Dapansutrile (Dapan) is a newly developed anti-inflammatory molecule that supresses the production of NLRP3 inflammasome-dependent IL-1β. Its hepatoprotective effects against autoimmune hepatitis (AIH) have not yet been explored. Hence, this study was conducted to examine the possible protective effects of Dapan against concanavalin A (Con A)-induced hepatitis in mice.

Mice were randomly divided into five groups (n = 6): control, Con A (15 mg/kg), Dapan (60 mg/kg), Dapan (6 mg/kg) + Con A, and Dapan (60 mg/kg) + Con A. Mice were euthanised at the end of the study, and blood and hepatic tissues were collected.

Hepatic function testing using lactate dehydrogenase, alanine aminotransferase, and aspartate aminotransferase levels, in addition to hepatic tissue histological examination, revealed that intraperitoneal administration of Dapan noticeably ameliorated Con A-induced hepatic enzyme impairment and histopathological disruption. Moreover, Dapan-treated mice had significantly lower malondialdehyde hepatic content and elevated reduced glutathione, superoxide dismutase, and total antioxidant capacity levels than non-treated mice in a dose-dependent manner. The Dapan-treated groups showed significantly lower levels of the inflammatory mediators, NLRP3, TNF-α, IL-6, and IL-1β, in addition to the immunomodulators CD8, CD4, INF-γ, and NFκB and inhibition of JNK and p38 MAPK levels compared to the Con A-treated group.

Our results showed that intraperitoneal administration of Dapan could be a therapeutic opportunity to inhibit the development of AIH via inhibition of inflammatory pathways.

Deciphering the gastrointestinal microbial response to oral SS DNA vaccines with different doses is helpful for identifying the mechanism for effective utilization of the vaccine for improving animal production. Here, we conduct a comparative study with different doses of vaccine (control: empty plasmid; low dose: 1 × 107 CFU vaccine; high dose: 1 × 1012 CFU vaccine) using goat as a case to investigate the potential of somatostatin vaccination from the entire gastrointestinal microbiota perspective. Our results show that body weight gain and slaughter rate are greater in the L_SS group than in the C_SS group. Compared with the C_SS group, the GH concentration is reduced, while the SS concentration is elevated in the cecum of L_SS goats. Moreover, the SCFAs concentration is elevated in the L_SS goats, the acetate molar proportion is lower in the rumen, the proportion of the acetate is decreased, and propionate is increased in the cecum of L_SS goats. Our data indicate that the low-dose somatostatin vaccine possesses a more efficient improvement in the productivity of goats, emphasizing that the dosage should be considered to reach its optimal effect on the host. Moreover, we find that different doses of the SS vaccination select distinct microbial communities in the gastrointestinal tract. Beta diversity analysis shows a significant interaction. Microorganisms capable of converting nutrients, including Ruminococcacease, Butyrivibrio, Akkermansia, and Lachnospiraceae are enriched, altering the gastrointestinal fermentation response to SS DNA vaccination of ruminants. Moreover, the correlation analysis results revealing these biomarkers have a close association with the phenotypes of productivity. These results imply that somatostatin immunoneutralization might directly alter the gastrointestinal tract commensal bacterial structure, improving gastrointestinal homeostasis, and, thus, modifying the fermentability and effected hormone level to improve the productivity of goats. Our study extends the understanding of the somatostatin vaccine regulation of ruminants' growth through the entire gastrointestinal microbial perspective.

Intrauterine adhesion (IUA) poses a serious threat to women's health, and its specific pathogenesis has not yet been elucidated. Our study found through high-throughput sequencing that differentially expressed genes of the endometrial tissues from healthy individuals or IUA patients were enriched in the toll-like receptor (TLR), nuclear factor-kappa B (NF-kB), and nucleotide-binding oligomerization domain-like receptor (NLR) signaling pathways. Meanwhile, we observed that compared to the controls, long non-coding RNA (lncRNA) growth arrest-specific transcripts 5 (GAS5) was significantly upregulated in the endometrial tissue of IUA patients and scratching/lipopolysaccharide (LPS)-induced IUA model mice. Subsequently, results from the functional verification assay, including hematoxylin-eosin staining, enzyme-linked immunosorbent assay, and western blot, showed that knockdown of GAS5 improved endometrial injury and uterine adhesions, decreased the levels of TIMP1, α-SMA, Vimentin, and COL1A1, but elevated MMP9 level to reduce excessive accumulation of extracellular matrix (ECM), and inhibited the expression of NLRP3, cleaved caspase-1, GSDMD, and nuclear p65 to ameliorate pyroptosis in IUA model mice. As confirmed by bioinformatics analysis and dual luciferase reporter gene system, GAS5 sponged microRNA (miR)-205-5p to upregulate TLR4, further activating the NF-kB and NLRP3 signaling in endometrial stromal cells (ESCs). The in vitro functional recovery experiments suggested that GAS5 knockdown alleviated LPS-induced activation of the NF-kB and NLRP3 signaling, pyroptotic cell death, and ECM deposition in ESCs, which was counteracted by overexpressing TLR4 and NLRP3. In a word, our study proved that targeting the GAS5/TLR4/NLRP3 signaling cascade inhibits ESCs pyroptosis and prevents the progression of IUA, providing promising therapeutic strategies for IUA disease.

