Gut microbesYan Cheng, Zhanxuan E Wu, Ruoyue Huang, Qingmei Li, Dongmei Yan, Yuqi Chen, WeiFeng Zhu, Fei Li
Ulcerative colitis (UC) is a systemic disease that can involve multiple organs, and hepatobiliary diseases in UC patients are frequently observed. However, the pathogenesis of UC and its associated hepatobiliary complications remains elusive, and limited therapeutic options are available. This study revealed that disrupted hepatic lipid metabolism plays a pivotal role in driving the progression of UC and its extraintestinal hepatobiliary manifestations. Mechanistically, colitis-elevated circulating endogenous corticosterone (CORT) mediates the downregulation of hepatic LXRα-SCD1 signaling, resulting in diminished monounsaturated fatty acid (MUFA), reduced unsaturated lysophospholipids, and the accumulation of alkyl lysophospholipids, ceramide and hexosylceramide. These alterations contribute to liver lipotoxicity and, in turn, exacerbate colitis. A similar lipid profile is observed in UC patients. Importantly, pristimerin, a natural compound structurally similar to the star molecule celastrol, has been demonstrated to alleviate UC and concomitant liver injury by remodeling hepatic lipid metabolism in a microbiota-dependent manner. The gut commensal Lactobacillus johnsonii mediates the effects of PSM by activating hepatic LXRα-SCD1 signaling and increasing the potential anti-inflammation lipid species LPC20:2 and LPC20:3. This investigation suggests a novel therapeutic strategy for UC and associated liver injury based on the L. johnsonii-hepatic LXRα-SCD1 axis. This study also opens new avenues for mechanistic exploration of systemic diseases and therapeutic strategies of multi-organ comorbidity.
The membrane receptor MerTK is critical for the resolution of inflammation and thus is of pharmacological interest. MerTK function is inhibited by the proteolytic cleavage of its extracellular domain leading to the formation of soluble Mer (sMer). We describe here the NANOBODY molecule A0445046C08 and its half-life-extended version A044500050. Both bound selectively to MerTK and blocked lipopolysaccharide-induced MerTK cleavage in primary macrophages without influencing ligand binding or kinase activity of MerTK. A044500050 reduced Zymosan-induced sMer levels in the peritoneal lavage fluid of a mouse model with sterile peritonitis. The study demonstrates that NANOBODY molecules can be generated that selectively inhibit ectodomain shedding and outlines a novel pharmacological approach for targeting membrane proteins where aberrant cleavage plays a pathogenic role.
Gut microbesNesa Kazemifard, Shabnam Shahrokh, Georges Dimitrov, Mehdi Totonchi, Stefan Dimitrov
Inflammatory bowel disease (IBD), including Crohn's disease and ulcerative colitis, is increasingly recognized not merely as an immune-mediated disorder, but as a systems-level condition arising from dynamic interactions among host genetics, environmental exposures, the gut microbiome, and epigenetic regulation. While genetic susceptibility confers risk, accumulating evidence indicates that epigenetic mechanisms act as molecular integrators that translate environmental and microbial signals into sustained transcriptional programs governing immune tolerance, epithelial integrity and tissue repair. Concurrently, intestinal dysbiosis, characterized by loss of short-chain fatty acid-producing commensals and expansion of pro-inflammatory taxa, reshapes host metabolism and chromatin states through microbial-derived metabolites including short-chain fatty acids, secondary bile acids, and tryptophan catabolites. These metabolites affect epigenetic enzymes and modulate the epigenetic chromatin landscape as well as mitochondrial bioenergetics, linking microbial ecology to inflammatory gene regulation. In turn, epigenetic alterations in epithelial and immune compartments influence antimicrobial defense, barrier function, and cytokine networks, thereby sculpting microbial community organization. This bidirectional microbiome-epigenome dialogue creates self-reinforcing circuits that can either sustain mucosal homeostasis or drive chronic inflammation and colitis-associated tumorigenesis. In this review, we synthesize emerging insights into the microbiome-epigenome-mitochondrial axis in IBD and propose a conceptual framework in which metabolic, microbial, and genome-mediated signals converge to determine disease trajectory. We discuss how this integrative perspective may assist biomarker discovery and therapeutic innovation, including epigenetic modulators and microbiota-targeted interventions. Understanding IBD as a dynamically regulated host-microbe ecosystem may accelerate the development of precision strategies aimed at restoring resilient mucosal equilibrium.
