Biology subjects

Abo, H.

Publications and source records attributed to Abo, H..

4 recordsLinked to original sources

bioRxiv2026

Gut Microbiota Dysbiosis Drives Myocardial Hypertrophy Through GBP2b/GBP1-Mediated Immune Reprogramming and Exosomal Signaling in Chronic Colitis

BACKGROUNDPatients with inflammatory bowel disease (IBD) are at increased risk of cardiovascular disease, yet the mechanisms linking chronic intestinal inflammation to cardiac dysfunction remain poorly understood. IBD is characterized by profound gut microbiota dysbiosis, which we hypothesize drives systemic immune dysregulation and contributes to cardiac dysfunction. METHODSA chronic colitis mouse model was used to assess gut microbiota dysbiosis, systemic immune cell metabolism, and cardiac remodeling. Cardiac outcomes were evaluated by echocardiography, histology, and molecular analyses. Mechanisms were examined using fecal microbiota transplantation, immune cell depletion, exosome transfer, bone marrow chimeras, RNA-seq, co-immunoprecipitation, confocal microscopy, and siRNA-mediated gene silencing. RESULTSChronic DSS colitis induced cardiac dysfunction, hypertrophy, and fibrosis in mice. These changes were accompanied by sustained gut microbiota dysbiosis, metabolic reprogramming, and mitochondrial dysfunction in circulating immune cells. Fecal microbiota transfer experiments demonstrated that colitis-associated microbiota were sufficient to reprogram systemic immune cells and promote cardiac dysfunction. Immune cell depletion studies identified macrophages as key mediators of colitis-associated cardiac injury. Colitis increased systemic lipopolysaccharide (LPS) translocation, bone marrow chimera experiments demonstrated that hematopoietic TLR4 signaling was required for immune cell metabolic remodeling and cardiac dysfunction during chronic colitis. Transcriptomic analysis identified guanylate-binding protein 2b (GBP2b/GBP1, hereafter referred to as GBP1) as a key downstream effector of LPS-TLR4 signaling. Upon LPS stimulation, GBP1 localized to mitochondria, where it interacted with DRP1 and FIS1 to promote mitochondrial fission, oxidative stress, and enhanced immune cell migration into the heart. In addition, GBP1 was secreted via exosomes, which were taken up by cardiomyocytes and contributed to hypertrophic remodeling, and cardiac dysfunction. CONCLUSIONSThese findings establish the LPS-TLR4-GBP1 axis as a key driver of colitis-associated cardiovascular dysfunction and highlight this pathway as a promising therapeutic target for reducing cardiovascular risk in patients with IBD. Novelty and SignificanceO_ST_ABSWhat Is Known?C_ST_ABSO_LIPatients with inflammatory bowel disease have an increased risk of cardiovascular dysfunction that cannot be fully explained by traditional cardiovascular risk factors. C_LIO_LIGut microbiota dysbiosis and chronic innate immune activation are hallmarks of inflammatory bowel disease, but their direct contribution to cardiac remodeling remains unclear. C_LI What New Information Does This Article Contribute?O_LIChronic colitis-associated gut microbiota dysbiosis induces systemic immune cell metabolic and mitochondrial reprogramming that is sufficient to drive cardiomyocyte hypertrophy and cardiac dysfunction. C_LIO_LIHematopoietic Toll-like receptor 4 signaling links colitis associated gut microbiota to immune metabolic dysfunction and cardiac impairment, establishing a causal gut-immune-heart axis. C_LIO_LIGuanylate-binding protein 2b (GBP2b/GBP1) is identified as a critical downstream effector that promotes mitochondrial fission, oxidative stress, immune cell cardiac infiltration, and exosome-mediated cardiac remodeling. C_LI

pathology↗

bioRxiv2025

Wheat fiber-induced peripheral regulatory T-cells suppress development of colitis