Ulcerative colitis (UC) is an inflammatory bowel disease marked by gut inflammation and microbial dysbiosis. Exopolysaccharides (EPS) from probiotic bacteria have been shown to regulate microbial composition and metabolism, but their role in promoting probiotic growth and alleviating inflammation in UC remains unclear. Here, we investigate BLEPS-1, a novel EPS derived from Bifidobacterium longum subsp. longum XZ01, for its ability to promote the growth of Lactobacillus strains. We then tested a synbiotic formulation of BLEPS-1 and L. acidophilus in a DSS-induced UC mouse model. The combination of BLEPS-1 and L. acidophilus alleviated DSS-induced intestinal inflammation, outperforming either component alone. Administration of BLEPS-1 decreased the proportion of M1 macrophages in the intestine, while M2 macrophages were more abundant following L. acidophilus treatment. Together, BLEPS-1 and L. acidophilus synergistically modulated macrophage polarization toward the M2-type. Administration of BLEPS-1 and L. acidophilus together modulated gut microbiota composition and altered the gut metabolic profile, with BLEPS-1 and L. acidophilus promoting metabolism of short-chain fatty acids and aromatic amino acids, respectively. Our study identified a novel synbiotic formulation with potent immunomodulatory and metabolic activity, laying the groundwork for a promising therapeutic strategy to treat intestinal inflammatory diseases such as colitis.

Programmed cell death (PCD) plays a crucial role in maintaining tissue homeostasis, with its primary forms including apoptosis, pyroptosis, and necroptosis. The caspase family is central to these processes, and its complex functions across different cell death pathways and other non-cell death roles have been closely linked to the pathogenesis of autoimmune diseases. This article provides a comprehensive review of the role of the caspase family in autoimmune diseases such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), type 1 diabetes (T1D), and multiple sclerosis (MS). It particularly emphasizes the intricate functions of caspases within various cell death pathways and their potential as therapeutic targets, thereby offering innovative insights and a thorough discussion in this field. In terms of therapy, strategies targeting caspases hold significant promise. We emphasize the importance of a holistic understanding of caspases in the overall concept of cell death, exploring their unique functions and interrelationships across multiple cell death pathways, including apoptosis, pyroptosis, necroptosis, and PANoptosis. This approach transcends the limitations of previous studies that focused on singular cell death pathways. Additionally, caspases play a key role in non-cell death functions, such as immune cell activation, cytokine processing, inflammation regulation, and tissue repair, thereby opening new avenues for the treatment of autoimmune diseases. Regulating caspase activity holds the potential to restore immune balance in autoimmune diseases. Potential therapeutic approaches include small molecule inhibitors (both reversible and irreversible), biological agents (such as monoclonal antibodies), and gene therapies. However, achieving specific modulation of caspases to avoid interference with normal physiological functions remains a major challenge. Future research must delve deeper into the regulatory mechanisms of caspases and their associated complexes linked to PANoptosis to facilitate precision medicine. In summary, this article offers a comprehensive and in-depth analysis, providing a novel perspective on the complex roles of caspases in autoimmune diseases, with the potential to catalyze breakthroughs in understanding disease mechanisms and developing therapeutic strategies.

Autoimmune hepatitis (AIH) is a liver disease marked by inflammation of unknown origin. If untreated, it can progress to cirrhosis or liver failure, posing a significant health risk. Currently, effective drug therapies are lacking in clinical practice. Sulforaphane (SFN), a natural anti-inflammatory and antioxidant compound found in various cruciferous vegetables, alleviate pyroptosis and improve impaired autophagic flux, both of which contribute to AIH progression. However, whether SFN modulates autophagic flux and pyroptosis in S100-induced EAH through the AMPK/mTOR pathway remains unclear. Therefore, this study aims to investigate whether SFN can regulate AIH and elucidate its potential mechanisms of action. In this study, experimental AIH (EAH) was induced in male C57BL/6 J mice through intraperitoneal (i.p.) injection of S100. SFN was administered intraperitoneally every other day. After 28 days, the mice were euthanized, and their livers and serum were collected for histological and biochemical analyses. AML12 cells were used for the in vitro studies. The results showed that SFN mitigated pyroptosis by inhibiting the NLRP3 inflammasome and improving autophagic flux, which alleviates S100-induced EAH. Conversely, the autophagy inhibitor 3-MA negated the protective effects of SFN against inflammasome-mediated pyroptosis. Furthermore, SFN activated the AMPK/mTOR signaling pathway, offering protection against S100-induced EAH. Selective inhibition of AMPK suppressed the improvement in autophagic flux and protected against SFN-induced pyroptosis. Overall, SFN significantly ameliorates S100-induced EAH by enhancing autophagic flux and mitigating pyroptosis through activation of the AMPK/mTOR signaling pathway.

