Biology subjects

Meng, C.

Publications and source records attributed to Meng, C..

At least 19 recordsLinked to original sources

bioRxiv2026

PlantRegMoD: An integrative and AI-driven multi-omics database for plant regeneration research

Plant regeneration underpins plant developmental plasticity, tissue culture, genetic transformation and crop improvement. Although numerous related omics datasets have been generated, specialized multi-omics databases for this field are still scarce. Here, we constructed PlantRegMoD, an AI-powered integrated database dedicated to plant regeneration. This platform hosts 20.54 TB standardized multi-omics data from 147 projects across 32 plant species and 2,593 samples. We established a unified hierarchical classification system covering five major categories and nine regeneration models, and curated 236 regeneration genes as well as their 28,190 homologs across 58 representative plant species. It contains extensive transcriptomic resources across all regeneration models, together with 196,423 single cells and over 8.81 million epigenetic peaks to dissect cellular heterogeneity and multi-layered epigenetic regulation. Equipped with nine online omics-related tools and a RAG-based intelligent Q&A system, PlantRegMoD greatly reduces bioinformatic barriers and serves as a robust resource for mechanistic, functional and evolutionary studies of plant regeneration.

plant biology↗

bioRxiv2026

Distinct colorectal cancer genotypes shape microbial ecosystems and reveal stage-specific microbiota dependencies

The gut microbiota has emerged as an important modifier of colorectal cancer (CRC), yet how tumor genotype influences host-microbiota interactions and whether microbial signals are required throughout tumor progression remain unclear. Here, we combined genetically engineered mouse models, microbial multi-omics and a germ-free-compatible orthotopic transplantation system to define the functional contribution of the microbiota across distinct stages of CRC evolution. Across multiple CRC genotypes, we identified tumor-associated microbial ecosystem states characterized by distinct taxonomic, functional and metabolic configurations. To directly test their contribution to tumor progression, we established the first orthotopic CRC transplantation platform compatible with long-term experimentation in germ-free mice, enabling side-by-side comparison of genetically identical tumors in the presence or absence of microbiota. Using organoids spanning low-grade adenoma, high-grade adenoma and adenocarcinoma states, we found that the dependence on the presence of microbiota progressively decreases during malignant evolution. Whereas adenoma-derived organoids exhibited profound dependence on microbial exposure and failed or were markedly impaired in establishing tumors under germ-free conditions, adenocarcinoma organoids engrafted and metastasized in both germ-free and specific pathogen-free (SPF) hosts. Unexpectedly, comprehensive histological, immunological and transcriptomic analyses revealed highly similar tumor ecosystem states in advanced tumors arising under both microbial conditions, arguing against broad immune or epithelial defects as a primary explanation for the observed phenotype. Together, our findings demonstrate that distinct oncogenic drivers establish specific microbial ecosystem states and reveal a stage-dependent role of the microbiota during colorectal tumorigenesis. Whereas microbial signals are critical during early stages of tumor progression and may promote malignant transformation, advanced tumors progressively acquire microbiota-independent growth programs and increasingly impose genotype-specific ecological signatures on the surrounding microbial ecosystem. More broadly, we establish a versatile framework for the causal dissection of tumor-microbiota interactions in cancer.

cancer biology↗

bioRxiv2026

Improve the Efficacy of B7-H3-Targeting Antibody-Drug Conjugate DS-7300a in TP53-deficient Tumors by Inducing Ferroptosis

Immune checkpoint B7-H3 is an emerging target for immunotherapy. DS-7300a is an advanced B7-H3-targeting antibody-drug conjugate (ADC) warheaded with the topoisomerase I inhibitor DXd. DS-7300a has demonstrated clinical activity, but molecular biomarkers to predict its therapeutic response remain elusive. TP53 is one of the most mutated tumor suppressor genes across cancers, and effective therapies are urgently needed for TP53-deficient cancers. Using prostate cancer (PCa) as a model system, we reported that DS-7300as anti-tumor efficacy is highly dependent on functional p53 in cancer cells, and TP53 defects confer resistance to DS-7300a. Mechanistically, we found that DS-7300a and its payload, DXd, induce DNA damage and activate the ATM/ATR/CHK signaling cascade, thereby stabilizing p53 and inducing a pro-apoptotic and senescence-associated transcriptome. In contrast, TP53-deficient cells fail to detect DXd-induced DNA damage, maintain a high proliferation rate, and exhibit low levels of apoptosis and senescence, thereby conferring resistance to DS-7300a. Ferroptosis is an iron-dependent form of regulated cell death triggered by lipid peroxidation, which is mechanistically and morphologically distinct from apoptosis. Interestingly, DS-7300a treatment elevates lipid peroxidation in TP53-deficient cancer cells and upregulates glutathione peroxidase 4 (GPX4), an antioxidant enzyme that mitigates lipid peroxidation. Using isogeneic xenograft models and a newly developed humanized B7-H3 PCa model, we demonstrated that inducing ferroptosis by pharmacological inhibition of GPX4 enhances DS-7300as efficacy in TP53-deficient tumors. Our studies demonstrate that TP53 status dictates anti-tumor responses to DS-7300a, and ferroptosis induction represents a promising therapeutic approach to overcome resistance to DS-7300a in malignancies harboring TP53 defects.