Fusobacterium nucleatum (F. nucleatum) has been increasingly implicated in the pathogenesis of inflammatory bowel disease (IBD), yet the mechanisms underlying its effects remain incompletely defined. In this study, we integrated human fecal and mucosal samples, comparative metabolomics, multiple experimental colitis models, bacterial genetic manipulation, macrophage functional assays, and host signaling analyses to identify a macrophage-centered mechanism through which F. nucleatum exacerbates colitis. We show that F. nucleatum colonization increases intestinal and systemic levels of its metabolite succinic acid, upregulates the expression of its cognate receptor SUCNR1 on intestinal macrophages, activates NF-κB signaling, and promotes pro-inflammatory macrophage activation. This macrophage inflammatory response is associated with epithelial barrier disruption, increased epithelial apoptosis, and aggravated mucosal and systemic inflammation. A fumarate reductase-deficient (frdA-KO) F. nucleatum strain with impaired succinic acid production showed a markedly reduced capacity to activate macrophage NF-κB signaling, induce macrophage inflammatory activation, and aggravate colitis, whereas exogenous succinic acid restored these effects in the frdA-KO setting. Moreover, siSUCNR1 and pharmacological NF-κB inhibition substantially attenuated succinic acid-induced macrophage inflammatory activation, supporting the involvement of a SUCNR1-NF-κB signaling cascade. Collectively, these findings demonstrate that F. nucleatum exacerbates colitis by producing succinic acid and engaging SUCNR1-NF-κB-dependent inflammatory activation of macrophages, highlighting the F. nucleatum-succinic acid-SUCNR1-NF-κB axis as a potential therapeutic target in IBD.
Hematology (Amsterdam, Netherlands)Ojan Ghodsi, Ali Ghasemi, Saleh Ahangari
OBJECTIVE: Gastrointestinal bleeding (GIB) is a major cause of morbidity in von Willebrand disease (vWD), most commonly resulting from angiodysplasia. Current obscure gastrointestinal bleeding (OGIB) algorithms are primarily anatomy-based and often overlook underlying hemostatic disorders, delaying diagnosis and promoting recurrent bleeding. This review summarizes current evidence on the molecular basis, diagnosis, and management of vWD-associated GIB and proposes a mechanism-oriented diagnostic framework. METHODS: A comprehensive narrative review of experimental, translational, and clinical studies was conducted, focusing on inherited vWD, acquired von Willebrand syndrome (AvWS), gastrointestinal angiodysplasia, endothelial biology, and diagnostic and therapeutic strategies. RESULTS: Deficiency or dysfunction of high-molecular-weight von Willebrand factor (vWF) multimers promotes angiodysplasia by disrupting Weibel-Palade body homeostasis, enhancing Ang-2/Tie2 and VEGF signaling, impairing integrin αvβ3 function, and fostering pro-inflammatory endothelial activation. Genetic and epigenetic modifiers, including FLI1, STXBP5, ABO blood group, and miR-24, further influence vascular susceptibility. Based on these mechanisms, we propose a four-stage diagnostic framework integrating bleeding assessment, platelet function screening, and targeted vWF testing with conventional endoscopic evaluation to facilitate earlier recognition of vWD/AvWS in patients with recurrent or obscure GIB. This strategy supports mechanism-based treatment combining hemostatic replacement therapies with selected anti-angiogenic approaches. CONCLUSION: vWD-associated GIB should be regarded as a systemic vascular-hemostatic disorder rather than an isolated structural gastrointestinal disease. Integrating hemostatic evaluation into OGIB pathways may improve diagnostic accuracy, reduce unnecessary procedures, and enable personalized management of patients with recurrent bleeding.
