Besides TLR2 and TLR4, NLRP3 is also involved in regulating Escherichia coli infection-induced inflammatory responses in mice.

Abstract Background The inhibitory effect of fumonisins on ceramide synthases results in several effects on the sphingolipidome, and recent results in chickens suggest that the C22–24:C16 sphingolipid ratios may be complementary biomarkers to Sa:So. Feeding diets containing fumonisins, deoxynivalenol, or zearalenone alone or in combination up to the maximum levels recommended by the European Commission for 35 days in chickens and 12 days in ducks resulted in no effects on performance or toxicity. The aim of this study was to investigate their effects on the liver sphingolipidome. Results Sphingolipids were characterised by UHPLC-MSMS. Numerous significant effects of fusariotoxins on sphingolipids were observed at the class and analyte levels. Fusariotoxins alone decreased sphingolipids in chickens but had weak effects in ducks. Feeding fumonisins in combination with deoxynivalenol and zearalenone increased sphingolipid levels in chickens but not in ducks. These increases were mainly due to an increase in C22–24 sphingolipids, whereas C16 sphingolipids decreased. The Sa:So ratio and the C22–24:C16 ratio for ceramides, sphingomyelins, monohexosylceramides, dihydroceramides, and dihydrosphingomyelins were unaffected in chickens and ducks fed the diets containing deoxynivalenol or zearalenone but increased in animals fed the fumonisin diets. Interestingly, while the effects of feeding fumonisins alone or in combination on the total amount of sphingolipids differed in chickens, the Sa:So and C22-24:C16 ratios were similar. Partial least squares-discriminant analysis of sphingolipids did not allow discrimination of the animals exposed to deoxynivalenol or zearalenone from the unexposed animals. By contrast, good discrimination of the animals fed the diets containing fumonisins was achieved. Sphinganine, d20 sphinganine, a large number of C16 sphingolipids, and dihydrosphingomyelins for which the fatty acid contains more than 18 carbon atoms, were important variables in the models obtained in chickens and ducks. Conclusions The C22–24:C16 ratios of sphingolipids are increased in chickens and ducks by intake of fumonisins but not deoxynivalenol or zearalenone. The increases were similar when fumonisins were fed alone or in combination with deoxynivalenol or zearalenone. The increase in the C22–24:C16 ratio may be an important factor in explaining the interspecies differences in sensitivity to fumonisin toxicity. 

Fumonisins alone or mixed with other fusariotoxins increase the C22–24:C16 sphingolipid ratios in chickens and ducks, while deoxynivalenol and zearalenone have no effect

Inflammatory bowel disease (IBD), comprising Crohn’s disease and ulcerative colitis, represents the two predominant clinical entities within this spectrum of gastrointestinal disorders. Current evidence indicates that the etiology of IBD is multifactorial, involving a complex interplay between host genetic susceptibility and environmental determinants. In recent years, non-pharmacological strategies such as physical exercise and vagus nerve stimulation have gained increasing attention as adjunctive therapeutic approaches. Vagus nerve stimulation has emerged as a promising therapeutic modality, particularly in conditions characterized by autonomic dysfunction and diminished vagal tone. Conversely, vagotomy, by disrupting vagal control, abolishes parasympathetic reflexes and may potentiate inflammatory responses and exacerbate IBD symptomatology under stress conditions. Physical exercise has likewise been investigated as a non-pharmacological intervention in Crohn’s disease and ulcerative colitis. Although the precise mechanisms remain to be fully elucidated, accumulating evidence suggests that skeletal muscle contractions promote the secretion of myokines, with recognized anti-inflammatory properties. These myokines act on the intestinal microenvironment, conferring protection against malignant transformation and modulating the composition and function of the gut microbiota. In this review, we critically examine the interplay between physical exercise, vagus nerve stimulation, and vagotomy in the pathophysiology and management of IBD, with particular emphasis on their immunomodulatory and therapeutic potential. 