cancer biology↗

bioRxiv2026

THIK-1 channel mediates microglial glucose sensing and modulates AgRP neurons

Microglia play essential roles in maintaining energy homeostasis, and their dysfunction contributes to metabolic disease. Although high-fat diet (HFD) exposure induces microglial activation, the underlying mechanisms remain poorly defined. Here, we identified a previously unrecognized role for THIK-1 channel in mediating glucose sensing of microglia in arcuate nucleus of the hypothalamus (ARH), during HFD-induced obesity. Pharmacological inhibition of THIK-1 channel with tetrapentylammonium (TPA) suppresses feeding and attenuates body-weight gain in diet induced obese mice. Mechanistically, inhibition of agouti-related peptide (AgRP) neurons is indispensable for TPA-induced hypophagia. Moreover, THIK-1 inhibition promotes microglial phagocytosis of perineuronal nets (PNNs), leading to reduced AgRP neuronal activity and feeding suppression. Together, these findings establish THIK-1 as a critical glucose sensor in hypothalamic microglia and uncover a microglia-dependent pathway through which overnutrition modulates AgRP neuronal activity via PNN remodeling to regulate energy balance, highlighting THIK-1 as a potential therapeutic target for treatment of diet-induced obesity.

neuroscience↗

bioRxiv2025

Semi-rational Engineering of Terminal Deoxynucleotidyl Transferase for High-efficiency Enzymatic de Novo DNA Synthesis

The 21st century has witnessed rapid advancements in synthetic biology, with DNA synthesis emerging as a foundational technology. Conventional phosphoramidite-based methods face significant limitations, including short DNA elongation lengths (<300 nt), hazardous chemical waste, and low stepwise incorporation efficiency. Enzymatic DNA synthesis using terminal deoxynucleotidyl transferase (TdT) offers a promising alternative, enabling kilobase-scale assembly with greater efficiency and minimal environmental impact. Here, we identified Bos taurus TdT (BtTdT) through UniProt database mining as a catalytically active scaffold for natural and 3'-modified dNTPs. Comprehensive characterization of BtTdTs enzymatic properties--including pH, temperature, metal ion dependence, and substrate specificity--revealed its optimal conditions. Truncation of the BRCT domain generated variants with enhanced activity compared to wild-type BtTdT. Guided by AlphaFold3-predicted structural models, we engineered a quintuple mutant (M5: Bt15AAR336L/K338G/L397M/E456S/D395G) optimized for 3'-ONH2-dNTP incorporation. M5 exhibited 30-fold activity enhancement relative to the triple mutant M3 (Bt15AAR336L/K338G/L397M) and achieved stepwise incorporation efficiency exceeding 98% in de novo synthesis of 10-nt ssDNA, demonstrating its potential for scalable enzymatic DNA synthesis. This work establishes a rational framework for TdT engineering through rational domain truncation and computational design, showing potential toward industrial-scale enzymatic DNA manufacturing.

synthetic biology↗

bioRxiv2025

Context-Dependent Metabolic Adaptation in Microbial Communities: From Monocultures to Complex Ecological Interactions