Gut microbesPranvera Hiseni, Kari Furu, Vivian Wang Pedersen, Lise Øverland, Graceline Tina Kirubakaran, Christina Casén
Defining clinically meaningful reference states of the human gut microbiota remains a major barrier to the clinical translation of microbiome testing, largely due to variability across populations. We aimed at evaluating whether dysbiosis can be identified in a standardized, geography-independent manner, using a composite, system-level microbiome diagnostic framework. We performed a retrospective observational analysis of 831 adult stool samples collected from healthy individuals and patients with inflammatory bowel disease, irritable bowel syndrome, or other chronic inflammatory conditions across seven countries. In addition, U.S. National Institute of Standards Technology (NIST) human fecal reference materials were analyzed. Dysbiosis was assessed using a fixed microbial marker panel and composite distance metrics anchored to a clinically validated healthy Scandinavian reference population, using GA-map® Dysbiosis Test as an exemplar of this diagnostic framework. The diagnostic framework reproducibly identified normobiosis and dysbiosis across geographically distinct populations (USA, Canada, Germany, Italy, and the UK). Severe dysbiosis was detected with high specificity (93.6%) and positive predictive value (90.2%), independent of subjects' country of origin. Healthy individuals showed highly comparable dysbiosis index distributions across regions. These findings demonstrate that clinically useful dysbiosis diagnostics do not require geographically tailored reference populations and support the feasibility of standardized, geography-independent microbiome diagnostics for clinical application.
Gut microbesAnna A Bogdanova, Andrea Borbón-García, Ruth E Ley, Alexander V Tyakht
Flagellin, the structural protein of bacterial flagella, activates the innate immune receptor Toll-like receptor 5 (TLR5). However, the ability of different flagellins to bind and stimulate TLR5 varies widely, suggesting that the composition of an individual's flagellin repertoire, defined as flagellome, may influence host-microbiome interactions and inflammation. Here, we developed FlaPro, a computational pipeline for quantification and functional annotation of human gut flagellomes. Functional categories in FlaPro are derived from a machine learning model trained on experimentally characterized flagellins with defined TLR5-binding and stimulatory activities. Application of FlaPro to a multi-omics inflammatory bowel disease (IBD) cohort revealed a marked depletion of flagellome diversity and a reduced ratio of silent to stimulatory flagellins in Crohn's disease and ulcerative colitis. These alterations were consistent across genomic and transcriptional layers, indicating a disease-associated shift toward more stimulatory flagellome profiles. Our findings suggest that specific features of the gut flagellome contribute to TLR5-mediated immune activation and may serve as functionally interpretable microbiome markers for future microbiome-wide association studies in health and disease. The workflow implemented in Snakemake is openly available at https://github.com/leylabmpi/FlaPro.
OncoimmunologySabina Niyazova, Christine Sers, Hendrik Bläker, David Horst, Wolfgang Schmitt, Zehra Karadeniz, Simon Schallenberg, Alexej Ballhausen, Dominik P Modest, Colin…
Early-stage colorectal cancer (CRC) with confirmed microsatellite instability generally has a favorable prognosis associated with pronounced immune infiltration. However, some patients still develop metastases. The underlying mechanisms, particularly those related to the tumor immune microenvironment, remain incompletely understood. The study included tissue samples from 217 patients with dMMR/MSI-H CRC, comprising 89 stage III/IV and 128 stage I/II cases. Tissue microarrays and immunohistochemical analyzes were performed for all cases. We evaluated immune markers identifying T cells, B cells, dendritic cells, natural killer cells, macrophages, immunosuppressive markers, and immune checkpoint targets in epithelial and stromal compartments, and additionally performed a cohort-derived immune infiltration score (IIS). The survival analysis assessed the prognostic impact of immune markers stratified by tumor stage. Stage I/II dMMR/MSI-H CRCs showed significantly higher CD3⁺ T-cell and natural killer cell levels, higher IIS metrics across all regions, and higher CD4⁺ T helper cell levels in the stroma. Stage III/IV cases exhibited increased epithelial expression of indoleamine 2,3-dioxygenase 1. Given the limited number of stage IV patients, an additional stage III vs. stage I/II comparison was performed, revealing that these immune differences were already evident at the level of nodal progression. In addition, CD3⁺, CD4⁺, and CD8⁺ T cells and the IIS showed varying prognostic associations across tumor stages. These findings suggest that the overall immunogenicity and prognostic relevance of immune markers in dMMR/MSI-H CRC depend on tumor stage. Immune profiling could be used for early-stage patient stratification and also suggests the potential benefit of early immunotherapeutic intervention.