Role of physical exercise, vagal nerve stimulation, and vagotomy in inflammatory bowel disease

Mastitis represents one of the most economically devastating diseases in dairy production, causing billions of dollars in annual losses through reduced milk quality and quantity. Recent advances in microbiome research have unveiled a critical gut–mammary axis that fundamentally influences mastitis susceptibility and pathogenesis in dairy cattle. Through comprehensive analysis of microbial communities across multiple anatomical sites, we demonstrate that mastitis development involves systematic disruption of both mammary and gastrointestinal microbiomes, characterized by reduced beneficial bacterial populations and increased pathogenic species. Healthy animals maintain balanced microbial ecosystems dominated by protective taxa including Firmicutes, Bacteroidetes, and beneficial Lactobacillus species, while mastitis-affected animals exhibit dysbiotic shifts toward Proteobacteria dominance, elevated Streptococcus and Staphylococcus populations, and compromised microbial diversity. Mechanistic investigations reveal that gut microbiota disruption compromises systemic immune competence, alters metabolite production including short-chain fatty acids and bile acids, and influences inflammatory mediators that circulate to mammary tissue. Therapeutic interventions targeting this axis, including probiotics, prebiotics, and plant-derived compounds, demonstrate significant efficacy in restoring microbiome homeostasis and reducing mastitis severity. These findings establish the gut–mammary axis as a fundamental regulatory mechanism in mastitis pathogenesis, opening new avenues for microbiome-based prevention and treatment strategies that could significantly enhance dairy health management while addressing antimicrobial resistance concerns. 

Targeting the Gut–Mammary Axis for Understanding Mastitis Pathogenesis and Therapeutic Strategies

Zearalenone (ZEA), a prevalent mycotoxin in moldy feeds, induces apoptosis by disrupting cellular homeostasis, leading to multi-organ damage, particularly in the kidneys, intestines, and reproductive system. Selenomethionine (SeMet), a natural amino acid with antioxidant and anticancer properties, was investigated for its protective effects against ZEA-induced nephrotoxicity. In this study, rabbits were exposed to ZEA and varying concentrations of SeMet, followed by renal tissue analysis. Pathological examination revealed significant structural damage in ZEA-treated kidneys, including glomerular atrophy, fibrosis, impaired glycogenolysis, and inflammatory injury due to dysregulated pro-inflammatory and anti-inflammatory factor expression. Mechanistically, ZEA suppressed PI3K/Akt/mTOR signaling, triggering excessive autophagy initiation but impairing autophagic flux, ultimately disrupting cellular homeostasis. This dysregulation upregulated pro-apoptotic proteins (Cyt C, Caspase-3, Caspase-9) while downregulating Bcl-2, exacerbating renal apoptosis. SeMet supplementation counteracted these effects by restoring PI3K/Akt/mTOR pathway activity, normalizing autophagy, and rebalancing apoptotic protein expression. Notably, 0.35 mg/kg SeMet demonstrated optimal renal protection. These findings highlight SeMet's potential as a dietary supplement to mitigate ZEA-induced kidney injury via modulation of autophagy and apoptosis pathways. 

SeMet attenuates zearalenone-induced autophagy in rabbit kidney to alleviate apoptosis through activation of PI3K/Akt/mTOR signaling pathway

In this study, we investigated the roles of bacterial outer membrane component BLP in regulating inflammatory responses and lethality in mice that were induced by a ubiquitous and serious pathogen, Escherichia coli. BLP could alleviate the mortality of mice and organ damage, as well as decrease proinflammatory cytokines and chemokine production and enhance anti-inflammatory cytokine production in mouse serum and organs. ABSTRACT Escherichia coli (E. coli), a Gram-negative bacterium, is an important pathogen that causes several mammalian diseases. The outer membrane components of E. coli, namely, lipopolysaccharide (LPS) and bacterial lipoprotein, can induce the host innate immune response through pattern recognition receptors (PRRs). However, the detailed roles of the E. coli Braun lipoprotein (BLP) in the regulation of host inflammatory response to E. coli infection remain unclear. In this study, we sought to determine the effects of BLP on E. coli-induced host inflammatory response and lethality using mouse models. Experiments using the E. coli DH5α strain (BLP-positive), E. coli JE5505 strain (BLP-negative), and E. coli JE5505 strain combined with BLP indicated that the presence of BLP could alleviate mortality and organ (liver and lung) damage and decrease proinflammatory cytokine (tumor necrosis factor alpha [TNF-α] and interleukin-1β [IL-1β]) and chemokine (regulated on activation normal T-cell expressed and secreted [RANTES]) production in mouse serum and organs. Conversely, E. coli JE5505, E. coli DH5α strain, and E. coli JE5505 combined with BLP treatment induce enhanced anti-inflammatory cytokine (interleukin 10 [IL-10]) production in mouse serum and organs. In addition, BLP could regulate the secretion of proinflammatory cytokines (TNF-α and IL-1β), chemokines (RANTES), and anti-inflammatory factors (IL-10) through mitogen-activated protein kinase (MAPK) and nuclear factor-kappaB (NF-κB) signaling pathways in macrophages. Altogether, our results demonstrate that the bacterial component BLP plays crucial and protective roles in E. coli-infected mice, which may influence the outcome of inflammation in host response to E. coli infection. IMPORTANCE In this study, we investigated the roles of bacterial outer membrane component BLP in regulating inflammatory responses and lethality in mice that were induced by a ubiquitous and serious pathogen, Escherichia coli. BLP could alleviate the mortality of mice and organ damage, as well as decrease proinflammatory cytokines and chemokine production and enhance anti-inflammatory cytokine production in mouse serum and organs. Overall, our results demonstrate that the bacterial component BLP plays crucial and protective roles in E. coli-infected mice through regulating the production of an inflammatory mediator, which may influence the outcome of inflammation in host response to E. coli infection. Our findings provide new information about the basic biology involved in immune responses to E. coli and host-bacterial interactions, which have the potential to translate into novel approaches for the diagnosis and treatment of E. coli-related medical conditions, such as bacteremia and sepsis.

