129 results on '"Beng San Yeoh"'
Search Results
2. Sex Dimorphic Effects of Bile Acid Metabolism in Liver Cancer in MiceSummary
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Rachel M. Golonka, Beng San Yeoh, Piu Saha, Yuan Tian, John Y.L. Chiang, Andrew D. Patterson, Andrew T. Gewirtz, Bina Joe, and Matam Vijay-Kumar
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Hepatocellular Carcinoma ,Cholestasis ,Farnesoid X Receptor ,Portosystemic Shunt ,Diseases of the digestive system. Gastroenterology ,RC799-869 - Abstract
Background & Aims: Hepatocellular carcinoma (HCC) is a male-dominant disease, but targeted sex hormone therapies have not been successful. Bile acids are a potential liver carcinogen and are biomolecules with hormone-like effects. A few studies highlight their potential sex dimorphism in physiology and disease. We hypothesized that bile acids could be a potential molecular signature that explains sex disparity in HCC. Methods & Results: We used the farnesoid X receptor knockout (FxrKO) mouse model to study bile acid-dependent HCC. Temporal tracking of circulating bile acids determined more than 80% of FxrKO females developed spontaneous cholemia (ie, serum total bile acids ≥40 μmol/L) as early as 8 weeks old. Opposingly, FxrKO males were highly resistant to cholemia, with ∼23% incidence even when 26 weeks old. However, FxrKO males demonstrated higher levels of deoxycholate than females. Compared with males, FxrKO females had more severe cholestatic liver injury and further aberrancies in bile acid metabolism. Yet, FxrKO females expressed more detoxification transcripts and had greater renal excretion of bile acids. Intervention with CYP7A1 (rate limiting enzyme for bile acid biosynthesis) deficiency or taurine supplementation either completely or partially normalized bile acid levels and liver injury in FxrKO females. Despite higher cholemia prevalence in FxrKO females, their tumor burden was less compared with FxrKO males. An exception to this sex-dimorphic pattern was found in a subset of male and female FxrKO mice born with congenital cholemia due to portosystemic shunt, where both sexes had comparable robust HCC. Conclusions: Our study highlights bile acids as sex-dimorphic metabolites in HCC except in the case of portosystemic shunt. more...
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- 2024
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Catalog
3. Metastatic Colon Cancer in an Individual Following Prolonged Daily Inulin Consumption
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Beng San Yeoh, Andrew T. Gewirtz, and Matam Vijay-Kumar
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Gut Microbiota ,Supplemental Fermentable Fiber ,Dietary Inulin ,Colon Cancer ,Diseases of the digestive system. Gastroenterology ,RC799-869 - Abstract
Studies in rodents suggest that inulin supplements may be carcinogenic. We present a case implicating that this risk extends to humans. A healthy male from a family lacking history of cancer had his first cancer-screening colonoscopy at age 56. No intestinal polyps/abnormalities were detected. A second colonoscopy, performed 7 years later, revealed a tumor in the cecum, with evidence of metastasis to lymph nodes. The only known change in patient’s lifestyle during that seven-year period was the addition of 4g of inulin powder as a daily supplement during the last 2 years. Such inulin consumption is a plausible contributor to his disease. more...
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- 2024
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4. Psyllium fiber protects mice against western diet-induced metabolic syndrome via the gut microbiota-dependent mechanism
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Alexis Bretin, Beng San Yeoh, Vu L. Ngo, Lavanya Reddivari, Michael Pellizzon, Matam Vijay-Kumar, and Andrew T. Gewirtz
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Obesity ,diabetes ,short-chain fatty acids ,Diseases of the digestive system. Gastroenterology ,RC799-869 - Abstract
ABSTRACTImpacts of dietary fiber on intestinal inflammation are complex, but some specific semi-purified fibers, particularly psyllium, can protect humans and rodents against colitis. Mechanisms underlying such protection are not fully understood but may involve activation of the FXR bile acid receptor. Obesity and its associated consequences, referred to as metabolic syndrome, are associated with, and promoted by, low-grade inflammation in a variety of tissues including the intestine. Hence, we examined whether psyllium might ameliorate the low-grade intestinal inflammation that occurs in diet-induced obesity and, moreover, the extent to which it might ameliorate adiposity and/or dysglycemia in this disease model. We observed that enriching a high-fat diet with psyllium provided strong protection against the low-grade gut inflammation and metabolic consequences that were otherwise induced by the obesogenic diet. Such protection was fully maintained in FXR-deficient mice, indicating that distinct mechanisms mediate psyllium’s protection against colitis and metabolic syndrome. Nor did psyllium’s protection associate with, or require, fermentation or IL−22 production, both of which are key mediators of beneficial impacts of some other dietary fibers. Psyllium’s beneficial impacts were not evident in germfree mice but were observed in Altered Schaedler Flora mice, in which psyllium modestly altered relative and absolute abundance of the small number of taxa present in these gnotobiotic mice. Thus, psyllium protects mice against diet-induced obesity/metabolic syndrome by a mechanism independent of FXR and fermentation but nonetheless requires the presence of at least a minimal microbiota. more...