High molecular weight polysaccharides (GLPH, ≥300 kDa) are the major compounds of Ganoderma lucidum with improving liver function. However, the effect of GLPH on improving acute liver injury (ALI) wasn't revealed. Herein, the ameliorating effects and mechanisms of GLPH were revealed in lipopolysaccharide (LPS)-ALI mice. The results indicated that GLPH intervention (100 mg/kg day) reduced the serum ALT (22.67 ± 6.48 U/L), AST (21.19 ± 7.08 U/L), ALP (56.98 ± 12.71 U/L), GGT (1.48 ± 0.22 U/L) levels in ALI mice (p < 0.01). GLPH activated the hepatic antioxidant enzymes activity [SOD (3.75 ± 1.17 U/mg prot.) and CAT (3.01 ± 0.85 U/mg prot.)] and suppressed the hepatic inflammatory cytokines production [TNF-α (40.14 ± 8.15 pg/mg prot.), IL-1β (35.47 ± 10.90 pg/mg prot.), and IL-6 (8.44 ± 1.71 pg/mg prot.)] by regulating the Nrf2/OH-1 and Tlr4/NF-κB pathway (p < 0.05). Furthermore, GLPH regulated the abundance of Bifidobacterium, Akkermansia, Anaerovorax, and Tyzzerella, which associated with cecal SCFAs, hepatic inflammatory cytokines and antioxidant enzymes. GLPH significantly changed 85 liver metabolites (p < 0.01), which is beneficial for prevent the development of ALI. These results suggested GLPH displayed promising prebiotic properties in relieving ALI, regulating gut microbiota and liver metabolism.

Sepsis is a life-threatening organ dysfunction that occurs due to a dysregulated host response to infection. Septic-associated liver injury (SALI) has been closely linked to the prognosis and mortality of sepsis. Recent investigations have delved into the gut-liver axis and its association with SALI, identifying its pivotal role in the gut microbiota. Bacterial translocation and the onset of SALI can occur due to an imbalance in the gut microbiota, impairing the function of the gut barrier. Moreover, their metabolites might exacerbate or initiate SALI by modulating immune responses. Nevertheless, interventions to restore the balance of the gut microbiota, such as the administration of probiotics, fecal microbiota transplantation, or dietary adjustments, may ameliorate SALI and enhance the prognosis and survival rates of septic patients. This review aimed to elucidate the function of the gut microbiota in the genesis and procession of SALI and its potential therapeutic value, offering a deeper understanding of the pathogenesis and therapeutic avenues for SALI.

The gut microbiota plays a critical role in maintaining human health, influencing a wide range of physiological processes, including immune regulation, metabolism, and neurological function. Recent studies have shown that imbalances in gut microbiota composition can contribute to the onset and progression of various diseases, such as metabolic disorders (e.g., obesity and diabetes) and neurodegenerative conditions (e.g., Alzheimer's and Parkinson's). These conditions are often accompanied by chronic inflammation and dysregulated immune responses, which are closely linked to specific forms of cell death, including pyroptosis and ferroptosis. Pathogenic bacteria in the gut can trigger these cell death pathways through toxin release, while probiotics have been found to mitigate these effects by modulating immune responses. Despite these insights, the precise mechanisms through which the gut microbiota influences these diseases remain insufficiently understood. This review consolidates recent findings on the impact of gut microbiota in these immune-mediated and inflammation-associated conditions. It also identifies gaps in current research and explores the potential of advanced technologies, such as organ-on-chip models and the microbiome-gut-organ axis, for deepening our understanding. Emerging tools, including single-bacterium omics and spatial metabolomics, are discussed for their promise in elucidating the microbiota's role in disease development.

Chronic sleep deprivation (CSD) plays an important role in mood disorders. However, the changes in the gut microbiota and metabolites associated with CSD-induced anxiety/depression-like behavior in female mice have not been determined. Due to the influence of endogenous hormone levels, females are more susceptible than males to negative emotions caused by sleep deprivation. Here, we aim to investigate how CSD changes the gut microbiota and behavior and uncover the relationship between CSD and gut microbiota and its metabolites in female mice.

We used a 48-day sleep deprivation (SD) model using the modified multiple platform method (MMPM) to induce anxiety/depression-like behavior in female C57BL/6J mice and verified our results using the open field test, elevated plus maze, novel object recognition test, forced swim test, and tail suspension test. We collected fecal samples of mice for 16S rDNA sequencing and untargeted metabolomic analysis and colons for histopathological observation. We used Spearmen analysis to find the correlations between differential bacterial taxa, fecal metabolites, and behaviors.

Our study demonstrates that CSD induced anxiety/depressive-like behaviors in female mice. The results of 16S rDNA sequencing suggested that the relative abundance of the harmful bacteria g_ Rothia, g_ Streptococcus, g_ Pantoea, and g_ Klebsiella were significantly increased, while the beneficial bacteria g_ Rikenella, g_ Eubacterium]-xylanophilum-group, and g_ Eisenbergiella were significantly decreased after SD. Glycerophospholipid metabolism and glutathione metabolism were identified as key pathways in the fecal metabolism related to oxidative stress and inflammatory states of the intestine. Histological observation showed hyperplasia of epithelial cells, a decrease in goblet cells, and glandular atrophy of the colon in SD mice. There were correlations between some of the differential bacterial taxa, fecal metabolites, and behaviors.

In summary, we found that CSD induced anxiety/depression-like behavior, caused gut microbiota dysbiosis, altered fecal metabolism, and damaged the colon barrier in female mice.

