Biology subjects

Nakato, G.

Publications and source records attributed to Nakato, G..

3 recordsLinked to original sources

bioRxiv2025

Development of the genetic toolkit identifies capsular polysaccharides as a competitive colonization factor in Ruminococcus gnavus

Ruminococcus gnavus is a commensal bacterium in the human gut associated with various diseases, and its abundance often increases in the intestines of patients with active inflammatory bowel disease (IBD). However, the genetic factors that establish gut colonization and virulence remain elusive due to the lack of a system for genetic modification. This study develops several genetic tools, including a shuttle vector, an inducible promoter, fluorescent proteins, and gene disruption or deletion systems in R. gnavus to identify the genes involved in R. gnavus colonization. Using these genetic tools, we found the respective sortase enzymes necessary for both cell wall localization of the superantigens and capsular polysaccharide (CPS) production in R. gnavus ATCC 29149. We identified the putative new gene cluster responsible for CPS production in the adjacent region of the sortase gene and confirmed that CPS production is crucial for competitive fitness during colonization in germ-free mouse intestines and that CPS production is inversely correlated with the inflammatory activity of R. gnavus. Furthermore, CPS cluster-possessing strains tended to be more prevalent in healthy human isolates compared to those from Crohns disease patients. This implies that CPS production is involved in their inflammatory activities and pathogenesis of intestinal diseases such as IBD. We highlight the potential of precise gene modification systems to identify the genetic factors that facilitate intestinal colonization and pathogenesis in gut bacteria.

microbiology↗

bioRxiv2022

Akkermansia Muciniphila induces chronic extramedullary hematopoiesis through cooperative IL-1R and TLR signals

Bacterial infections can activate and mobilize hematopoietic stem and progenitor cells (HSPCs) from the bone marrow (BM) to spleen, which is termed as extramedullary hematopoiesis (EMH). Recent studies suggest that commensal bacteria, particularly the microbiota, regulates not only the host immune system but also hematopoietic homeostasis. However, the impact of gut microbial species on hematopoietic pathology remains largely unknown. Here we found that systemic injection of Akkermansia muciniphila (A. m.), a mucin-degrading bacterium abundantly existing in the human gut rapidly activates BM myelopoiesis, and induces a slow but long-lasting hepato-splenomegaly, characterized by the expansion and differentiation of functional HSPCs, which we termed chronic EMH. Genetic deletion of Toll-like receptor-2 and -4 (TLR2/4) partially diminished A. m.-induced chronic EMH, while additional pharmacological inhibition of the interleukin-1 receptor (IL-1R) completely alleviated splenomegaly and EMH. Our results demonstrate that cooperative IL-1R- and TLR-mediated innate immune signals regulate commensal bacteria-driven EMH, which might be relevant for certain autoimmune disorders. Article SummaryThe aim of our study is to understand how Akkermansia muciniphila (A.m.), one of the major mucin-degrading microbial species in the human gut activate the immune and hematopoietic systems in a mouse model. We found that a single injection of the A.m. membrane fraction can induce long-lasting hepatosplenomegaly with splenic EMH through cooperative IL-1R- and TLR-mediated innate immune signals.

microbiology↗

bioRxiv2021

Hematopoietic stem and progenitor cells integrate Bacteroides-derived innate immune signals to promote gut tissue repair

Bone marrow (BM)-resident hematopoietic stem and progenitor cells (HSPCs) are often activated by bacterial insults to replenish the host hemato-immune system, but how they integrate the associated tissue damage signals to initiate distal tissue repair is largely unknown. Here, we showed that acute gut inflammation expands HSPCs in the BM through GM-CSFR activation, and directs them to inflamed mesenteric lymph nodes for further differentiation into myeloid cells specialized in gut tissue repair. We also identified that this process is exclusively mediated by Bacteroides, a commensal gram-negative bacteria, that activates innate immune signaling. In contrast, chronic gut inflammation reduces HSC potential for hematopoietic reconstitution and immune response against infection. Similarly, microbial signals contribute to aging-associated HSPC expansion. These findings establish a cross-organ communication that promotes tissue regeneration, but if sustained, impairs tissue homeostasis that may be relevant to aging and chronic disorders. SummaryThe infiltrating microbiota Bacteroides upon acute colitis directed MPP migration from the BM to the MLN for their subsequent expansion and differentiation into tissue-repairing Ly6C+/G+ cells, whereas chronic colitis impairs HSC functionality similarly as aging.

pathology↗