Gut microbial co-metabolite 2-methylbutyrylcarnitine exacerbates thrombosis via binding to and activating integrin α2ß1.

Thrombosis represents the leading cause of death and disability upon major adverse cardiovascular events (MACEs). Numerous pathological conditions such as COVID-19 and metabolic disorders can lead to a heightened thrombotic risk; however, the underlying mechanisms remain poorly understood. Our study illustrates that 2-methylbutyrylcarnitine (2MBC), a branched-chain acylcarnitine, is accumulated in patients with COVID-19 and in patients with MACEs. 2MBC enhances platelet hyperreactivity and thrombus formation in mice. Mechanistically, 2MBC binds to integrin α2ß1 in platelets, potentiating cytosolic phospholipase A2 (cPLA2) activation and platelet hyperresponsiveness. Genetic depletion or pharmacological inhibition of integrin α2ß1 largely reverses the pro-thrombotic effects of 2MBC. Notably, 2MBC can be generated in a gut-microbiota-dependent manner, whereas the accumulation of plasma 2MBC and its thrombosis-aggravating effect are largely ameliorated following antibiotic-induced microbial depletion. Our study implicates 2MBC as a metabolite that links gut microbiota dysbiosis to elevated thrombotic risk, providing mechanistic insight and a potential therapeutic strategy for thrombosis.

The preventive effects of Lactobacillus casei 03 on Escherichia coli-induced mastitis in vitro and in vivo.

BACKGROUND: Lactobacillus casei possesses many kinds of bioactivities, such as anti-inflammation and anti-oxidant, and has been applied to treating multiple inflammatory diseases. However, its role in mastitis prevention has remained ambiguous. METHODS: This study aimed to examine the mechanisms underlying the preventive effects of L. casei 03 against E. coli- mastitis utilizing bovine mammary epithelial cells (BMECs) and a mouse model. RESULTS: In vitro assays revealed pretreatment with L. casei 03 reduced the apoptotic ratio and the mRNA expression levels of IL1ß, IL6 and TNFα and suppressed phosphorylation of p65, IκBα, p38, JNK and ERK in the NF-κB signaling pathway and MAPK signaling pathway. Furthermore, in vivo tests indicated that intramammary infusion of L. casei 03 relieved pathological changes, reduced the secretion of IL1ß, IL6 and TNFα and MPO activity in the mouse mastitis model. CONCLUSIONS: These data suggest that L. casei 03 exerts protective effects against E. coli-induced mastitis in vitro and in vivo and may hold promise as a novel agent for the prevention and treatment of mastitis.

The Prevention Effect of Lactobacillus plantarum 17-5 on Escherichia coli-Induced Mastitis in Mice.

Mastitis is the most economically important disease affecting the dairy industry worldwide. Lactobacillus plantarum, an important probiotic with a wide range of applications, has potential anti-inflammatory properties and has become a currently strong candidate for mastitis therapies. In the current study, we evaluated the prevention effect of Lactobacillus plantarum 17-5 on Escherichia coli-induced mastitis in mice. The results showed that pretreatment with L. plantarum 17-5 maintained the integrity of tight junctions; improved inflammatory injury; decreased MPO activity and the mRNA expression levels of IL1ß, IL6, and TNFα; and inhibited the NF-κB and MAPK signaling pathways in mice mammary tissue. The results indicated that Lactobacillus plantarum 17-5 had excellent anti-inflammatory activities and could be developed into microecological preparation for clinical use to prevent mastitis.

Lactobacillus plantarum 17-5 attenuates Escherichia coli-induced inflammatory responses via inhibiting the activation of the NF-κB and MAPK signalling pathways in bovine mammary epithelial cells.

BACKGROUND: Mastitis is one of the most prevalent diseases and causes considerable economic losses in the dairy farming sector and dairy industry. Presently, antibiotic treatment is still the main method to control this disease, but it also brings bacterial resistance and drug residue problems. Lactobacillus plantarum (L. plantarum) is a multifunctional probiotic that exists widely in nature. Due to its anti-inflammatory potential, L. plantarum has recently been widely researched in complementary therapies for various inflammatory diseases. In this study, the apoptotic ratio, the expression levels of various inflammatory mediators and key signalling pathway proteins in Escherichia coli-induced bovine mammary epithelial cells (BMECs) under different doses of L. plantarum 17-5 intervention were evaluated. RESULTS: The data showed that L. plantarum 17-5 reduced the apoptotic ratio, downregulated the mRNA expression levels of TLR2, TLR4, MyD88, IL1ß, IL6, IL8, TNFα, COX2, iNOS, CXCL2 and CXCL10, and inhibited the activation of the NF-κB and MAPK signalling pathways by suppressing the phosphorylation levels of p65, IκBα, p38, ERK and JNK. CONCLUSIONS: The results proved that L. plantarum 17-5 exerted alleviative effects in Escherichia coli-induced inflammatory responses of BMECs.