Inflammatory bowel disease (IBD) is a chronic immune-inflammatory disease. Gut microbes, intestinal immunity, and gut barrier function play a critical role in IBD. Growing evidence suggests that synbiotic may offer therapeutic benefits for individuals with colitis, suggesting an alternative therapy against colitis. With this in mind, we creatively prepared a new synbiotic combination consisting of a probiotic strain (Limosilactobacillus reuteri) along with one prebiotic chitooligosaccharides (COS). The protective effects of the synbiotic on DSS-induced colitis and the underlying mechanisms were investigated. We demonstrated that the synbiotic ameliorated colitis in mice, as evidenced by a significant remission in body weight loss and colon shortening, and a decreased disease activity index (DAI). Notably, synbiotic reduced the intestinal inflammation and injury by synergistically decreasing inflammatory factors, inhibiting TLR4/Myd88/NF-κB/NLRP3 signaling, preventing macrophage infiltration, and enhancing the integrity of the intestinal barrier. Moreover, synbiotic selectively promoted the growth of beneficial bacteria (e.g., Akkermansia, Lactobacillus) but decreased the pathogenic bacteria (e.g., Helicobacter). BugBase's analysis supported its ameliorated role in reducing pathogenic bacteria. Collectively, our findings revealed the novel synbiotic had a potential to treat colitis, which was associated with its anti-inflammatory and microbiota-balancing properties. This study will contribute to the development of functional synbiotic products for IBD therapy and will provide valuable insights into their mechanisms.

Long-term heat stress (HS) severely restricts the growth performance of beef cattle and causes various health problems. The gut microbiota plays a crucial role in HS-associated inflammation and immune stress involving lymphocyte function. This study investigated the effects of dietary tea polysaccharide (TPS), a natural acidic glycoprotein, on HS-induced anorexia, inflammation, and gut microbiota dysbiosis in Simmental beef cattle.

The cattle were divided into two groups, receiving either normal chow or normal chow plus TPS (8 g/kg, 0.8%). Transcriptome sequencing analysis was used to analysis the differential signaling pathway of liver tissue. 16S rDNA sequencing was performed to analysis gut microbiota of beef cattle. Serum metabolite components were detected by untargeted metabolomics analysis.

Hepatic transcriptomics analysis revealed that differentially expressed genes in TPS-fed cattle were primarily enriched in immune processes and lymphocyte activation. TPS administration significantly reduced the expression of the TLR4/NF-κB inflammatory signaling pathway, alleviating HS-induced hepatic inflammation. Gut microbiota analysis revealed that TPS improved intestinal homeostasis in HS-affected cattle by increasing bacterial diversity and increasing the relative abundances of Akkermansia and Alistipes while decreasing the Firmicutes-to-Bacteroidetes ratio and the abundance of Agathobacter. Liquid chromatography-tandem mass spectrometry (LC‒MS/MS) analysis indicated that TPS significantly increased the levels of long-chain fatty acids, including stearic acid, linolenic acid, arachidonic acid, and adrenic acid, in the serum of cattle.

These findings suggest that long-term consumption of tea polysaccharides can ameliorate heat stress-induced hepatic inflammation and gut microbiota dysbiosis in beef cattle, suggesting a possible liver-gut axis mechanism to mitigate heat stress.

The disturbed gut microbiota is a key factor in activating the aflatoxin B1 (AFB1)-induced liver pyroptosis by promoting inflammatory hepatic injury; however, the pathogen associated molecular pattern (PAMP) from disturbed gut microbiota and its mechanism in activating liver pyroptosis remain undefined. By transplanting AFB1-originated fecal microbiota and sterile fecal microbial metabolites filtrate, we determined the association of PAMP in AFB1-induced liver pyroptosis. Notably, AFB1-originated sterile fecal microbial metabolites filtrate were more active in triggering liver pyroptosis in mice, as compared to parental fecal microbiota. This result supported a critical role of the metabolic homeostasis of gut microbiota in AFB1-induced liver pyroptosis, rather than an injurious response to direct exposure of AFB1 in liver. Among the gut-microbial metabolites, pipecolic acid and norepinephrine were proposed to bind TLR4 and NLRP3, the upstream proteins of pyroptosis signaling pathway. Besides, the activations of TLR4 and NLRP3 were linearly correlated with the concentrations of pipecolic acid and norepinephrine in the serum of mice. In silenced expression of TLR4 and NLRP3 in HepG2 cells, pipecolic acid or norepinephrine did not able to activate hepatocyte pyroptosis. These results demonstrated the necessity of gut microbial metabolism in sustaining liver homeostasis, as well as the potential to provide new insights into targeted intervention for AFB1 hepatotoxicity.

The functions of mitochondria, including energy production and biomolecule synthesis, have been known for a long time. Given the rising incidence of cancer, the role of mitochondria in cancer has become increasingly popular. Activated by components released by mitochondria, various pathways interact with each other to induce immune responses to protect organisms from attack. However, mitochondria play dual roles in the progression of cancer. Abnormalities in proteins, which are the elementary structures of mitochondria, are closely linked with oncogenesis. Both the aberrant accumulation of intermediates and mutations in enzymes result in the generation and progression of cancer. Therefore, targeting mitochondria to treat cancer may be a new strategy. Several drugs aimed at inhibiting mutated enzymes and accumulated intermediates have been tested clinically. Here, we discuss the current understanding of mitochondria in cancer and the interactions between mitochondrial functions, immune responses, and oncogenesis. Furthermore, we discuss mitochondria as hopeful targets for cancer therapy, providing insights into the progression of future therapeutic strategies.