Gut microbesFernanda Raya Tonetti, Hui Han, Marcos F Fondevila, Wenchao Wei, Burcin Özdirik, Jasmohan S Bajaj, Mitchell L Schubert, Masoumeh Sikaroodi, Patrick M Gillevet,…
Gastric acid-suppressive medications, particularly proton pump inhibitors (PPIs), are commonly used in patients with alcohol-associated liver disease (ALD) to prevent and manage upper gastrointestinal bleeding, gastroesophageal reflux disease, and non-steroidal anti-inflammatory/aspirin-induced gastroesophageal damage. By inhibiting the gastric H⁺/K⁺-ATPase, PPIs suppress acid secretion and impair bacterial killing, thereby promoting gut dysbiosis that disrupts barrier integrity and enhances bacterial translocation, ultimately exacerbating liver injury. PPIs are frequently co-administered with antibiotics for indications such as gastrointestinal bleeding, Spontaneous Bacterial Peritonitis (SBP), other infections, or hepatic encephalopathy prophylaxis, but the consequences of this combined therapy on gut microbial ecology and disease outcomes remain unclear. Our study addresses this gap by showing how PPI use, alone or with antibiotics, reshapes the gut microbiome and aggravates liver disease progression. In previous studies, we showed that PPIs promote dysbiosis and ALD progression in mice and humans by facilitating intestinal expansion and hepatic translocation of Gram-positive Enterococcus. Fecal cytolysin, an Enterococcus faecalis exotoxin that induces hepatocyte death, predicts mortality in patients with alcohol-associated hepatitis (AH). In this study, we have examined the mechanism by which PPIs alone and in combination with non-absorbable antibiotics targeting Gram-positive bacteria influence ALD, as well as the disease mechanisms associated with cytolytic Enterococcus faecalis and the development of therapeutic strategies. In mice, alcohol administration during gastric acid suppression promoted expansion of Gram-positive taxa, including cytolysin-producing Enterococcus. Similarly, PPI use in patients with AH was associated with increased fecal Enterococcus and higher 30-d mortality, underscoring the translational relevance of our findings. Unexpectedly, treatment of acid-suppressed mice with non-absorbable antibiotics designed to suppress Gram-positive bacteria worsened ethanol-induced steatohepatitis: while Enterococcus abundance decreased, Streptococcus and other potentially pathogenic taxa expanded, leading to increased bacterial translocation and aggravated liver injury. In patients with cirrhosis or metabolic dysfunction-associated steatotic liver disease (MASLD), PPIs did not promote Enterococcus expansion, indicating etiology-dependent microbiome responses. Finally, we identified dipalmitoylphosphatidylcholine and Caspase-1 inhibitor as in vitro and in vivo modulators of cytolysin activity, highlighting potential therapeutic avenues. Collectively, our study demonstrates how PPIs and non-absorbable antibiotics targeting Gram-positive bacteria interact with the gut microbiome to drive ALD, underscoring the need for careful therapeutic management.
Cancer biology & therapyMengting Luo, Feng Shen, Wanli Xu, Christopher Corpe, Jin Wang
Pancreatic ductal adenocarcinoma (PDAC) is among the most aggressive human malignancies and has an extremely poor prognosis. Its progression is largely driven by a highly complex and immunosuppressive tumor microenvironment (TME), highlighting the urgent need for a deeper understanding of its molecular mechanisms. Recent advances in single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics (ST) have provided unprecedented opportunities to dissect cellular heterogeneity, spatial organization, and gene expression dynamics within the TME. In this review, we summarize the major scRNA-seq and ST technologies and their unique strengths in cancer research and highlight their integrated applications in revealing PDAC heterogeneity, stromal-immune interactions, and mechanisms of therapeutic resistance. We further discuss how these approaches can inform biomarker discovery and guide the development of novel therapeutic strategies. Together, these findings suggest that integrated single-cell and spatial transcriptomics offers transformative potential to advance precision oncology and improve outcomes for patients with pancreatic cancer.