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- 2023
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5. Bacterial flagellin is a dominant, stable innate immune activator in the gastrointestinal contents of mice and rats
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Matam Vijay-Kumar, Venugopal R. Bovilla, Beng San Yeoh, Rachel M. Golonka, Piu Saha, Bina Joe, and Andrew T. Gewirtz
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Gut microbiota ,LPS ,MyD88 ,toll-like Receptor-5 ,toll-like Receptor-4 ,cytokines ,Diseases of the digestive system. Gastroenterology ,RC799-869 - Abstract
ABSTRACTIntestinal contents comprise the largest repository of immunogenic ligands of microbial origin. We undertook this study to assess the predominant microbe-associated molecular patterns (MAMPs) present therein and the receptors) that mediate the innate immune responses to them. Here, we demonstrated that intestinal contents from conventional, but not germ-free, mice and rats triggered robust innate immune responses in vitro and in vivo. Such immune responses were abrogated in the absence of either myeloid differentiation factor 88 (MyD88) or Toll-like receptor (TLR) 5, but not TLR4, suggesting that the stimuli was flagellin (i.e., protein subunit of flagella that drives bacterial motility). Accordingly, pre-treating intestinal extracts with proteinase, thereby degrading flagellin, was sufficient to block their ability to activate innate immune responses. Taken together, this work serves to underscore flagellin as a major, heat-stable and bioactive MAMP in the intestinal content that confers this milieu strong potential to trigger innate immune responses. more...
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- 2023
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6. Psyllium Fiber Protects Against Colitis Via Activation of Bile Acid Sensor Farnesoid X ReceptorSummary
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Alexis Bretin, Jun Zou, Beng San Yeoh, Vu L. Ngo, Shawn Winer, Daniel A. Winer, Lavanya Reddivari, Michael Pellizzon, William A. Walters, Andrew D. Patterson, Ruth Ley, Benoit Chassaing, Matam Vijay-Kumar, and Andrew T. Gewirtz more...
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inflammatory bowel disease ,dietary fiber ,Diseases of the digestive system. Gastroenterology ,RC799-869 - Abstract
Background & Aims: Fiber-rich foods promote health, but mechanisms by which they do so remain poorly defined. Screening fiber types, in mice, revealed psyllium had unique ability to ameliorate 2 chronic inflammatory states, namely, metabolic syndrome and colitis. We sought to determine the mechanism of action of the latter. Methods: Mice were fed grain-based chow, which is naturally rich in fiber or compositionally defined diets enriched with semi-purified fibers. Mice were studied basally and in models of chemical-induced and T-cell transfer colitis. Results: Relative to all diets tested, mice consuming psyllium-enriched compositionally defined diets were markedly protected against both dextran sulfate sodium- and T-cell transfer-induced colitis, as revealed by clinical-type, histopathologic, morphologic, and immunologic parameters. Such protection associated with stark basal changes in the gut microbiome but was independent of fermentation and, moreover, maintained in mice harboring a minimal microbiota (ie, Altered Schaedler Flora). Transcriptomic analysis revealed psyllium induced expression of genes mediating bile acids (BA) secretion, suggesting that psyllium’s known ability to bind BA might contribute to its ability to prevent colitis. As expected, psyllium resulted in elevated level of fecal BA, reflecting their removal from enterohepatic circulation but, in stark contrast to the BA sequestrant cholestyramine, increased serum BA levels. Moreover, the use of BA mimetics that activate the farnesoid X receptor (FXR), as well as the use of FXR-knockout mice, suggested that activation of FXR plays a central role in psyllium’s protection against colitis. Conclusions: Psyllium protects against colitis via altering BA metabolism resulting in activation of FXR, which suppresses pro-inflammatory signaling. more...