Alveolar echinococcosis (AE) may affect the composition of the host's gut microbiota, potentially disrupting the balance between the gut microbiota and metabolites. Metagenomics and untargeted metabolomics were employed to characterize changes in the gut microbiota and metabolites in mouse models infected with E. multilocularis. Pearson correlation coefficients were calculated to compare the distribution of microbiota and metabolites, revealing synergistic or mutually exclusive relationships. Functional outputs of the gut microbiota were explored using the CAZy database and six enzymes involved in carbohydrate metabolism were identified with statistically significant differential expression between infected and control groups. The resistome was characterized by identifying antibiotic resistance genes annotated in the Comprehensive Antibiotic Resistance Database from the metagenomes of the groups. Firmicutes are the main carrier of ARGs in the host gut with tetQ being most prevalent. Antibiotic efflux, inactivation and target modification were the principal mechanisms of resistance. Comparison and analysis of two sets of antibiotic metabolic pathways allowed the identification of enzyme reactions unique to infected mice. KEGG pathway overview shows phenazine biosynthesis involving phzG to be one of them. In conclusion, infection with AE in mice leads to an overall disruption of gut microbiota and metabolites with the involvement of enzymes related to carbohydrate metabolism. Furthermore, antibiotic-resistance genes may play a role in disease progression, offering potential insights into the relationship between antibiotic use in AE and treatment outcomes.

The purpose of this study was to investigate the involvement of the TLR4/NF-κB/NLRP3 signaling pathway and its underlying mechanism in diabetic dry eye.

Two models of diabetic dry eye were established in high glucose-induced human corneal epithelial (HCE-T) cells and streptozotocin (STZ)-induced C57BL/6 mice, and the TLR4 inhibitor fosfenopril (FOS) was utilized to suppress the TLR4/NF-κB/NLRP3 signaling pathway. The expression changes in TLR4, NF-κB, NLRP3, and IL-1β, and other factors were detected by Western blot and RT‒qPCR, the wound healing rate was evaluated by cell scratch assay, and the symptoms of diabetic mice were evaluated by corneal sodium fluorescein staining and tear secretion assay.

In the diabetic dry eye model, the transcript levels of TLR4, NF-κB, NLRP3, and IL-1β were raised, and further application of FOS, a TLR4 inhibitor, downregulated the levels of these pathway factors. In addition, FOS was found to be effective in increasing the wound healing rate of high glucose-induced HCE-T cells, increasing tear production, and decreasing corneal fluorescence staining scores in diabetic mice, as measured by cell scratch assay, corneal sodium fluorescein staining assay, and tear production.

The current study found that the TLR4/NF-κB/NLRP3 signaling pathway regulates diabetic dry eye in an in vitro and in vivo model, and that FOS reduces the signs of dry eye in diabetic mice, providing a new treatment option for diabetic dry eye.

The role of lipopolysaccharide binding protein (LBP), an inflammation marker of bacterial translocation from the gastrointestinal tract, in Alzheimer's disease (AD) is not clearly understood.

In this study the concentrations of LBP were measured in n = 79 individuals: 20 apolipoprotein E (APOE)3/E3 carriers with and 20 without AD dementia, and 19 APOE3/E4 carriers with and 20 without AD dementia. LBP was found to be enriched in the 1.21-1.25 g/mL density fraction of plasma, which has previously been shown to be enriched in intestinally derived high-density lipoproteins (HDL). LBP concentrations were measured by ELISA.

LBP was significantly increased within the 1.21-1.25 g/mL density fraction of plasma in APOE3/E3 AD patients compared to controls, but not APOE3/E4 patients. LBP was positively correlated with Clinical Dementia Rating (CDR) and exhibited an inverse relationship with Verbal Memory Score (VMS).

These results underscore the potential contribution of gut permeability to bacterial toxins, measured as LBP, as an inflammatory mediator in the development of AD, particularly in individuals with the APOE3/E3 genotype, who are genetically at 4-12-fold lower risk of AD than individuals who express APOE4.

TIR domain-containing adaptor inducing IFN-β (TRIF) is a crucial adaptor molecule downstream of toll-like receptors 3 (TLR3) and 4 (TLR4). TRIF directly binds to TLR3 through its TIR domain, while it associates with TLR4 indirectly through the bridge adaptor molecule TRIF-related adaptor molecule (TRAM). TRIF plays a pivotal role in regulating interferon beta 1 (IFN-β) response, nuclear factor kappa B (NF-κB) signaling, apoptosis, and necroptosis signaling mediated by TLR3 and TLR4. It accomplishes these by recruiting and activating various kinases or transcription factors via its distinct domains. In this review, we comprehensively summarize the TRIF-dependent signaling pathways mediated by TLR3 and TLR4, elucidating key target molecules and downstream pathways. Furthermore, we provide an overview of TRIF's impact on several liver disorders, including drug-induced liver injury, ischemia-reperfusion liver injury, autoimmune hepatitis, viral hepatitis, alcohol-associated liver disease (ALD), metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH). We also explore its effects on liver steatosis, inflammation, fibrosis, and carcinogenesis. A comprehensive understanding of the TRIF-dependent signaling pathways, as well as the intricate relationship between TRIF and liver diseases, can facilitate the identification of potential drug targets and the development of novel and effective therapeutics against hepatic disorders.