Gut microbesDominik Awad, Holly Attebury, Ryan Hong, Kwi Kim, Li Zhang, Allison Bischoff, Sajan Achi, Aaron denDekker, Nick Lesniak, Stephanie The, Joseph A Nieto Carrion,…
Pancreatic ductal adenocarcinoma has a unique tumor microbiome, and the depletion of gut bacteria or fungi using antibiotic/antifungal cocktails has been shown to decrease pancreatic tumor burden in mice. However, functional studies evaluating the role of tumor-associated microbes are few due to the limited availability of clinically relevant microbiota. Here, we describe in detail an effective workflow for the isolation of bacteria and fungi from the duodenum and tumor of pancreatic cancer patients, specifically optimized for cryopreserved, low biomass samples. Using this workflow we also isolated microbiota from normal pancreatic tissue and duodenum from organ donors, and we confirmed the presence of bacteria and fungi isolated from tissue samples with 16S and ITS sequencing analysis. Isolation and sequencing results show distinct similarities between the pancreatic and duodenal microbiomes and highlight unique bacterial strains that survive in the tumor microenvironment. As a proof of concept, we characterized a select Klebsiella oxytoca strain (UMKO1) isolated from a pancreatic tumor, using whole genome sequencing, metabolomics, and ex- vivo tumor cultures to determine its potential impact on the pancreatic tumor microenvironment. In summary, this optimized workflow allows for the isolation of a variety of bacteria and fungi from low biomass, cryopreserved pancreatic and duodenal tissues, which can then be used for functional studies characterizing clinically relevant tumor-associated microbiota.
Journal of biological dynamicsTahir Khan, Shehla Ibrar, Yunil Roh, Il Hyo Jung, Hafiza Elbadie, Muntasir Suhail
Using an appropriate mathematical model, this study aims to examine the transmission dynamics and optimal control of hepatitis B virus spreading, employing the Beddington-DeAngelis incidence function, a hybrid method of 4th order Runge-Kutta method (RK4) and feed-forward neural network (FFNN), as the integration of epidemiological models with neural network is particularly important for representing disease propagation. The well-posedness, local and global stability conditions are obtained using the threshold parameter. Some sensitive epidemic parameters and their relative impacts are quantified. Based on the local and global properties of the model and sensitivity analysis, a control problem is formulated to control the infection by minimizing the HBV-infected population and maximizing the recovered population using three control measures. Finally, a hybrid method of supervised FFNN and RK4 with two hidden layers is used to effectively approximate the temporal dynamics of HBV transmission and verify the theoretical results, as well as the effects of controls.
Colorectal cancer (CRC) progression is driven by dynamic interactions among tumor cells, immune infiltrates, and the gut microbiota. While regulatory T cells (Tregs) may contribute to immune suppression in CRC, the role of non-conventional Tregs remains poorly defined. We identified a non-conventional population of microbiota-induced Tregs in the human colonic mucosa that co-expressed CD4, CD8α, CXCR6, and CCR6, termed DP8α Tregs, that exert potent immunomodulatory properties in different inflammatory settings. Their status and role in CRC, however, have not been investigated. Here, using multiparametric flow cytometry in a prospective cohort of CRC patients, we showed that DP8α Tregs are significantly enriched in tumors compared to paired non-tumoral colonic mucosa. Tumor-infiltrating DP8α Tregs displayed elevated expression of the CD39/CD73 ectonucleotidases, as well as CCR5, consistent with a suppressive phenotype within the tumor microenvironment. Functional co-culture assays further demonstrated that sorting DP8α Tregs from CRC tumors inhibited both CD4 and CD8 T-cell proliferation, an effect largely reversed by pharmacological inhibition of CD39 and CD73, which was associated with reduced IL-2 levels. Together, these findings show that DP8α Tregs enriched in the CRC tumor microenvironment, are able to suppress effector T-cell responses through the purinergic pathway and support further investigation of their contribution to immune regulation in CRC.
