Abstract Acute kidney injury (AKI) has considerably high morbidity and mortality but we do not have proper treatment for it. There is an urgent need to develop new prevention or treatment methods. Gut microbiota has a close connection with renal diseases and has become the new therapy target for AKI. In this study, we found the oral administration of the probiotic Limosilactobacillus reuteri had a prevention effect on the AKI induced by lipopolysaccharide (LPS). It reduced serum concentration of creatinine and urea nitrogen and protected the renal cells from necrosis and apoptosis. Meanwhile, L. reuteri improved the gut barrier function, which is destroyed in AKI, and modulated the gut microbiota and relevant metabolites. Compared with the LPS group, L. reuteri increased the proportion of Proteobacteria and reduced the proportion of Firmicutes, changing the overall structure of the gut microbiota. It also influenced the fecal metabolites and changed the metabolite pathways, such as tyrosine metabolism, pentose and glucuronate interconversions, galactose metabolism, purine metabolism, and insulin resistance. These results showed that L. reuteri is a potential therapy for AKI as it helps in sustaining the gut barrier integrity and modulating gut microbiota and related metabolites.
We sincerely appreciate the letter from you asking for more information about our work. Dr. Jaeschke and Dr. Ramachandran asked some questions which are useful for us to address. We will answer the questions as follows.
The global prevalence of allergic rhinitis (AR) remains high, posing challenges due to its chronic nature and propensity for recurrence. Gut microbiota dysbiosis contributes to immune dysregulation, impacting AR pathogenesis. Limosilactobacillus reuteri ( L. reuteri ) has great potential in regulating immune function to alleviate AR symptoms. However, the specific active components and mechanisms underlying its therapeutic effects in AR remain incompletely clarified. This study aimed to explore the potential mechanisms of L. reuteri and its metabolites in alleviating AR. The AR mouse model was constructed using ovalbumin (OVA). The analysis of hematoxylin–eosin staining (HE staining) and enzyme-linked immunosorbent assay (ELISA) suggested that L. reuteri alleviated nasal inflammation, suppressed aberrant Th2 immune responses, and modulated the balance of Treg and Th17 cytokines. The 16S rRNA sequencing and untargeted metabolic analysis revealed that L. reuteri restored gut microbiota composition and significantly increased the abundance of Ligilactobacillus and the metabolite luteolin (LO). Through ELISA and Western blotting analysis, LO treatment restored the Th1/Th2 and Treg/Th17 cytokine balance and suppressed the MAPK/STAT3 signaling pathway in AR mice. The study highlights LO as a key metabolite contributing to the anti-inflammatory effects of L. reuteri , suggesting potential avenues for future therapeutic strategies in AR management.
Severe fever with thrombocytopenia syndrome (SFTS) has become a global threat to public health since its first report in China in 2009. However, the pathogenesis of SFTS virus (SFTSV) in humans remains unclear. Also, there are no effective therapeutics for SFTS. Cyclophilin A (CyPA) regulates protein folding and trafficking involved in various viral infectious diseases, but its role in SFTSV infection has not been elucidated.We detected plasma CyPA levels in 29 healthy subjects and 30 SFTS patients by ELISA. In THP-1 cells and normal human peripheral blood mononuclear cells (PBMCs), SFTSV-induced extracellular CyPA (eCyPA) was also detected by ELISA. In THP-1, the effects of CyPA on Mitogen-activated protein kinase (MAPK) pathway and NF-κB were determined by Western blot. We validated the interaction between CypA and CD147 by human recombinant CyPA (hrCyPA) and the CD147 inhibitor. Effects of CyPA inhibitor Cyclosporine A (CsA) on cytokines and SFTSV replication in THP-1 cells was also detected. 8-week-old Interferon-α/β Receptor (IFNAR) knockout (IFNAR-/-) C57BL/6 mice were divided into mock group, 106TCID50 SFTSV (Untreated) group and 106TCID50 SFTSV+CsA (CsA-treated) group. The changes of body weight, animal behavior and survival time of each group were recorded. Blood samples were collected from tail vein regularly. After death, the liver, spleen, lung, kidney and brain were collected for pathological HE staining and SFTSV-NP immunohistochemical staining.Compared to healthy subjects and SFTS patients in the febrile phase of the disease, plasma CyPA levels in SFTS patients at the multi-organ dysfunction (MOD) phase showed significantly elevated (P < 0.01). Extracellular CyPA activates the MAPK pathway by binding to CD147 in THP-1 infected with SFTSV. CsA inhibits the pro-inflammatory and promoting replication effects of CyPA after SFTSV infection in vitro. In vivo, CsA can prolong the survival time and delay the weight loss of SFTSV mice. CsA reduces multi-organ dysfunction in IFNAR-/- mice infected with SFTSV.Our results indicate that CyPA is associated with SFTSV-induced cytokine storm, which can be a potential target for SFTS therapy.