Reduced dietary fiber intake is associated with, and may have contributed to, the post-mid-20th century increase in immune-mediated chronic inflammatory diseases, including inflammatory bowel disease. Reduced fiber intake has resulted, in part, from highly refined foods. For example, modern methods of producing bread removes much of the fiber naturally present in wheat kernels. Accordingly, we hypothesized that wheat fiber might protect against chronic inflammatory diseases. We tested this notion in a murine T-cell transfer colitis model. Rag1-/- mice were fed open-source low-fiber diets enriched, or not with wheat fiber (WF) and then administered CD45Rbhi T-cells. WF conferred robust protection in this colitis model as assessed by an array of clinical, histopathologic, morphologic, and immune-related parameters. WFs protection against colitis associated with a microbiota-dependent increase in Foxp3+ T-cell (Tregs), which could be recapitulated in vitro. WF did not induce Tregs in CNS1-/- mice nor did WF protect against T cell transfer colitis driven by transplant of colitogenic T-cells from CNS1-/- mice. Thus, enriching diet with WF has potential to promote microbiota-dependent peripheral Treg development and, consequently, protect against chronic inflammatory diseases.

immunology↗

bioRxiv2025

Flagellin in the human gut microbiome is a diet-adjustable adjuvant for vaccination

The intestinal microbiota is thought to modulate immune responsiveness to vaccines. Human studies on this topic, however, have yielded inconsistent results1,2. We hypothesized that the microbiome would influence innate immune responses, and thus vaccine reactogenicity, more directly than vaccine immunogenicity. To test this, we established the {micro}HEAT (Microbial-Human Ecology And Temperature) study, which longitudinally profiled the fecal microbiota, oral body temperature and serum antibody responses of 171 healthy adults (18-40 years old) before and after vaccination for SARS-CoV-2. Increased temperature after vaccination ({Delta}T) was associated with habitual diet and with baseline metabolic and immune markers. The microbiomes of {Delta}T-high ({Delta}Thi) participants were characterized by high expression of flagellin and an overabundance of the flagellated bacterium Waltera. Fecal samples from {Delta}Thi participants induced more inflammation in human cells and stronger post-vaccine temperature responses in mice compared to {Delta}Tlo samples, suggesting a causal role for the microbiome. Moreover, Waltera flagellin replicated the inflammatory phenotypes in vitro and was modulable via a dietary additive. Overall, these data suggest that flagellin from the gut microbiome stimulates innate immunity and vaccine reactogenicity, and that this axis can be manipulated via diet. These findings have implications for improving human vaccine tolerance and immunogenicity.

microbiology↗

bioRxiv2025

Reprogramming of alveolar macrophages by intestinal segmented filamentous bacteria protects mice from lethal bacterial pneumoniae following influenza infection

The most severe outcomes of respiratory viral infection (RVI) result from secondary bacterial infection, which RVI promotes via depletion of alveolar macrophages (AM). Colonization of the intestine by the common but non-ubiquitous commensal, segmented filamentous bacteria (SFB), reprograms AM to resist RVI-induced depletion. Hence, we examined if SFB against secondary infection by S. pneumoniae, H. influenzae, or S. aureus, following primary infection by influenza virus (IAV). Indeed, SFB colonization conferred strong post-IAV protection against these lethal bacterial pathogens. AM depletion and transplant studies indicated that SFB reprogramming these cells was necessary and sufficient for such protection. Assay of AM, ex vivo, from SFB-colonized mice argued their protection against secondary bacterial infection was not only due to their withstanding IAV-induced depletion. Rather, AM from SFB-colonized mice displayed complement-dependent increases in phagocytosis and killing of these bacteria. Furthermore, AM from SFB-colonized mice stably held their enhanced anti-bacterial phenotype even when transplanted into an inflamed interferon-rich post IAV-environment. Thus, SFB, and perhaps gut microbiota composition in general influences proneness to bacterial pneumonia, especially post-RVI. One Sentence summarySFB colonization stably changed the phenotype of alveolar macrophages resulting in sustained clearance of bacterial pathogens even amidst an inflamed interferon-rich immune suppressed lung.

immunology↗