type, intensity, and duration, largely due to the different changes in gut microbiota. This article summarizes the possible mechanisms by which exercise affects gut microbiota and how gut microbiota influences depression. Additionally, we reviewed literature on the effects of exercise on depression at different intensities, types, and durations to provide a reference for future exercise-based therapies for depression.

Macrophages, neutrophils, and epithelial cells are pivotal components of the host's immune response against bacterial infections. These cells employ inflammasomes to detect various microbial stimuli during infection, triggering an inflammatory response aimed at eradicating the pathogens. Among these inflammatory responses, pyroptosis, a lytic form of cell death, plays a crucial role in eliminating replicating bacteria and recruiting immune cells to combat the invading pathogen. The immunological function of pyroptosis varies across macrophages, neutrophils, and epithelial cells, aligning with their specific roles within the innate immune system. This review centers on elucidating the role of pyroptosis in resisting gram-negative bacterial infections, with a particular focus on the mechanisms at play in macrophages, neutrophils, and intestinal epithelial cells. Additionally, we underscore the cell type-specific roles of pyroptosis in vivo in these contexts during defense.

Bioactive lipids have a multifaceted role in health and disease and are recognized to play an important part in gut immunity and disease conditions such as inflammatory bowel disease and colon cancer. Advancements in lipidomics, enabled by mass spectrometry and chromatographic techniques, have enhanced our understanding of lipid diversity and functionality. Bioactive lipids, including short-chain fatty acids, saturated fatty acids, omega-3 fatty acids, and sphingolipids, exhibit diverse effects on inflammation and immune regulation. Short-chain fatty acids like butyrate demonstrate anti-inflammatory properties, enhancing regulatory T cell function, gut barrier integrity, and epigenetic regulation, making them promising therapeutic targets for inflammatory bowel disease and colon cancer. Conversely, saturated fatty acids promote inflammation by disrupting gut homeostasis, triggering oxidative stress, and impairing immune regulation. Omega-3 lipids counteract these effects, reducing inflammation and supporting immune balance. Sphingolipids exhibit complex roles, modulating immune cell trafficking and inflammation. They can exert protective effects or exacerbate colitis depending on their source and context. Additionally, eicosanoids can also prevent pathology through prostaglandin defense against damage to epithelial barriers. This review underscores the importance of dietary lipids in shaping gut health and immunity and also highlights the potential use of lipids as therapeutic strategies for managing inflammatory conditions and cancer.

Hepatocellular carcinoma is among the most frequent forms of primary liver cancer and develops within a context of chronic inflammation, frequently associated with a multitude of risk factors, including viral infections, metabolic dysfunction-associated fatty liver disease, metabolic dysfunction-associated steatohepatitis and liver fibrosis. The tumor microenvironment is crucial for the progression of HCC, as immune cells, tumor-associated fibroblasts and hepatic stellate cells interact to promote chronic inflammation and tumor spread. Inflammasomes, the multiprotein complexes that launch the innate immune response, emerge as important mediators in the pathogenesis of HCC. Among others, the inflammasome Nucleotide-binding oligomerization domain, Leucine rich Repeat (NLR) and Pyrin (NLRP) 3 (NLRP3), and absent in melanoma 2 (AIM2), exhibit a dual role in HCC background. It has been reported that they can exert oncosuppressive functions by triggering the inflammatory death of cancer cells. Vice versa, chronic activation contributes to the development of a pro-tumorigenic environment, thus supporting tumor growth. In addition, other inflammasomes such as Nucleotide-binding oligomerization domain, Leucine rich Repeat (NLR) and Pyrin (NLRP) 6 and 12 (NLRP6 and NLRP12, respectively) regulate HCC onset and progression, although more experimental evidence is required. This review focuses on the molecular mechanisms underpinning the inflammasome's contribution to the onset, progression and spread of HCC. Moreover, we will explore the potential therapeutic approaches currently under investigation, which aim to improve the efficacy and reduce the side effects of the treatments currently available. Targeting inflammasomes may be a promising therapeutic strategy for the treatment of HCC, offering new opportunities to improve patient prognosis.

Inflammatory bowel diseases are chronic disabling conditions with a complex and multifactorial etiology, still incompletely understood. OCTN1, an organic cation transporter, could have a role in modulating the inflammatory response, and some genetic polymorphisms of this molecule have been associated with increased risk of inflammatory bowel diseases. Until now, limited information exists on its potential in predicting/modulating patient's response to therapies. The aim of this study was to evaluate the role of OCTN1 in modifying gut microbiota and mucosal immunity in response to infliximab therapy in murine colitis.

A dextran sodium sulphate model of colitis was used to assess the clinical efficacy of infliximab administered intravenously in ocnt1 gene knockout mice and their C57BL/6 controls. Stool, colon, and mesenteric lymph node samples were collected to evaluate differences in gut microbiota composition, histology, and T cell populations, respectively.

Octn1 -/- influences the microbiota profile and is associated with a worse dysbiosis in mice with colitis. Infliximab treatment attenuates colitis-associated dysbiosis, with an increase of bacterial richness and evenness in both strains. In comparison with wild type, octn1-/- mice have milder disease and a higher baseline percentage of Treg, Tmemory, Th2 and Th17 cells.

Our data support the murine model to study OCTN1 genetic contribution to inflammatory bowel diseases. This could be the first step towards the recognition of this membrane transporter as a biomarker in inflammatory conditions and a predictor of response to therapies.

