Biology subjects

Sasaki, N.

Publications and source records attributed to Sasaki, N..

10 recordsLinked to original sources

bioRxiv2026

Microbiota-derived pantothenic acid rapidly restores colonic mucus barrier after antibiotic-induced dysbiosis

The intestinal mucus layer forms the primary physical barrier separating the host epithelium from the gut microbiota. Antibiotic-induced dysbiosis compromises this barrier, yet the microbial metabolites and host mechanisms responsible for its rapid restoration remain poorly understood. Here, we identify pantothenic acid (vitamin B5) as a microbial metabolite that rapidly restores colonic mucus integrity following antibiotic administration. Integrated 16S rRNA gene sequencing and metabolomic profiling of murine feces revealed a positive association between Muribaculaceae abundance, fecal pantothenic acid level, and colonic mucus thickness. Among four isolated Muribaculaceae species, only Sangeribacter muris produced pantothenic acid. An exogenous pantothenic acid supplement quickly restored the thin mucus layer. This rapid response occurred without detectable transcriptional activation. This response did not recur in isolated colonic epithelium or colonic organoids, indicating that pantothenic acid acts through a non-epithelial, non-autonomous mechanism. Together, these findings identify a previously unrecognized microbe-metabolite-host signaling pathway that rapidly regulates colonic mucus barrier homeostasis and reveal a local barrier-protective function of microbiota-derived pantothenic acid.

microbiology↗

bioRxiv2026

Maternal progesterone signaling establishes lifelong oral homeostasis

Pregnancy is accompanied by profound endocrine remodeling, yet the mechanisms by which maternal hormonal signals establish long-term tissue homeostasis remain largely unknown. Here we identify maternal progesterone signaling as a developmental cue that establishes lifelong oral homeostasis through a hormone-lipid-microbiome axis. We show that the membrane progesterone receptor mPR{delta} is selectively expressed in the developing and maternal submandibular glands, where it mediates non-genomic progesterone signaling to promote epithelial differentiation by driving the selective mobilization of docosahexaenoic acid (DHA). Loss of this pathway disrupts salivary gland maturation, reshapes the oral microbial ecosystem through the selective expansion of Pasteurellaceae, and causes local inflammation as well as systemic metabolic dysfunction. Mechanistically, antibiotic treatment abolishes these phenotypes, whereas transfer of the oral microbiota recapitulates disease, demonstrating that developmental defects in the host are translated into long-term pathology through the oral microbiome. Remarkably, maternal--but not adult--DHA supplementation restores salivary gland development and microbial homeostasis and prevents adult disease phenotypes, identifying a critical developmental window during which oral homeostasis is durably established. Collectively, these findings reveal a previously unrecognized maternal endocrine mechanism that establishes lifelong host-microbiome homeostasis and identify developmental programming as a fundamental principle linking maternal physiology to adult health. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=188 SRC="FIGDIR/small/743932v1_ufig1.gif" ALT="Figure 1"> View larger version (56K): org.highwire.dtl.DTLVardef@178cc90org.highwire.dtl.DTLVardef@1be04beorg.highwire.dtl.DTLVardef@29759dorg.highwire.dtl.DTLVardef@1e89994_HPS_FORMAT_FIGEXP M_FIG C_FIG

physiology↗

bioRxiv2025

Ketone-body receptor GPR109A suppresses hepatic inflammation via gut-liver axis regulation

The ketogenic diet (KD) promotes ketone body synthesis and has been used as an effective treatment for disorders such as epilepsy. Although elevated ketone bodies, including {beta}-hydroxybutyrate ({beta}HB) and acetoacetate, are thought to meditate the beneficial effects of the KD, the mechanisms underlying their metabolic actions remain incompletely understood. In this study, we focused on GPR109A, a receptor for {beta}HB with an unclear role in metabolic homeostasis. We employed KD and fasting models to examine metabolic changes under two distinct ketogenic conditions. Under KD conditions, Gpr109a-/- mice exhibited increased hepatic lipid accumulation, and subsequent hepatic inflammation and fibrosis. However, Gpr109a deletion did not exacerbate hepatic lipid accumulation or inflammation during short-term fasting, suggesting that GPR109A-mediated liver protection is specific to KD-induced metabolic stress rather than under fasting conditions. Mechanistic analysis revealed that GPR109A protects the liver from inflammation by maintaining intestinal barrier integrity. These findings highlight the novel protective mechanism of GPR109A, via the gut-liver axis, to sustain metabolic homeostasis during the KD. This study provides valuable insights into the physiological effects of ketone bodies.

physiology↗

bioRxiv2025

The pivotal role of a novel free fatty acid receptor GPR164 in the intestinal barrier function