Aflatoxin B1 (AFB1) causes serious immunotoxicity and has attracted considerable attention owing to its high sensitivity and common chemical-viral interactions in living organisms. However, the sensitivity of different species to AFB1 widely varies, which cannot be explained by the different metabolism in species. The gut microbiota plays a crucial role in the immune system, but the interaction of the microbiota with AFB1-induced immunotoxicity still needs to be determined. Our results indicated that AFB1 exposure disrupted the structure of the gut microbiota and damaged the gut barrier, which caused translocation of microbiota metabolites, lipopolysaccharides, to the spleen. Subsequently, pyroptosis of the spleen was activated. Interestingly, AFB1 exposure had little effect on the splenic pyroptosis of pseudo-germfree mice (antibiotic mixtures eliminated their gut microbiota, ABX). Then, fecal microbiota transplant (FMT) and sterile fecal filtrate (SFF) were employed to validate the function of the gut microbiota and its metabolites in AFB1-induced splenic pyroptosis. The AFB1-disrupted microbiota and its metabolites significantly promoted splenic pyroptosis, which was worse than that in control mice. Overall, AFB1-induced splenic pyroptosis is associated with the gut microbiota and its metabolites, which was further demonstrated by FMT and SFF. The mechanism of AFB1-induced splenic pyroptosis was explored for the first time, which paves a new way for preventing and treating the immunotoxicity from mycotoxins by regulating the gut microbiota.

Obstructive sleep apnea (OSA) is a multifactorial sleep disorder with a high prevalence in the general population. OSA is associated with an increased risk of developing cardiovascular diseases (CVDs), particularly hypertension, and is linked to worse outcomes. Although the correlation between OSA and CVDs is firmly established, the mechanisms are poorly understood. Continuous positive airway pressure is primary treatment for OSA reducing cardiovascular risk effectively, while is limited by inadequate compliance. Moreover, alternative treatments for cardiovascular complications in OSA are currently not available. Recently, there has been considerable attention on the significant correlation between gut microbiome and pathophysiological changes in OSA. Furthermore, gut microbiome has a significant impact on the cardiovascular complications that arise from OSA. Nevertheless, a detailed understanding of this association is lacking. This review examines recent advancements to clarify the link between the gut microbiome, OSA, and OSA-related CVDs, with a specific focus on hypertension, and also explores potential health advantages of adjuvant therapy that targets the gut microbiome in OSA.

Although probiotics have been used in food products and supplements for decades, there has been a considerable increase in their use more recently. Recent technological advances have thus led to major advances in knowledge of the gut microbiota, enabling a significant development of biotics. In this review, we discuss the uses of traditional probiotics but also the discovery of next-generation probiotics that could be used as live biotherapeutics. These novel preventive and therapeutic strategies hold promise for the treatment of numerous diseases such as inflammatory bowel diseases such as Crohn's disease and ulcerative colitis. Probiotic bacteria can be consumed alone, or in combination with prebiotics as synbiotics, or mixed with other probiotic strains to form a consortium for enhanced effects. We also discuss the benefits of using postbiotics.

Taraxacum mongolicum (TM) is a kind of medicinal and edible homologous plant which is included in the catalogue of feed raw materials in China. It is rich in polyphenols, flavonoids, polysaccharides and other active substances, and shows many benefits to livestock, poultry and aquatic products. The study aimed to assess the potential of TM aqueous extract (TMAE) as a substitute for poultry AGPs.

A total of 240 one-day-old Arbor Acker broilers were randomly assigned to four groups and fed a basal diet (Con) supplemented with 500, 1000, and 2000 mg/kg TMAE (Low, Medium, and High groups). The growth performance of the broilers was measured on day 21 and day 42. At the end of the trial, the researchers measured slaughter performance and collected serum, liver, spleen, ileum, and intestinal contents to investigate the effects of TMAE on serum biochemistry, antioxidant capacity, immune function, organ coefficient, intestinal morphology, flora composition, and short-chain fatty acids (SCFAs).

The results showed that broilers treated with TMAE had a significantly higher average daily gain from 22 to 42 days old compared to the Con group. Various doses of TMAE resulted in different levels of improvement in serum chemistry. High doses increased serum alkaline phosphatase and decreased creatinine. TMAE also increased the antioxidant capacity of serum, liver, and ileum in broilers. Additionally, middle and high doses of TMAE enhanced the innate immune function of the liver (IL-10) and ileum (Occludin) in broilers. Compared to the control group, the TMAE treatment group exhibited an increase in the ratio of villi length to villi crypt in the duodenum. TMAE increased the abundance of beneficial bacteria, such as Alistipes and Lactobacillus, while reducing the accumulation of harmful bacteria, such as Colidextracter and Sellimonas. The cecum's SCFAs content increased with a medium dose of TMAE. Supplementing broiler diets with TMAE at varying doses enhanced growth performance and overall health. The most significant benefits were observed at a dose of 1000 mg/kg, including improved serum biochemical parameters, intestinal morphology, antioxidant capacity of the liver and ileum, immune function of the liver and ileum, and increased SCFAs content. Lactobacillus aviarius, norank_f_norank_o__Clostridia_UCG-014, and Flavonifractor are potentially dominant members of the intestinal microflora.

In conclusion, TMAE is a promising poultry feed additive and 1000 mg/kg is an effective reference dose.