International journal of qualitative studies on health and well-beingCarina Göransson, Ing-Marie Carlsson, Ingrid Larsson
PURPOSE: To explore the experiences of older people and formal caregivers of value-creating continence care, focusing on toileting and containment strategies, in relation to the Art of Connectedness framework. METHOD: A qualitative, explorative design. The interviews were conducted with 14 older people. Individual interviews and focus groups were held with 14 formal caregivers. An abductive qualitative content analysis was conducted, alternating between deductive interpretation-based on the three themes in the framework-and inductive analysis of the interview data. RESULTS: In relation to the co-created care theme, establishing a relationship and respecting preferences were highlighted by the participants and aligned with the framework, while trust was less prominent. In personalized care, meeting individual needs were described in ways that extended the framework: older people stressed the importance of time, while formal caregivers highlighted incontinence pads being individualized. Maintaining self-determination was emphasized by formal caregivers, as in the framework, but varied among older people. In the reflective care theme, showing empathy and upholding dignity were valued by older people in nursing homes and by formal caregivers, which was consistent with the framework. CONCLUSIONS: The findings reveal aspects of care that contribute to value-creating continence care for older people receiving toileting assistance and containment strategies. While the framework provided a useful structure, variations emerged between older people and formal caregivers what they considered important. This indicates the importance of developing a self-reported instrument to evaluate older people's satisfaction with the assistance they receive. The findings provide insights that can help increase awareness of the value of how promoting well-being for older people in daily continence care practice. The findings could inform community care policy aimed at improving continence care for older people.
Gut microbesTroels Holger Vaaben, Ditte Olsen Lützhøft, Karl Alex Hedin, Linda Ahonen, Ruben Vazquez-Uribe, Morten Otto Alexander Sommer
The gut microbiome shapes cancer progression and treatment responses, yet scalable microbiome-targeted interventions remain limited. We screened commercial probiotics for activation of the host aryl hydrocarbon receptor (AhR) and identified the yeast Saccharomyces boulardii as a consistent AhR activator. In an immunocompetent syngeneic colorectal cancer model, daily oral gavage of S. boulardii slowed growth of established subcutaneous tumors without detectable tumor colonization. Integrated profiling of the gut microbiome, circulating metabolites, cytokines, and tumor transcriptomes revealed a coordinated systemic response. S. boulardii increased microbial diversity and functionally rebalanced the gut microbiota, enriching taxa with lower genome-encoded biosynthetic autonomy. These changes were accompanied by elevated plasma levels of several indole metabolites, including the AhR agonists 5-hydroxyindole-3-acetic acid (5-HIAA) and indole-3-propionic acid (IPA). Targeted LC-MS/MS showed that S. boulardii can produce 5-HIAA under culture conditions, whereas IPA was not detected, suggesting that increased plasma levels of these metabolites may arise through a combination of probiotic activity and broader microbiome-associated processes. Circulating IL-17A and CTLA-4 were reduced, and tumors exhibited downregulation of programs linked to invasion, inflammation, and KRAS signaling. Multi-omics integration showed strong covariation across microbial, metabolic, immune signaling, and tumor compartments, highlighting coordinated cross-compartment responses during S. boulardii-associated tumor suppression.