https://doi.org/10.1128/spectrum.03541-22

Braun Lipoprotein Protects against Escherichia coli-Induced Inflammatory Responses and Lethality in Mice

Staphylococcus aureus (S. aureus) is one of the most infamous and widespread bacterial pathogens, causing a hard-to-estimate number of uncomplicated skin infections and probably hundreds of thousands to millions of more severe, invasive infections globally per year. S. aureus may also be acquired from animals, especially in the livestock industry. The interaction mechanism of host and S. aureus has significance for finding ways to against S. aureus infection and control inflammatory response of host, while the molecular biological activities after S. aureus infection, particular in inflammatory and immune cells are not fully clear. The present study aimed to explore whether pattern recognition receptors (PRRs) mediate prostaglandin D2 (PGD2) synthesis and PGD2 participates in the regulation of inflammatory response in macrophages during S. aureus infection or synthetic bacterial lipopeptide (Pam2CSK4) stimulation. PGD2 secretion level was enhanced by mice peritoneal macrophages infected with the S. aureus. The results indicated that PGD2 secretion was impaired in S. aureus infected-macrophages from toll-like receptors 2 (TLR2)-deficient and NLR pyrin domain-containing 3 (NLRP3)-deficient mice. PGD2 synthetase (hematopoietic PGD synthase, HPGDS) inhibitors could reduce the activation of macrophage mitogen-activated protein kinase (MAPK)/nuclear factor-κ-gene binding (NF-κB) signaling pathways. HPGDS inhibition impaired cytokines (TNF-α, IL-1β, IL-10 and RANTES) secretion and macrophage phagocytosis during S. aureus infection. In addition, inhibition of endogenous PGD2 synthesis was unable to affect the TLR2 and NLRP3 expression in S. aureus-infected macrophages. Taken together, macrophage PGD2 secretion after S. aureus infection depended on receptors TLR2 and NLRP3, and the induced PGD2 participated in the regulation of inflammatory response in S. aureus-infected macrophages. Interestingly, it was found that exogenous PGD2 down-regulated the cytokines secretion and had no effect on phagocytosis in the S. aureus-infected macrophages. 

Prostaglandin D2 is involved in the regulation of inflammatory response in Staphylococcus aureus-infected mice macrophages.

Mastitis is an inflammatory response of the mammary tissue caused by pathogenic bacterial infections, especially Staphylococcus aureus (S. aureus). Zearalenone (ZEA) is one of the common mycotoxins in moldy feed, which usually affects the cow's resistance to pathogenic microorganisms. However, it is not well understood whether ZEA affects the development of mastitis. Therefore, this study aimed to investigate the role of ZEA in the development of S. aureus-induced mastitis in mice. The results showed that administered daily by gavage for one week of ZEA (40 mg/kg) aggravated the severity of mastitis induced by S. aureus. Furthermore, we found that ZEA promotes the adhesion and invasion of S. aureus into mouse mammary epithelial cells (MMEC) by activating autophagy, and the activation of autophagy mediated by ROS-AMPK-m-TOR pathway. Taken together, the results showed that ZEA enhances S. aureus-induced mastitis susceptibility through activating autophagy mediated by ROS-AMPK-mTOR signaling pathway. 

ZEA mediates autophagy through the ROS-AMPK-m-TOR pathway to enhance the susceptibility of mastitis induced by Staphylococcus aureus in mice.

Associations of Ruminal Microbiota with Susceptibility to subacute Ruminal Acidosis in Dairy Goats.

Disturbances of the gut microbiota-derived tryptophan metabolites as key actors in vagotomy-induced mastitis in mice.

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