Gouty arthritis (GA) is an inflammatory disease characterized by pain. The primary goal of current treatment strategies during GA flares remains the reduction of inflammation and pain. Research suggests that the gut microbiota and microbial metabolites contribute to the modulation of the inflammatory mechanism associated with GA, particularly through their effect on macrophage polarization. The increasing understanding of the gut-joint axis emphasizes the importance of this interaction. The primary objective of this review is to summarize existing research on the gut-immune-joint axis in GA, aiming to enhance understanding of the intricate processes and pathogenic pathways associated with pain and inflammation in GA, as documented in the published literature. The refined comprehension of the gut-joint axis may potentially contribute to the future development of analgesic drugs targeting gut microbes for GA.

Acute leukemia (AL), one of the hematological malignancies, shows high heterogeneity. Tremendous progresses are achieved in treating AL with novel targeted drugs and allogeneic hematopoietic stem cell transplantation, there are numerous issues including pathogenesis, early diagnosis, and therapeutic efficacy of AL to be solved. In recent years, an increasing number of studies regarding microbiome have shed more lights on the role of gut microbiota in promoting AL progression. Mechanisms related to the role of gut microbiota in enhancing AL genesis are summarized in the present work, especially on critical pathways like leaky gut, bacterial dysbiosis, microorganism-related molecular patterns, and bacterial metabolites, resulting in AL development. Additionally, the potential of gut microbiota as the biomarker for early AL diagnosis is discussed. It also outlooks therapies targeting gut microbiota for preventing AL development.

The risks of Zinc oxide nanoparticles (ZnO NPs) applications in biological medicine, food processing industry, agricultural production and the biotoxicity brought by environmental invasion of ZnO NPs both gradually troubled the public due to the lack of research on detoxification strategies. TFEB-regulated autophagy-pyroptosis pathways were found as the crux of the hepatotoxicity induced by ZnO NPs in our latest study. Here, our study served as a connecting link between preceding toxic target and the following protection mechanism of Paeoniflorin (PF). According to a combined analysis of network pharmacology/molecular docking-intestinal microbiota-metabolomics first developed in our study, PF alleviated the hepatotoxicity of ZnO NPs from multiple aspects. The hepatic inflammatory injury and hepatocyte pyroptosis in mice liver exposed to ZnO NPs was significantly inhibited by PF. And the intestinal microbiota disorder and liver metabolic disturbance were rescued. The targets predicted by bioinformatics and the signal trend in subacute toxicological model exhibited the protectiveness of PF related to the SIRT1-mTOR-TFEB pathway. These evidences clarified multiple protective mechanisms of PF which provided a novel detoxification approach against ZnO NPs, and further provided a strategy for the medicinal value development of PF.

Autoimmune hepatitis (AIH) is a serious chronic liver disease that may last for decades and eventually develop into cirrhosis and liver failure. In recent years, people have paid more attention to the microbiome-gut-liver axis, which provides guidance for all to explore the role of microbiome in the occurrence and development of liver diseases. In this review, the possible mechanism of intestinal microbes promoting the occurrence of AIH, mainly expounding the key ways such as bacterial ecological imbalance, intestinal leakage, and molecular simulation between microbes and autoantigens is summarized. In addition, this paper also discusses that intestinal microbiome has great potential as a biomarker for early diagnosis of AIH, and intestinal microbiome is also a candidate target for prevention and treatment of AIH. Finally, the study summarizes and prospects the targeted therapy of intestinal microorganisms to prevent the occurrence and development of AIH.

Xiongdanjiuxin pill (XP) is a traditional Chinese medicine formula for the prevention and treatment of hyperlipidemia (HLP) and related complications. In this study, the gut-liver axis was used as the breakthrough point to analyze the therapeutic effect and potential mechanism of XP on HLP model rats and related complications.

We used high-fat diet (HFD) to establish the HLP model of rats and treated them with XP. The 16S rRNA sequencing method was used to explore the effect of XP on the gut microbiota of HFD rats, and the effects of XP on ileum pathology, intestinal barrier and circulatory inflammation in HFD rats were also investigated. We further explored the molecular mechanism of XP treating liver inflammation in rats with HFD by regulating toll-like receptor 4 (TLR4) signaling.

We found that XP could regulate the imbalance of gut microbiota in HFD rats, and up-regulate the expression of tight junction protein in intestinal epithelium of HFD rats, thereby improving the intestinal barrier damage and intestinal inflammatory response. In addition, XP could significantly reduce the levels of inflammatory cytokines in HFD rats, and inhibit TLR4 signaling pathway, thereby reducing liver inflammation in HFD rats.

XP can effectively improve the imbalance of gut-liver axis in hyperlipidemic rats and alleviate the inflammatory damage of liver. Its mechanism may be related to regulating the disorder of gut microbiota and inhibiting TLR4 signal pathway, so as to achieve the therapeutic effect on hyperlipidemic fatty liver in rats.

Nicotine dependence is a key factor influencing the diversity of gut microbiota, and targeting gut microbiota may become a new approach for the prevention and treatment of nicotine dependence. However, the causal relationship between the two is still unclear. This study aims to investigate the causal relationship between nicotine dependence and gut microbiota.