Drug deliveryYanping Yin, Lulu Zhang, Yanli Yin, Jinyi Zhao, Rui Gong, Xuan Zhou, Haiyue Zhang, Fei Mu, Jingwen Wang
Sepsis-induced liver injury (SILI) is an important cause of death in intensive care patients, which seriously affects clinical prognosis. Wedelolactone (WEL) exhibits hepatoprotective properties, however, its clinical application is constrained by its poor solubility and insufficient targeting ability. Therefore, in this study, an innovative exosome (Exo)-based drug delivery system loaded with WEL (Exo@WEL) was constructed. The aim was to enhance the liver-targeting efficacy and therapeutic performance of WEL. Exo were extracted from the mice macrophages cell line RAW264.7 by differential centrifugation, and WEL was successfully loaded using ultrasonic incubation. Exo@WEL was characterized by TEM, particle size analysis, and NTA, confirming its structural suitability as an exogenous agent. DiR labeling revealed that Exo@WEL had a significantly enhanced liver-targeting ability compared to WEL. Safety was confirmed by HE staining test. In the SILI models, Exo@WEL showed better hepatoprotection over WEL. Beyond entinfinmtory actvity menifested y decreased ro infammatory rokines, Exo@WEL reinforced antioxidant function and efectively restained feroptosis. Importantly, pharmacological inhibition of ML385, a selective Nrf2 inhibitor, confirmed the critical regulatory role of the Nrf2 pathway in mediating these multifaceted liver protective effects. This study pioneered the development of a targeted Exo-based nanoplatform (Exo@WEL) for SILI therapy. The mechanism study has revealed a potential therapeutic strategy for inhibiting oxidative stress and ferroptosis by regulating the Nrf2/SLC7A11/GPX4 axis. This preparation provides a novel nanotherapeutic strategy that combines high efficiency and safety for the treatment of SILI. These findings also lay a theoretical foundation for the clinical translation of Exo drug delivery systems.
Gut microbesMargaux de Seilhac, Margaux Verdon, Lucas Goisnard, Aurore Duquenoy, Nathalie Corvaia, Emilie Plantamura, Nicolas Lapaque, Fabienne Beguet-Crespel, Bastien Lap…
While the role of gut microbiota in health has been demonstrated, deciphering the involvement of individual bacterial species in diseases with unmet clinical needs represents a major research interest. Over the last decade, DP8α regulatory T cells (Tregs) have been identified to respond to Faecalibacterium duncaniae and protect against inflammatory bowel diseases (IBD) and acute graft-versus-host disease (aGvHD). To better understand, on the one hand, physiological DP8α Treg activation processes, and, on the other hand, the underlying mechanisms used by anti-inflammatory bacterial species to protect the host, we investigated whether additional key species could be recognized by DP8α Tregs. Here we showed that Blautia obeum, Roseburia intestinalis, and Akkermansia muciniphila indeed represent sources of antigens for DP8α Treg activation and priming, likely through their unique ability to induce tolerogenic antigen presenting cells. This study provides considerable mechanistic insight into the gut microbiota/regulatory T cell interplay and further establishes the role of DP8α Tregs, and their emerging dedicated ability to respond to gut microbiota, in local and systemic homeostasis.
INTRODUCTION: Lenvatinib is a first-line therapy for hepatocellular carcinoma (HCC), but its clinical efficacy is limited by drug resistance. ABHD17C, a depalmitoylation enzyme involved in HCC progression, has not been investigated in lenvatinib response. This study aimed to determine whether ABHD17C regulates the anti-tumor efficacy of lenvatinib in HCC. METHODS: Published single-cell RNA sequencing (scRNA-seq) data were analyzed to characterize ABHD17C expression in the HCC tumor microenvironment. Functional assays were performed in HCC cell lines to evaluate the effects of lenvatinib and ABHD17C modulation. The findings were validated using HCC xenograft mouse models and patient-derived tumor organoids. RESULTS: scRNA-seq analysis showed that ABHD17C is associated with an immunosuppressive tumor microenvironment characterized by reduced CD8⁺ T cell infiltration, increased T cell exhaustion, and abnormal intercellular communication. In vitro, lenvatinib inhibited proliferation, migration, and invasion while inducing apoptosis and cell cycle arrest in HCC cells. These effects were significantly attenuated by ABHD17C overexpression but enhanced by ABHD17C depletion. In vivo, ABHD17C-overexpressing xenografts were less responsive to lenvatinib, exhibiting increased tumor growth and reduced apoptosis. Similarly, in patient-derived organoids, ABHD17C overexpression diminished lenvatinib efficacy. Notably, lenvatinib reduced ABHD17C expression in organoids, suggesting potential feedback regulation. CONCLUSION: ABHD17C promotes an immunosuppressive tumor microenvironment and attenuates the anti-tumor effects of lenvatinib in HCC. Targeting ABHD17C may represent a potential strategy to enhance lenvatinib sensitivity and improve therapeutic outcomes.