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- 2023
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7. Genetically engineered Lactobacillus paracasei rescues colonic angiotensin converting enzyme 2 (ACE2) and attenuates hypertension in female Ace2 knock out rats
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Xue Mei, Blair Mell, Sachin Aryal, Ishan Manandhar, Ramakumar Tummala, Jasenka Zubcevic, Khanh Lai, Tao Yang, Qiuhong Li, Beng San Yeoh, and Bina Joe
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Bacterial engineering, human ACE2 ,Lactobacillus paracasei ,Ace2-/- ,Hypertension ,Sex-specific ,Therapeutics. Pharmacology ,RM1-950 - Abstract
Engineered gut microbiota represents a new frontier in medicine, in part serving as a vehicle for the delivery of therapeutic biologics to treat a range of host conditions. The gut microbiota plays a significant role in blood pressure regulation; thus, manipulation of gut microbiota is a promising avenue for hypertension treatment. In this study, we tested the potential of Lactobacillus paracasei, genetically engineered to produce and deliver human angiotensin converting enzyme 2 (Lacto-hACE2), to regulate blood pressure in a rat model of hypertension with genetic ablation of endogenous Ace2 (Ace2-/- and Ace2-/y). Our findings reveal a sex-specific reduction in blood pressure in female (Ace2-/-) but not male (Ace2-/y) rats following colonization with the Lacto-hACE2. This beneficial effect of lowering blood pressure was aligned with a specific reduction in colonic angiotensin II, but not renal angiotensin II, suggesting the importance of colonic Ace2 in the regulation of blood pressure. We conclude that this approach of targeting the colon with engineered bacteria for delivery of ACE2 represents a promising new paradigm in the development of antihypertensive therapeutics. more...
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- 2023
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8. Crosstalk between Gut Microbiota and Host Immunity: Impact on Inflammation and Immunotherapy
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Connor Campbell, Mrunmayee R. Kandalgaonkar, Rachel M. Golonka, Beng San Yeoh, Matam Vijay-Kumar, and Piu Saha
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gut microbiota dysbiosis ,innate immune system ,adaptive immune system ,infection ,cancer ,inflammatory bowel diseases ,Biology (General) ,QH301-705.5 - Abstract
Gut microbes and their metabolites are actively involved in the development and regulation of host immunity, which can influence disease susceptibility. Herein, we review the most recent research advancements in the gut microbiota–immune axis. We discuss in detail how the gut microbiota is a tipping point for neonatal immune development as indicated by newly uncovered phenomenon, such as maternal imprinting, in utero intestinal metabolome, and weaning reaction. We describe how the gut microbiota shapes both innate and adaptive immunity with emphasis on the metabolites short-chain fatty acids and secondary bile acids. We also comprehensively delineate how disruption in the microbiota–immune axis results in immune-mediated diseases, such as gastrointestinal infections, inflammatory bowel diseases, cardiometabolic disorders (e.g., cardiovascular diseases, diabetes, and hypertension), autoimmunity (e.g., rheumatoid arthritis), hypersensitivity (e.g., asthma and allergies), psychological disorders (e.g., anxiety), and cancer (e.g., colorectal and hepatic). We further encompass the role of fecal microbiota transplantation, probiotics, prebiotics, and dietary polyphenols in reshaping the gut microbiota and their therapeutic potential. Continuing, we examine how the gut microbiota modulates immune therapies, including immune checkpoint inhibitors, JAK inhibitors, and anti-TNF therapies. We lastly mention the current challenges in metagenomics, germ-free models, and microbiota recapitulation to a achieve fundamental understanding for how gut microbiota regulates immunity. Altogether, this review proposes improving immunotherapy efficacy from the perspective of microbiome-targeted interventions. more...
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- 2023
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9. Ketone body β-hydroxybutyrate is an autophagy-dependent vasodilator
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Cameron G. McCarthy, Saroj Chakraborty, Gagandeep Singh, Beng San Yeoh, Zachary J. Schreckenberger, Avinash Singh, Blair Mell, Nicole R. Bearss, Tao Yang, Xi Cheng, Matam Vijay-Kumar, Camilla F. Wenceslau, and Bina Joe more...
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Vascular biology ,Medicine - Abstract
Autophagy has long been associated with longevity, and it is well established that autophagy reverts and prevents vascular deterioration associated with aging and cardiovascular diseases. Currently, our understanding of how autophagy benefits the vasculature is centered on the premise that reduced autophagy leads to the accumulation of cellular debris, resulting in inflammation and oxidative stress, which are then reversed by reconstitution or upregulation of autophagic activity. Evolutionarily, autophagy also functions to mobilize endogenous nutrients in response to starvation. Therefore, we hypothesized that the biosynthesis of the most physiologically abundant ketone body, β-hydroxybutyrate (βHB), would be autophagy dependent and exert vasodilatory effects via its canonical receptor, Gpr109a. To the best of our knowledge, we have revealed for the first time that the biosynthesis of βHB can be impaired by preventing autophagy. Subsequently, βHB caused potent vasodilation via potassium channels but not Gpr109a. Finally, we observed that chronic consumption of a high-salt diet negatively regulates both βHB biosynthesis and hepatic autophagy and that reconstitution of βHB bioavailability prevents high-salt diet–induced endothelial dysfunction. In summary, this work offers an alternative mechanism to the antiinflammatory and antioxidative stress hypothesis of autophagy-dependent vasculoprotection. Furthermore, it reveals a direct mechanism by which ketogenic interventions (e.g., intermittent fasting) improve vascular health. more...