Microbial communities perform myriad functions in various environments, including the mammalian gut. These functions are largely based on the metabolic activity of microbial communities, which arises from the individual members contributions and their interactions. However, microbial functions and interactions are often inferred from simplified systems such as pure or pairwise cultures. Larger communities, in particular, are mainly analysed by metagenomics and the activity is deduced from the genetic potential of their community members. Although these approaches allow detailed insights into compositions, pairwise interactions and potential functions, they neglect the complexities of microbial communities, as evident in higher-order relationships, competition outcomes and the regulatory influence of environmental factors and other community members. Here, we study a mouse gut community along a gradient of complexity - from monocultures, to in vitro communities, to the mouse gut, to probe how bacteria adapt metabolically to their biotic and abiotic environments. Using metaproteomics to analyze realized bacterial niches and metabolic modeling to infer community interactions, we found that bacteria substantially modify their carbon source usage, biosynthetic activities, and protein allocation when grown in communities versus isolation. Furthermore, communities themselves adapted to their growth environment, changing in functionality as well as in the metabolic network between members. Host-associated communities isolated from the mouse gut invested in resource acquisition and utilized a broader spectrum of carbon sources, resulting in a large increase of predicted interactions between them. Our findings demonstrate the remarkable adaptability of microbes and microbial communities across environmental contexts. This underscores the critical need to study microbiomes under near-natural conditions and incorporate context-specific data into functional analyses.

systems biology↗

bioRxiv2025

Exploiting TGF-β-mediated Stromal Programming in Homologous Recombination-Deficient Pancreatic Cancer

The tumor microenvironment (TME) actively contributes to pancreatic ductal adenocarcinoma (PDAC) pathogenesis through dynamic bidirectional tumor-stroma interactions. Here, we demonstrate that homologous recombination-defective (HRD) tumor epithelium reprograms the TME in a genotype-specific manner to enhance cancer aggressiveness. Using genetically engineered mouse models, pancreatic stellate cell (PSC) and cancer-associated fibroblast (CAF) co-culture systems, single-nucleus multiomics, and human PDAC models, we show that tumoral loss of ATM serine/threonine kinase drives CAFs toward SMA+ myofibroblastic differentiation, independently of P53 status. These myCAFs, in turn, promote cancer aggressiveness and chemoresistance. Mechanistically, ATM deficiency increases reactive oxygen species and contractility signaling, enhancing TGF-{beta}1 secretion. Pharmacological TGF-{beta} inhibition reverses myCAF differentiation, sensitizes tumors to chemotherapy, and impairs tumor progression in both murine and human ATM-null models. Our findings reveal that ATM-deficient tumors shape a cancer-promoting niche via TGF-{beta} signaling and identify dual targeting of intrinsic and extrinsic vulnerabilities as a promising precision oncology strategy. SIGNIFICANCEHRD pancreatic cancers reprogram the tumor microenvironment in a genotype-specific manner through TGF-{beta}-driven myCAF-enrichment. Targeting this stromal axis alongside platinum-based chemotherapy improves therapeutic efficacy in ATM-deficient models. These findings highlight the need to integrate epithelial genotype and stromal context for truly personalized treatment strategies in PDAC.

cancer biology↗

bioRxiv2024

Adaptation to cystine limitation stress promotes PDAC tumor growth and metastasis through translational upregulation of OxPPP

Cystine/cysteine is critical for antioxidant response and sulfur metabolism in cancer cells and is one of the most depleted amino acids in the microenvironment of pancreatic ductal adenocarcinoma (PDAC). The effects of cystine limitation stress (CLS) on PDAC progression are poorly understood. Here we report that adaptation to CLS (CLSA) promotes PDAC cell proliferation and tumor growth through translational upregulation of the oxidative pentose phosphate pathway (OxPPP). OxPPP activates the de novo synthesis of nucleotides and fatty acids to support tumor growth. On the other hand, CLSA-mediated lipidomic reprogramming depends on triacylglycerides synthesis and lipid droplet formation to mitigate lipotoxicity. Through drug screening, we identify lomitapide as an inhibitor of CLSA PDAC tumor growth and a potent sensitizer of chemotherapy. Lomitapide inhibits triacylglycerides synthesis to interfere with CLSA and chemotherapy-induced lipidomic reprogramming. Taken together, we demonstrate that CLSA promotes PDAC tumor growth through metabolic reprogramming and lomitapide could be used to target the dysregulated lipid metabolism in PDAC.

cancer biology↗

bioRxiv2024

Intelligence and Cognitive Flexibility Selectively Modulate Working Memory Functioning