Gut microbesJessica K Josephson, Jacqueline A Barnett, Emad Yuzbashian, Andrea Verdugo-Meza, Susan J Murch, Tyler J Wenzel, Andis Klegeris, Keith A Sharkey, Deanna L Gibson
Globally, the incidence of inflammatory bowel disease (IBD) is projected to reach 0.5% of the population by 2030, with increasing recognition of neurobehavioral comorbidities, including anxiety, depression, and cognitive dysfunction. The mechanisms underlying these comorbidities remain unclear but may involve interacting pathways, including microbial dysbiosis, inflammation and imbalanced neurometabolite production. Here, we investigated whether microbiome-associated alterations in neurometabolites are correlated with behavioral changes in a chronic colitis model. Specific pathogen-free (SPF) and germ-free (GF) mucin 2 knockout mice (Muc2-/-) alongside mucin 2 expressing mice (Muc2+/+) were evaluated for behavioral patterns of anxiety, depressive-like patterns and memory dysfunction. Tryptophan and metabolite concentrations were measured in the colon, serum and brain. Blood-brain barrier integrity and neuroimmune activation were assessed through tight-junction protein claudin-5 expression, glial fibrillary acid protein (GFAP) and ionized calcium-binding adaptor molecule 1 (IBA-1) protein expression. Microbiome composition was characterized in relation to the tryptophan utilization pathways. To assess causality, early-life nutrient supplementation was used to address potential metabolite depletion. Female Muc2-/- displayed reduced anxiety-like behavior, while males displayed memory dysfunction. These changes coincided with decreased intestinal tryptophan, kynurenine, and serotonin within the gastrointestinal tract. GF Muc2-/- mice displayed normalized intestinal metabolite levels without concurrent brain metabolite changes. Notably, behavioral phenotypes were lost in GF Muc2-/- mice, revealing a key role for the microbiome played in these comorbidities. Muc2-/- exhibited reduced claudin-5, suggesting impaired blood‒brain barrier integrity. Microbiome analysis revealed a shift towards indole production and NAD+ salvage pathways with reduced abundance of Anaerotruncus, Enterocloster and Intestinimonas. Although early-life nutrient supplementation partially restored colonic tryptophan, it failed to fully rescue behavioral outcomes. Collectively, these findings demonstrate that chronic colitis is associated with microbiome-mediated disruption of host tryptophan metabolism, which correlates with neurobehavioral dysfunction. Targeting microbiome-driven metabolic alterations may represent a therapeutic strategy for both intestinal and neurobehavioral manifestations of IBD.
Gut microbesLouise Dupraz, Giovanna Orianne, Grégory Da Costa, Romain Gauthier, Amy Blondeau, Marie Boinet, Ambrîne Farfar, Laura Creusot, Aurélie Magniez, Léonard Dubois,…
The gut microbiota constitutes a complex ecosystem essential for host defense against infection and immune system maturation. Inflammatory bowel diseases (IBD), such as ulcerative colitis and Crohn's disease, are characterized by a severe inflammation of the intestine, arising from dysregulated control of host-microbiota crosstalk. However, neither the genetic bases of IBD nor the immune responses involved are fully understood. Pathobionts are currently under investigation for their active role in the development and severity of IBD. These bacteria are present in the gut microbiota of healthy individuals without causing disease, but have pathogenic potential when the intestinal environment is disturbed. Here, we highlight Sutterella sp. as a new commensal pathobiont for its capacity to modulate the host's immune functions. This anaerobic Gram-negative bacterium inhibits the production of IL-22 and IL-17 by lymphoid cells, ex vivo and in vivo. In the DSS-colitis model, Sutterella sp. can increase intestinal inflammation and inhibit IL-22 production. Moreover, the production of IL-22 and IL-17 by human lymphoid cells is also reduced by Sutterella sp. The bacterium acts directly on lymphoid cells through the secretion of protein-based compounds that antagonize AhR signaling. These data enhance our understanding of the mechanisms that regulate host immune functions and pave the way for new therapeutic strategies to control gut inflammation.