Biology subjects

Kunisawa, J.

Publications and source records attributed to Kunisawa, J..

3 recordsLinked to original sources

bioRxiv2026

Akkermansia muciniphila-derived LPS links gut dysbiosis to pathogenic miR-21 signaling in experimental autoimmune encephalomyelitis.

Multiple sclerosis (MS) is a chronic T cell-mediated autoimmune disease characterized by blood-brain barrier (BBB) disruption, neuroinflammation, and demyelination of the central nervous system (CNS). Emerging evidence links gut microbiota to disease pathogenesis, but the microbial factors that regulate pathogenic microRNA (miRNA) programs are largely unknown. Here, using experimental autoimmune encephalomyelitis (EAE, a MS mouse model), we investigated whether gut microbiota exacerbate EAE pathogenesis by modulating host miRNA expression. Antibiotic-induced depletion of the gut microbiota markedly attenuated EAE scores and reduced circulating inflammatory miRNAs, with miR-21 emerging as the dominant pathogenic candidate. Functional inhibition of miR-21 significantly ameliorated disease severity and reduced CNS T-cell infiltration. Mechanistically, miR-21 enhanced IL-17 and GM-CSF production by CD4 T cells and promoted immune-cell entry into the CNS through endothelial activation and blood-brain barrier dysfunction. We identified a transient expansion of Akkermansia muciniphila during the prodromal phase of EAE that positively correlated with circulating miR-21 levels. Colonization of antibiotic-treated mice with A. muciniphila exacerbated EAE and increased serum miR-21, whereas monocolonization of germ-free mice was insufficient to induce systemic miR-21, indicating a requirement for an inflammatory host environment. Further analyses revealed that atypical lipopolysaccharides (LPS) derived from A. muciniphila induce epithelial miR-21 production through coordinated TLR2/TLR4 signaling. Circulating miR-21 subsequently promoted endothelial dysfunction through the TIMP3-ADAM17 pathway, facilitating pathogenic T-cell migration into the CNS. Importantly, circulating miR-21 was also elevated in patients with MS. Collectively, these findings identify a previously unrecognized A. muciniphila-LPS-miR-21 axis linking gut dysbiosis to neuroinflammation and suggest that host-derived miRNAs function as systemic mediators through which microbial signals influence CNS autoimmunity.

immunology↗

bioRxiv2026

Lipid A counteracts doxorubicin-induced systemic dysfunction by boosting mitochondrial activity

Vaccine adjuvants are critical for enhancing immune responses and sustaining antibody production. Although their safety profiles are well established, assessments have largely focused on metabolic and excretory organs such as the liver and kidneys, with limited attention to the heart. Here, we systematically evaluated the cardiac effects of five representative adjuvants in mice: alum, MF59, AS03, Sigma Adjuvant Systems, and lipid A. None of the adjuvants impaired baseline cardiac contractile function. Notably, lipid A uniquely enhanced mitochondrial respiratory capacity in rat and human induced pluripotent stem cell-derived cardiomyocytes and promoted mitochondrial membrane hyperpolarization. We next examined its therapeutic potential in a doxorubicin (Dox)-induced heart failure model characterized by mitochondrial dysfunction. Co-administration of lipid A with influenza hemagglutinin (HA) antigen significantly ameliorated cardiac dysfunction. In parallel, lipid A prevented the Dox-induced decline in anti-HA antibody titers, an effect associated with preservation of splenic B cell populations. Collectively, these findings reveal a previously unappreciated cytoprotective dimension of lipid A, demonstrating that it not only potentiates immune responses but also counteracts chemotherapy-induced functional decline by enhancing mitochondrial activity.

pharmacology and toxicology↗

bioRxiv2019

Mucin O-glycans facilitate symbiosynthesis to maintain gut immune homeostasis

The dysbiosis of gut microbiota has been implicated in the pathogenesis of inflammatory bowel diseases (IBDs); however, the underlying mechanisms have not yet been elucidated. Heavily glycosylated mucin not only establishes a first-line barrier against pathogens, but also serves as a niche for microbial growth. We hypothesized that dysbiosis may cause abnormal mucin utilization and microbial metabolic dysfunction. To test this hypothesis, we analyzed short-chain fatty acids (SCFAs) and mucin components in the stool samples of 40 healthy subjects, 49 ulcerative colitis (UC) patients, and 44 Crohns disease (CD) patients from Japan. The levels of n-butyrate were significantly lower in the stools of both the CD and UC patients than in those of the healthy subjects. Correlation analysis identified 7 bacterial species positively correlated with n-butyrate levels, among which the major n-butyrate producer, Faecalibacterium prausnitzii, was particularly underrepresented in CD patients, but not in UC patients. In UC patients, there were inverse correlations between mucin O-glycan levels and the production of SCFAs, such as n-butyrate, suggesting that mucin O-glycans act as an endogenous fermentation substrate for n-butyrate production. Indeed, mucin-fed rodents exhibited enhanced n-butyrate production, leading to the expansion of RORgt+Treg cells and IgA-producing cells in the colonic lamina propria. Importantly, the availability of mucin-associated O-glycans to the microbiota was significantly reduced in n-butyrate-deficient UC patients. Taken together, our findings highlight the biological significance of the symbiosynthesis pathway in the production of n-butyrate, which maintains gut immune homeostasis.

microbiology↗