The nucleotide oligomerization domain (NOD)-like receptors containing pyrin (NLRP) family of cytosolic pattern-recognition receptors play an integral role in host defense following exposure to a diverse set of pathogenic and sterile threats. The canonical event following ligand recognition is the formation of a heterooligomeric signaling complex termed the inflammasome that produces pro-inflammatory cytokines. Dysregulation of this process is associated with many autoimmune, cardiovascular, metabolic, and neurodegenerative diseases. Despite the range of activating stimuli which affect varied cell types, recent literature makes evident that reactive oxygen species (ROS) are integral to the initiation and propagation of inflammasome signaling. Notably, ROS production and inflammasome activation act in a positive feedback loop to promote this potent immune response. While NLRP3 is by far the most extensively studied NLRP, there is also sufficient literature to make these conclusions for other NLRPs family members. In all cases, a knowledge gap exists regarding the molecular targets and effects of ROS. Future research to define these targets and to parse the order and timing of ROS-mediated NLRP activation will provide meaningful insights into inflammasome biology. This will create novel therapeutic opportunities for the numerous illnesses that are impacted by inflammasome activity.

Cervicitis is a common gynecological inflammatory disease. The Chinese herbal prescription Kang-Gong-Yan (KGY) is clinically effective against cervicitis; however, the chemical constituents and therapeutic mechanism of KGY remain elusive.

To analyze the chemical constituents of KGY and explore the potential mechanism of KGY in treating cervicitis.

UHPLC-Q-Exactive Plus Orbitrap MS was used to identify the active compounds of KGY; Sprague-Dawley (SD) female rats were randomly divided into the control, model, and KGY groups. Phenol mucilage (25%) was slowly injected into the vagina and cervix of the rats to establish the cervicitis model. Then, rats in the KGY groups (low dose: 1 g/kg/d; medium dose: 5 g/kg/d; high dose: 10 g/kg/d) were continuously gavaged KGY for one week. HE staining was used to observe the cervical tissues of rats; ELISA was used to detect inflammatory factors in plasma; non-targeted metabolomics was used to analyze metabolites; 16S rRNA sequencing was used to analyze intestinal microorganisms.

KGY exerted anti-cervicitis effects and decreased the levels of IL-6, IL-1β, and TNF-α. The mechanism of KGY in treating cervicitis is mainly associated with betaine, amino acid, pyrimidine, and phospholipid metabolism by regulating fifteen metabolites. Moreover, KGY reversed cervicitis-induced gut dysbiosis by mediating five bacteria.

The Chinese herbal prescription KGY may alleviate cervicitis by modulating metabolites and gut microbiota disorders. These findings provide a scientific basis for the clinical application of KGY and a new strategy for treating cervicitis in Chinese medicine.

Oral administration of homogalacturonan (HG) has shown significant potential in anti-colitis activity, yet the therapeutic efficacy of naturally sourced HG still requires enhancement. Herein, HG from the fruits of Ficus pumila L. was modified by chemical methods and the intervention effect of modified HG with different degrees of methyl-esterification (DM) and acetylation (DA) on dextran sulfate sodium-induced colitis in mice was explored. Our results indicated that low-DM HG (DM3 and DM25) primarily mitigated colitis by reducing inflammation (TNF-α, IL-1β, IL-17, and IL-6), while high-DM HG (DM54 and DM94) primarily repaired the intestinal barrier. These effects may be attributed to the differential regulation of gut microbiota by HG with varying DM, such as Lachnospiraceae_NK4A136_group, Lactobacillus, Mucispirillum, Escherichia-Shigella, Bifidobacterium, and Bacteroides. Increased DA reduced the solubility of HG, showing limited anti-inflammatory response but unique advantages in intestinal barrier repair and microbiome regulation (Bifidobacterium, Candidatus_Saccharimonas, Lachnospiraceae_NK4A136_group, Mucispirillum, and Escherichia-Shigella). Furthermore, various structural parameters and substitution degrees showed no significant impact on HG's regulation of oxidative stress reactions. This study emphasized the importance of substituent effect in determining HG's functional role, providing a robust foundation for the design and development of functional polysaccharides for the prevention of intestinal inflammation and other related conditions.

Previous observational studies have hinted at a potential correlation between aplastic anemia (AA) and the gut microbiome. However, the precise nature of this bidirectional causal relationship remains uncertain.

We conducted a bidirectional two-sample Mendelian randomization (MR) study to investigate the potential causal link between the gut microbiome and AA. Statistical analysis of the gut microbiome was based on data from an extensive meta-analysis (genome-wide association study) conducted by the MiBioGen Alliance, involving 18,340 samples. Summary statistical data for AA were obtained from the Integrative Epidemiology Unit database. Single -nucleotide polymorphisms (SNPs) were estimated and summarized using inverse variance weighted (IVW), MR Egger, and weighted median methods in the bidirectional MR analysis. Cochran's Q test, MR Egger intercept test, and sensitivity analysis were employed to assess SNP heterogeneity, horizontal pleiotropy, and stability.

The IVW analysis revealed a significant correlation between AA and 10 bacterial taxa. However, there is currently insufficient evidence to support a causal relationship between AA and the composition of gut microbiome.

This study suggests a causal connection between the prevalence of specific gut microbiome and AA. Further investigation into the interaction between particular bacterial communities and AA could enhance efforts in prevention, monitoring, and treatment of the condition.