Working memory is a key component of intelligence, which can be underpinned by task connectome, while cognitive flexibility plays a role in adaptive and executive function that supports working memory processes. However, it remains unknown how intelligence and cognitive flexibility modulate working memory functioning, in terms of behavioural performance and task-related brain hierarchy. Current study investigated the working memory task-related behaviour and brain connectomic gradient in healthy adults together with their intelligence and cognitive flexibility measures. Results showed cognitive flexibility and intelligence were not significantly correlated with each other but with working memory function. Principal component and partial least square analysis revealed that nearly half of variance was explained by their overlap component, which linked with task gradient values of frontoparietal and ventral attention network representing executive, control and cognitive functioning. Individuals with higher intelligence and cognitive flexibility showed less distance between frontoparietal/ventral attention network and unimodal regions in gradient axis during working memory performance. Further analyses demonstrated that task gradient of frontoparietal and ventral attention network was significantly associated with working memory function, and selectively mediated by cognitive flexibility and intelligence, which may suggest partly convergent neural mechanisms for higher order functions that are involved in working memory functioning. In conclusion, current study provides new insight into the relationship among task connectomic gradient, working memory, intelligence, and cognitive flexibility, which helps understand the multi-component model of working memory and underlying task gradient principle.

neuroscience↗

bioRxiv2024

Assembling Ruthenium Complexes to Form Ruthenosome Unleashing Ferritinophagy-mediated Tumor Suppression

AbstactWe introduce ruthenosomes, a fusion of liposomal and reactive oxygen species (ROS)-generating properties meticulously engineered as potent ferroptosis inducers (FINs), marking a significant advancement in metallodrug design for cancer therapy. Formed through the self-assembly of oleate-conjugated ruthenium complexes, these ruthenosomes exhibit exceptional cellular uptake, selectively accumulating in mitochondria and causing substantial disruption. This targeted mitochondrial damage significantly elevates ROS levels, triggering autophagy and selectively activating ferritinophagy. Together, these processes sensitize cancer cells to ferroptosis. In vivo, ruthenosomes effectively suppress colorectal tumor growth, underscoring their therapeutic potential. Our study pioneers a design strategy that transforms ruthenium complexes into liposome-like structures capable of inducing ferroptosis independent of light activation. By leveraging ruthenosomes as multifunctional nanocarriers, this research offers a versatile and powerful platform for ROS-mediated, ferroptosis-driven cancer cell eradication.

biochemistry↗

bioRxiv2024

Sodium butyrate is incorporated into central metabolism in fly head while inducing oxygen consumption increase

Butyrate has been proposed as a drug therapy by acting as a KDAC inhibitor and elevating protein acetylation, in particular on histones. Nonetheless, recent studies suggest that tissues such as the gut can utilize butyrate as a metabolite. We have previously shown that the addition of butyrate induces a rapid increase of oxygen consumption in whole Drosophila melanogaster heads. Here we show that while head oxygen consumption is increased by the addition of butyrate, no apparent changes are observed on the proteome and acetylome. Instead, we show that butyrate is metabolized and incorporated into the tricarboxylic acid cycle (TCA) cycle. Collectivity our data supports the notion that the therapeutic benefits of acute butyrate treatment may be also mediated by improving metabolic rates, rather than solely targeting the epigenome or acetylome.

biochemistry↗

bioRxiv2024

Microbiota metabolized Bile Acids accelerate Gastroesophageal Adenocarcinoma via FXR inhibition

BackgroundThe incidence of Barrett esophagus (BE) and Gastroesophageal Adenocarcinoma (GEAC) correlates with obesity and a diet rich in fat. Bile acids (BA) support fat digestion and undergo microbial metabolization in the gut. The farnesoid X receptor (FXR) is an important modulator of the BA homeostasis. The capacity of inhibiting cancer-related processes when activated, make FXR an appealing therapeutic target. In this work, we assess the role of diet on the microbiota-BA axis and evaluate the role of FXR in disease progression. ResultsHere we show that high fat diet (HFD) accelerated tumorigenesis in L2-IL1B mice (BE- and GEAC- mouse model) while increasing BA levels and enriching gut microbiota that convert primary to secondary BA. While upregulated in BE, expression of FXR was downregulated in GEAC in mice and humans. In L2-IL1B mice, FXR knockout enhanced the dysplastic phenotype and increased Lgr5 progenitor cell numbers. Treatment of murine organoids and L2-IL1B mice with the FXR agonist obeticholic acid (OCA) deacelerated GEAC progression. ConclusionWe provide a novel concept of GEAC carcinogenesis being accelerated via the diet-microbiome-metabolome axis and FXR inhibition on progenitor cells. Further, FXR activation protected with OCA ameliorated the phenotype in vitro and in vivo, suggesting that FXR agonists have potential as differentiation therapy in GEAC prevention. Statement of significanceIf its inhibition is linked to disease progression and its activation to cancer prevention, exploring the potential of FXR as a therapeutic target has great clinical relevance in GEAC context.