GPR164 is a novel free fatty acid receptor, activated by both short-chain fatty acids and medium-chain fatty acids, and expressed throughout the gastrointestinal tract. Although GPR164 is reported to be involved in the release of gut hormones, the physiological functions of this receptor in the maintenance of intestinal homeostasis remain unclear. In this study, we explored the role of GPR164 in regulating intestinal barrier function using mice lacking Gpr164 gene (Gpr164-/-). A loss-of-function mutation in GPR164 promoted cell proliferation and disrupted the intestinal barrier function in both Caco-2 cell line and mice. Genome-wide RNA-seq analysis revealed that GPR164 deletion caused aberrant wnt/{beta}-catenin signaling, and the intraperitoneal injection of wnt/{beta}-catenin inhibitor ameliorated a series of abnormalities of Gpr164-/- mice. Gpr164-/- mice also exhibited gut microbial dysbiosis and severe inflammation, indicating that deletion of Gpr164 causes similar pathologies observed in patients with inflammation bowel disease (IBD). Thus, our findings uncover the pivotal role of GPR164 in the maintenance of intestinal barrier function, providing an attractive clinical target for IBD.

physiology↗

bioRxiv2024

C-C chemokine receptor 4 deficiency exacerbates early atherosclerosis in mice

Chronic inflammation via dysregulation of T cell immune responses is critically involved in the pathogenesis of atherosclerotic cardiovascular disease. Improving the balance between proinflammatory T cells and anti-inflammatory regulatory T cells (Tregs) may be an attractive approach for treating atherosclerosis. Although C-C chemokine receptor 4 (CCR4) has been shown to mediate the recruitment of T cells to inflamed tissues, its role in atherosclerosis is unclear. Here, we show that genetic deletion of CCR4 in hypercholesterolemic mice accelerates the development of early atherosclerotic lesions characterized by an inflammatory plaque phenotype. This was associated with the augmentation of proinflammatory T helper type 1 (Th1) cell responses in peripheral lymphoid tissues, para-aortic lymph nodes, and atherosclerotic aorta. Mechanistically, CCR4 deficiency in Tregs impaired their suppressive function and tended to inhibit their migration to the atherosclerotic aorta, and subsequently augmented Th1 cell-mediated immune responses through defective regulation of dendritic cell function, which accelerated aortic inflammation and atherosclerotic lesion development. Thus, we revealed a previously unrecognized role for CCR4 in controlling the early stage of atherosclerosis via Treg-dependent regulation of proinflammatory T cell responses. Our data suggest that CCR4 is an important negative regulator of atherosclerosis.

immunology↗

bioRxiv2024

Comprehensive gene expression analysis of organoid-derived healthy human colonic epithelium and cancer cell line by stimulated with live probiotic bacteria

The large intestine has a dense milieu of indigenous bacteria, generating a complex ecosystem with crosstalk between individual bacteria and host cells. In vitro host cell modeling and bacterial interactions at the anaerobic interphase have elucidated the crosstalk molecular basis. Although classical cell lines derived from patients with colorectal cancer including Caco-2 cells are used, whether they adequately mimic normal colonic epithelial physiology is unclear. To address this, we performed transcriptome profiling of Caco-2 and Monolayer cells derived from healthy Human Colonic Organoid (MHCO) cultured hemi-anaerobically. Coculture with the anaerobic gut bacteria, Bifidobacterium longum subsp. longum differentiated the probiotic effects of test cells from those of physiologically normal intestinal and colorectal cancer cells. We cataloged non- or overlapping gene signatures where gene profiles of Caco-2 cells represented absorptive cells in the small intestinal epithelium, and MHCO cells showed complete colonic epithelium signature, including stem/progenitor, goblet, and enteroendocrine cells colonocytes. Characteristic gene expression changes related to lipid metabolism, inflammation, and cell-cell adhesion were observed in cocultured live Bifidobacterium longum and Caco-2 or MHCO cells. B. longum-stimulated MHCO cells exhibited barrier-enhancing characteristics, as demonstrated in clinical trials. Our data represent a valuable resource for understanding gut microbe and host cell communication.

ecology↗

bioRxiv2023

Ultra-Rapid and Specific Gelation of Collagen Molecules for Transparent and Tough Gels by Transition Metal Complexation