A two-sample bidirectional Mendelian randomization (MR) study was conducted using the largest existing gut microbiota and nicotine dependence genome-wide association studies (GWAS). Causal relationships between genetically predicted nicotine dependence and gut microbiota abundance were examined using inverse variance weighted, MR-Egger, weighted median, simple mode, weighted mode, and MR-PRESSO approaches. Cochrane's Q test, MR-Egger intercept test, and leave-one-out analysis were performed as sensitivity analyses to assess the robustness of the results. Multivariable Mendelian randomization analysis was also conducted to eliminate the interference of smoking-related phenotypes. Reverse Mendelian randomization analysis was then performed to determine the causal relationship between genetically predicted gut microbiota abundance and nicotine dependence.

Genetically predicted nicotine dependence had a causal effect on Christensenellaceae (β: -0.52, 95% CI: -0.934-0.106, P = 0.014). The Eubacterium xylanophilum group (OR: 1.106, 95% CI: 1.004-1.218), Lachnoclostridium (OR: 1.118, 95% CI: 1.001-1.249) and Holdemania (OR: 1.08, 95% CI: 1.001-1.167) were risk factors for nicotine dependence. Peptostreptococcaceae (OR: 0.905, 95% CI: 0.837-0.977), Desulfovibrio (OR: 0.014, 95% CI: 0.819-0.977), Dorea (OR: 0.841, 95% CI. 0.731-0.968), Faecalibacterium (OR: 0.831, 95% CI: 0.735-0.939) and Sutterella (OR: 0.838, 95% CI: 0.739-0.951) were protective factor for nicotine dependence. The sensitivity analysis showed consistent results.

The Mendelian randomization study confirmed the causal link between genetically predicted risk of nicotine dependence and genetically predicted abundance of gut microbiota. Gut microbiota may serve as a biomarker and offer insights for addressing nicotine dependence.

Adjuvant chemotherapy based on 5-fluorouracil (5-FU), such as FOLFOX, is suggested as a treatment for gastrointestinal cancer. Yet, intestinal damage continues to be a prevalent side effect for which there are no practical prevention measures. We investigated whether Babao Dan (BBD), a Traditional Chinese Medicine, protects against intestinal damage induced by 5-FU by controlling immune response and gut microbiota. 5-FU was injected intraperitoneally to establish the mice model, then 250 mg/kg BBD was gavaged for five days straight. 5-FU led to marked weight loss, diarrhea, fecal blood, and histopathologic intestinal damage. Administration of BBD reduced these symptoms, inhibited proinflammatory cytokine (IL-6, IL-1β, IFN-γ, TNF-α) secretion, and upregulated the ratio of CD3(+) T cells and the CD4(+)/CD8(+) ratio. According to 16S rRNA sequencing, BBD dramatically repaired the disruption of the gut microbiota caused in a time-dependent way, and increased the Firmicutes/Bacteroidetes (F/B) ratio. Transcriptomic results showed that the mechanism is mainly concentrated on the NF-κB pathway, and we found that BBD reduced the concentration of LPS in the fecal suspension and serum, and inhibited TLR4/MyD88/NF-κB pathway activation. Furthermore, at the genus level on the fifth day, BBD upregulated the abundance of unidentified_Corynebacteriaceae, Aerococcus, Blautia, Jeotgalicoccus, Odoribacter, Roseburia, Rikenella, Intestinimonas, unidentified_Lachnospiraceae, Enterorhabdus, Ruminiclostridium, and downregulated the abundance of Bacteroides, Parabacteroides, Parasutterella, Erysipelatoclostridium, which were highly correlated with intestinal injury or the TLR4/MyD88/NF-κB pathway. In conclusion, we established a network involving 5-FU, BBD, the immune response, gut microbiota, and key pathways to explain the pharmacology of oral BBD in preventing 5-FU-induced intestinal injury.

Numerous antibiotic resistance genes (ARGs) and virulence factors (VFs) found in animal manure pose significant risks to human health. However, the effects of graphene sodium selenite (GSSe), a novel chemical nano-Selenium, and biological nano-Selenium (BNSSe), a new bioaugmentation nano-Se, on bacterial Se metabolism, chemotaxis, ARGs, and VFs in animal manure remain unknown. In this study, we investigated the effects of GSSe and BNSSe on ARGs and VFs expression in broiler manure using high-throughput sequencing. Results showed that BNSSe reduced Se pressure during anaerobic fermentation by inhibiting bacterial selenocompound metabolism pathways, thereby lowering manure Selenium pollution. Additionally, the expression levels of ARGs and VFs were lower in the BNSSe group compared to the Sodium Selenite and GSSe groups, as BNSSe inhibited bacterial chemotaxis pathways. Co-occurrence network analysis identified ARGs and VFs within the following phyla Bacteroidetes (genera Butyricimonas, Odoribacter, Paraprevotella, and Rikenella), Firmicutes (genera Lactobacillus, Candidatus_Borkfalkia, Merdimonas, Oscillibacter, Intestinimonas, and Megamonas), and Proteobacteria (genera Desulfovibrio). The expression and abundance of ARGs and VFs genes were found to be associated with ARGs-VFs coexistence. Moreover, BNSSe disruption of bacterial selenocompound metabolism and chemotaxis pathways resulted in less frequent transfer of ARGs and VFs. These findings indicate that BNSSe can reduce ARGs and VFs expression in animal manure by suppressing bacterial selenocompound metabolism and chemotaxis pathways.