cancer biology↗

bioRxiv2023

Diurnal rhythmicity of fecal microbiota and metabolite profiles in the first year of life: a randomized controlled interventional trial with infant formula

Microbiota assembly in the infant gut is influenced by time and duration of dietary exposure to breast-milk, infant formula and solid foods. In this randomized controlled intervention study, longitudinal sampling of infant stool (n=998) showed similar development of fecal bacterial communities (16S rRNA/shallow metagenomics sequencing) between formula- and breast-fed infants during the first year of life (N=210). Infant formula supplemented with galacto-oligosaccharides (GOS) was most efficient to sustain high levels of bifidobacteria compared to formula containing B. longum and B. breve or placebo. In addition to primary endpoints, metabolite and bacterial profiling revealed 24-hour oscillations and data integration identified circadian networks. Rhythmicity in bacterial diversity, specific taxa and functional pathways increased with age and was strongest following breast-feeding and GOS-supplementation. Circadian rhythms in dominant taxa were discovered ex-vivo in a chemostat model. Hence, microbiota rhythmicity develops early in life, likely via bacterial intrinsic clock mechanism and is affected by diet.

microbiology↗

bioRxiv2023

Profiling of the Helicobacter pylori redox switch HP1021 regulon using a multi-omics approach

The gastric human pathogen Helicobacter pylori has developed mechanisms to combat stress factors, including reactive oxygen species (ROS), which are present in the stomachs harsh environment. Here, we present a comprehensive study on the redox switch protein HP1021 regulon combining transcriptomic, proteomic and DNA-protein interactions analyses. Our results indicated that HP1021 decides about H. pylori response to oxidative stress. HP1021 regulon included 498 genes, of which 411 responded to oxidative stress. HP1021 controlled typical ROS response pathways (katA, rocF) and less canonical ones, particularly DNA uptake and central carbohydrate metabolism. We identified HP1021 as the first molecular regulator of competence in H. pylori, as HP1021-dependent repression of the comB DNA uptake genes was relieved under oxidative conditions, increasing natural competence. Furthermore, HP1021 controlled glucose consumption by directly regulating the gluP transporter and had an important impact on maintaining the energetic balance in the cell.

molecular biology↗

bioRxiv2023

Untargeted metabolomics reveals PTI-associated metabolites in cultivated tomato

Plants employ a multi-layered innate immune system to detect and fend off invading fungal pathogens. In one such layer, recognition of Pathogen- or Microbe-Associated Molecular Patterns or elicitors, triggers a signaling cascade that leads to defence against the pathogen and ultimately Pattern-Triggered Immunity (PTI). Secondary Metabolites (SMs) are expected to play an important role in this kind of resistance, because they are potentially mycotoxic compounds. Tomato plants inoculated with Alternaria solani show clear symptoms of infection 5 days after inoculation. Whereas plants inoculated with Alternaria alternata remain symptomless. We hypothesized that pattern-triggered induction of resistance-related metabolites in Solanum lycopersicum contribute to the resistance against A. alternata, yet such SMs are suppressed in a compatible interaction. We compared the metabolomic profile (metabolome) of S. lycopersicum at two time points (3 and 24 hours) after treatments with A. alternata, A. solani and the fungal elicitor chitin and identified SMs that are involved in the early defence response of tomato plants. Our study revealed differential metabolome fingerprints and shows that the molecular composition of A. alternata and chitin-induced indeed show larger overlap with each other than with the A. solani-induced metabolome. We identify 65 candidate metabolites possibly associated with pattern-triggered resistance in tomato plants, including the alkaloid, trigonelline, for which we can confirm that it inhibits fungal growth in vitro when supplied at physiological concentrations. Our findings show that a true, pattern-triggered, chemical defence is mounted against A. alternata and that it contains mycotoxin compounds previously unidentified in tomato, that could be interesting for future crop protection strategies.

plant biology↗

bioRxiv2023

Regulation of adaptive growth decisions via phosphorylation of the TRAPPII complex in Arabidopsis