Collagen is one of the main components of tumor stromal tissues with a high elastic modulus, but there have been limitations when attempting to fabricate a tough collagen gel with cells like a cancer stroma. Here, we demonstrate the rapid and specific formation of collagen gels with high transparency and high elastic modulus by transition metal complexation within minutes. Transition metal ions such as K2PtCl4 exhibited rapid gelation due to the formation of a cross-linked network of the collagen triple-helix by Pt- O and/or Pt-N bonds. Interestingly, type I to IV collagens showed rapid gelation, while other extracellular matrices and DNA did not exhibit this phenomenon, suggesting the importance of intermolecular interaction in a rigid triple-helix structure. Live imaging of colon cancer organoids in three-dimensional culture indicated a collective migration property with modulating high elastic modulus, suggesting activation for metastasis progress. This technology that facilitates deep-live observation and mechanical stiffness adjustment will be useful as a new class of scaffolds. TeaserTransparent collagen gels with tunable mechanical properties allow deep-live observation of cells cultured in a tough environment like our bodies.

bioengineering↗

bioRxiv2021

Violet light modulates the central nervous system to regulate memory and mood

Light stimuli from the external environment serves as a signal. Photoreceptors receive photons at the outer nuclear layer of the retina. Non-visual photoreceptors, such as opsin5 (also known as OPN5 or neuropsin), are expressed in the retinal ganglion cells (RGCs) and hypothalamus to regulate the circadian cycle and body temperature. Here, we show that violet light (VL) stimuli received by OPN5-positive RGCs are transmitted to the habenula brain region. VL improves memory in aged mice and simultaneously increases neural architecture-related genes such as oligodendrocyte-related genes in the hippocampus. In addition, VL improves depressive-like behaviors in the social defeat stress model in an OPN5 dependent manner. Following VL exposure, cFos activation is observed at the nucleus accumbens (NAc) and the paraventricular thalamic nucleus (PVT). Taken together, the results indicate that violet light modulates brain function such as memory and mood by transmitting the signal from RGCs to the habenula region in the brain.

neuroscience↗

bioRxiv2020

PD-L1 expression in equine malignant melanoma and functional effects of PD-L1 blockade

Programmed death-1 (PD-1) is an immunoinhibitory receptor expressed on exhausted T cells during chronic illness. Interaction of PD-1 with its ligand PD-ligand 1 (PD-L1) delivers inhibitory signals and impairs proliferation, cytokine production, and cytotoxicity of T cells. We reported that the PD-1/PD-L1 pathway is closely associated with T-cell exhaustion and disease progression in bovine chronic infections and canine tumors. Moreover, we found that blocking antibodies targeting PD-1 and PD-L1 restore T-cell functions and may be used in immunotherapy in cattle and dogs. However, the immunological role of the PD-1/PD-L1 pathway remains unclear for chronic equine diseases, including tumors. In this study, we identified nucleotide sequences of equine PD-1 (EqPD-1) and PD-L1 (EqPD-L1) and investigated the role of anti-bovine PD-L1 monoclonal antibodies (mAbs) against EqPD-L1 using in vitro assays. We also evaluated the expression of PD-L1 in tumor tissues of equine malignant melanoma (EMM). The amino acid sequences of EqPD-1 and EqPD-L1 share a high identity and similarity with homologs from other mammalian species. Two clones of the anti-bovine PD-L1 mAbs recognized EqPD-L1 in flow cytometry, and one of these cross-reactive mAbs blocked the binding of equine PD-1/PD-L1. Importantly, PD-L1 expression was confirmed in EMM tumor tissues by immunohistochemistry. A cultivation assay revealed that PD-L1 blockade enhanced the production of Th1 cytokines in equine immune cells. These results suggest that our anti-PD-L1 mAbs may be useful for investigating the expression and role of the equine PD-1/PD-L1 pathway. Further research is required to discover the immunological role of PD-1/PD-L1 in chronic equine diseases and elucidate a future application in immunotherapy for horse.

immunology↗

bioRxiv2018

cTAGE5 acts as a Sar1 GTPase regulator for collagen export

Secretory proteins synthesized within the endoplasmic reticulum (ER) are exported via coat protein complex II (COPII)-coated vesicles. The formation of the COPII-coated vesicles is initiated by activation of the small GTPase, Sar1. cTAGE5 directly interacts with a guanine-nucleotide exchange factor (GEF), Sec12, and a GTPase-activating protein (GAP) of Sar1, Sec23. We have previously shown that cTAGE5 recruits Sec12 to the ER exit sites for efficient production of activated Sar1 for collagen secretion. However, the functional significance of the interaction between cTAGE5 and Sec23 has not been fully elucidated. In this study, we showed that cTAGE5 enhances the GAP activity of Sec23 toward Sar1. In addition, the interaction of cTAGE5 with Sec23 is necessary for collagen exit from the ER. Our data suggests that cTAGE5 acts as a Sar1 GTPase regulator for collagen secretion.

cell biology↗