Acetaminophen (APAP) overdose is one of the most common causes of acute liver injury (ALI) in Western countries. Many studies have shown that the gut microbiota plays an important role in liver injury. Currently, the only approved treatment for APAP-induced ALI is N-acetylcysteine; therefore, it is essential to develop new therapeutic agents and explore the underlying mechanisms. We developed a novel monoclonal anti-Toll-like receptor 4 (TLR4) antibody (ATAB) and hypothesized that it has therapeutic effects on APAP-induced ALI and that the gut microbiota may be involved in the underlying mechanism of ATAB treatment. Male C57BL/6 mice were treated with APAP and ATAB, which produced a therapeutic effect on ALI and altered the members of the gut microbiota and their metabolic pathways, such as Roseburia, Lactobacillus, Akkermansia, and the fatty acid pathway, etc. Furthermore, we verified that purified short-chain fatty acids (SCFAs) could alleviate ALI. Moreover, a separate group of mice that received feces from the ATAB group showed less severe liver injury than mice that received feces from the APAP group. ATAB therapy also improved gut barrier functions in mice and reduced the expression of the protein zonulin. Our results revealed that the gut microbiota plays an important role in the therapeutic effect of ATAB on APAP-induced ALI. IMPORTANCE In this study, we found that a monoclonal anti-Toll-like receptor 4 antibody can alleviate APAP-induced acute liver injury through changes in the gut microbiota, metabolic pathways, and gut barrier function. This work suggested that the gut microbiota can be a therapeutic target of APAP-induced acute liver injury, and we performed foundation for further research.
Background Severe fever with thrombocytopenia syndrome (SFTS) is an emerging infectious disease that was caused by the Dabie bandavirus (DBV), and it has become a global public health threat. Cytokine storm is considered to be an important pathogenesis of critical SFTS. Tripartite motif-containing 3 (TRIM3), as a member of the TRIM protein family, may contribute to the regulation of the immune and inflammatory responses after viral infection. However, whether TRIM3 plays a major role in the pathogenesis of SFTS has not yet been investigated. Methods TRIM3 mRNA levels were detected in PBMCs between 29 SFTS patients and 29 healthy controls by qRT-PCR. We established the pathogenic IFNAR −/− SFTS mouse model successfully by inoculating subcutaneously with DBV and testing the expression levels of TRIM3 mRNA and protein by qRT-PCR and immunofluorescence in the livers, spleens, lungs, and kidneys. TRIM3 OE THP-1 cells and peritoneal macrophages extracted from TRIM3 −/− mice were infected with DBV. The effect of TRIM3 on cytokines was detected by qRT-PCR and ELISA. Then we examined Toll-like receptor 3 (TLR3) and protein phosphorylation in the MAPK pathway after DBV infection using Western blot. Flow cytometry was used to verify TLR3 expression on peripheral blood monocytes in SFTS patients. We further explored the interaction between TRIM3 and TLR3 using CO-IP and Western blot. Results Compared to healthy controls, TRIM3 mRNA expression in PBMCs is decreased in SFTS patients, especially in severe cases. TRIM3 mRNA and protein were synchronously reduced in the livers, spleens, lungs, and kidney tissues of the IFNAR −/− SFTS mice model. In the DBV-infected cell model, TRIM3 overexpression can inhibit the DBV-induced release of IL-1β, IL-6, and TNF-α, the expression of TLR3, and protein phosphorylation in the MAPK pathway, which plays an anti-inflammatory role, while TRIM3 deficiency exacerbates the pro-inflammatory effects. We further found that TRIM3 can promote TLR3 degradation through K48-linked ubiquitination. Conclusion TRIM3 can inhibit the production of cytokines by regulating the degradation of TLR3 through K48-linked ubiquitination, which can be a therapeutic target for improving the prognosis of SFTS.
Acetaminophen induced acute liver injury (ALI) has a high incidence and is a serious medical problem, but there is a lack of effective treatment. The enterohepatic axis is one of the targets of recent attention due to its important role in liver diseases. Disulfiram (DSF) is a multitarget drug that has been proven to play a role in a variety of liver diseases and can affect intestinal flora, but whether it can alleviate ALI is not clear. We utilised bacterial 16S rRNA gene profiling, antimicrobial treatments, and faecal microbiota transplantation tests to explore whether DSF therapy for ALI is dependent on gut microbiota. Our findings indicate that DSF primarily restores intestinal microbiome balance by modulating the abundance of Akkermansia muciniphila (A. muciniphila), leading to significant alleviation of ALI symptoms in a gut microbiota dependent manner. We also found that A. muciniphila can promote the activation of PI3K/Akt pathway, correct the Bcl-2/Bax ratio, and further inhibit hepatocyte apoptosis. In conclusion, DSF ameliorates ALI by modulating the intestinal microbiome and activating the PI3K/AKT pathway through A. muciniphila.
Acetaminophen (APAP) overdose is one of the most common causes of acute liver injury (ALI) in Western countries. Many studies show that the gut microbiota plays an important role in liver injury. Currently, the only approved treatment for APAP-induced ALI is N-acetylcysteine; therefore, it is essential to develop new therapeutic agents and explore the underlying mechanisms. We developed a novel monoclonal anti-Toll-like receptor 4 (TLR4) antibody (ATAB) and hypothesized that it has therapeutic effects on APAP-induced ALI and that gut microbiota may be involved in the underlying mechanism of ATAB treatment. Male C57BL/6 mice were treated with APAP and ATAB, which produced a therapeutic effect on ALI and altered the gut microbiota and their metabolic pathway, such as Roseburia, Lactobacillus, Akkermansia, and the fatty acid pathway, etc. Furthermore, we verified that purified short-chain fatty acids (SCFAs) could alleviate ALI. Moreover, a separate group of mice that received feces from the ATAB group showed less severe liver injury compared with the mice receiving feces from the APAP group. ATAB therapy also improved the gut barrier functions in mice and reduced the expression of protein zonulin. Our results revealed that gut microbiota plays an important role in the therapeutic effect of ATAB on APAP-induced ALI. IMPORTANCE In this study, we found the monoclonal anti-Toll-like receptor 4 antibody can alleviate APAP-induced acute liver injury through the change of the gut microbiota, metabolic pathways, and gut barrier function. This work suggested the gut microbiota can be the therapeutic target of the APAP-induced acute liver injury, and we performed the fundamental research for further research.
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