Plants often adapt to adverse or stress conditions via differential growth. The trans-Golgi Network (TGN) has been implicated in stress responses, but it is not clear in what capacity it mediates adaptive growth decisions. In this study, we assess the role of the TGN in stress responses by exploring the interactome of the Transport Protein Particle II (TRAPPII) complex, required for TGN structure and function. We identified physical and genetic interactions between TRAPPII and shaggy-like kinases (GSK3/AtSKs). Kinase assays and pharmacological inhibition provided in vitro and in vivo evidence that AtSKs target the TRAPPII-specific subunit AtTRS120/TRAPPC9. GSK3/AtSK phosphorylation sites in AtTRS120/TRAPPC9 were mutated, and the resulting AtTRS120 phosphovariants subjected to a variety of single and multiple stress conditions in planta. The non-phosphorylatable TRS120 mutant exhibited enhanced adaptation to multiple stress conditions and to osmotic stress whereas the phosphomimetic version was less resilient. Higher order inducible trappii atsk mutants had a synthetically enhanced defect in root gravitropism. Our results suggest that the TRAPPII phosphostatus mediates adaptive responses to abiotic cues. AtSKs are multifunctional kinases that integrate a broad range of signals. Similarly, the TRAPPII interactome is vast and considerably enriched in signaling components. An AtSK-TRAPPII interaction would integrate all levels of cellular organization and instruct the TGN, a central and highly discriminate cellular hub, as to how to mobilize and allocate resources to optimize growth and survival under limiting or adverse conditions.

plant biology↗

bioRxiv2023

The Intestinal Clock Regulates Host Metabolism through the Fiber-Dependent Microbiome and Macronutrient Transcriptome.

Circadian disruption, e.g. through shift work, causes microbial dysbiosis and increases the risk of metabolic diseases. Microbial rhythmicity in mice depends on a functional intestinal clock and frequent jetlag as well as high-caloric energy intake induces loss of these oscillations. Similarly, arrhythmic microbiota was found in obese and T2D populations. However, the interplay between the intestinal circadian clock, the microbiome, diet and host metabolism is poorly understood. In intestinal-specific Bmal1 knockout mice (Bmal1IEC-/-) we demonstrate the relevance of the intestinal clock in microbiome oscillations and host and microbial nutrient metabolism. Microbiota transfer from Bmal1IEC-/- mice into germ-free recipients led to obesity, reflected by increased bodyweight and fat mass. Western diet-fed Bmal1IEC-/- mice increased bodyweight likely through mechanisms involving the intestinal clock-control of lipid and hexose transporters. Additionally, we identified dietary fiber as novel link between circadian microbial rhythmicity, intestinal clock functioning and host physiology. Thus, revealing the potential of fiber-rich diet intervention as a non-invasive strategy targeting microbial oscillations in metabolic disease prevention.

molecular biology↗

bioRxiv2023

Targeting the intestinal circadian clock by meal timing ameliorates gastrointestinal inflammation

ObjectiveImpaired clock genes expression has been observed in biopsy samples from patients with inflammatory bowel disease (IBD). Disruption of circadian rhythms, which occurs in shift workers, has been linked to an increased risk of gastrointestinal diseases, including IBD. The intestinal clock balances gastrointestinal homeostasis by regulating the microbiome. Here we characterize intestinal immune functions in mice lacking the intestinal clock and IBD-relevant mouse model under different feeding conditions to describe the functional impact of the intestinal clock in the development of gastrointestinal inflammation. DesignTissues and fecal samples from intestinal clock-deficient mice (Bmal1IEC-/-) and mouse models for colitis (IL-10-/-, Bmal1IEC-/-xIL-10-/-, dextran sulfate sodium (DSS) administration) under ad libitum and restricted feeding (RF) conditions were used to determine the causal role of the intestinal clock for colitis. ResultsIn IL-10-/- mice, inflammation correlated with disrupted colon clock genes expression. Genetic loss of intestinal clock functions promoted DSS and IBD inflammatory phenotypes and dramatically reduces survival, and colonization with disease-associated microbiota in germ- free Bmal1IEC-/- hosts increased their inflammatory responses, demonstrating the causal role of colonic clock disruption and the severity of IBD. RF in IL-10-/- mice restored the colon clock and related immune functions, improved the inflammatory responses and rescued the histopathological phenotype. In contrast, RF failed to improve IBD symptoms in Bmal1IEC-/- xIL-10-/- demonstrating the significance of the colonic clock to gate the effect of RF. ConclusionWe provide evidence that inflammation-associated intestinal clock dysfunction triggers host immune imbalance and promotes the development and progression of IBD-like colitis. Enhancing intestinal clock function by RF modulates the pathogenesis of IBD and thus could become a novel strategy to ameliorate the symptoms in IBD patients.

physiology↗