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- 2021
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10. 'Western Diet'-Induced Adipose Inflammation Requires a Complex Gut MicrobiotaSummary
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Hao Q. Tran, Alexis Bretin, Aneseh Adeshirlarijaney, Beng San Yeoh, Matam Vijay-Kumar, Jun Zou, Timothy L. Denning, Benoit Chassaing, and Andrew T. Gewirtz
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Diseases of the digestive system. Gastroenterology ,RC799-869 - Abstract
Background & Aims: Consumption of a low-fiber, high-fat, Western-style diet (WSD) induces adiposity and adipose inflammation characterized by increases in the M1:M2 macrophage ratio and proinflammatory cytokine expression, both of which contribute to WSD-induced metabolic syndrome. WSD-induced adipose inflammation might result from endoplasmic reticulum stress in lipid-overloaded adipocytes and/or dissemination of gut bacterial products, resulting in activation of innate immune signaling. Hence, we aimed to investigate the role of the gut microbiota, and its detection by innate immune signaling pathways, in WSD-induced adipose inflammation. Methods: Mice were fed grain-based chow or a WSD for 8 weeks, assessed metabolically, and intestinal and adipose tissue were analyzed by flow cytometry and quantitative reverse transcription polymerase chain reaction. Microbiota was ablated via antibiotics and use of gnotobiotic mice that completely lacked microbiota (germ-free mice) or had a low-complexity microbiota (altered Schaedler flora). Innate immune signaling was ablated by genetic deletion of Toll-like receptor signaling adaptor myeloid differentiation primary response 88. Results: Ablation of microbiota via antibiotic, germ-free, or altered Schaedler flora approaches did not significantly impact WSD-induced adiposity, yet dramatically reduced WSD-induced adipose inflammation as assessed by macrophage populations and cytokine expression. Microbiota ablation also prevented colonic neutrophil and CD103- dendritic cell infiltration. Such reduced indices of inflammation correlated with protection against WSD-induced dysglycemia, hypercholesterolemia, and liver dysfunction. Genetic deletion of myeloid differentiation primary response 88 also prevented WSD-induced adipose inflammation. Conclusions: These results indicate that adipose inflammation, and some aspects of metabolic syndrome, are not purely a consequence of diet-induced adiposity per se but, rather, may require disturbance of intestine-microbiota interactions and subsequent activation of innate immunity. Keywords: Metabolic Syndrome, Microbiota, Germ-Free, Antibiotics, Altered Schaedler Flora, High-Fat Diet, MyD88 more...
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- 2020
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11. Enterobactin induces the chemokine, interleukin-8, from intestinal epithelia by chelating intracellular iron
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Piu Saha, Beng San Yeoh, Xia Xiao, Rachel M. Golonka, Ahmed A. Abokor, Camilla F. Wenceslau, Yatrik M. Shah, Bina Joe, and Matam Vijay-Kumar
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siderophores ,enterochelin ,il-8 ,labile iron pool ,lipocalin 2 ,Diseases of the digestive system. Gastroenterology ,RC799-869 - Abstract
Iron is an indispensable nutrient for both mammals and microbes. Bacteria synthesize siderophores to sequester host iron, whereas lipocalin 2 (Lcn2) is the host defense protein that prevent this iron thievery. Enterobactin (Ent) is a catecholate-type siderophore that has one of the strongest known affinities for iron. Intestinal epithelial cells (IECs) are adjacent to large microbial population and are in contact with microbial products, including Ent. We undertook this study to investigate whether a single stimulus of Ent could affect IEC functions. Using three human IEC cell-lines with differential basal levels of Lcn2 (i.e. HT29 more...
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- 2020
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12. Distinct iron homeostasis in C57BL/6 and Balb/c mouse strains
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Piu Saha, Xia Xiao, Yaqi Li, Rachel M. Golonka, Ahmed A. Abokor, Beng San Yeoh, and Matam Vijay‐Kumar
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ferroportin ,hepcidin ,hypoferremia of inflammation ,innate immunity ,labile iron pool ,Physiology ,QP1-981 - Abstract
Abstract C57BL/6 (BL6) and Balb/c mice exhibit prototypical Th1‐ and Th2‐dominant immune predispositions, respectively. Iron is a proinflammatory metal ion; however, limited information is documented on the differences in iron homeostasis between BL6 and Balb/c strains. The objective of this study was to investigate the extent to which strain‐level differences in these mice dictates the regulation of iron homeostasis during physiologic and inflammatory conditions. At basal levels, Balb/c mice displayed significantly higher levels of iron in systemic circulation and tissue compared to BL6 mice. Moreover, Balb/c mice had greater iron absorption as indicated by higher gene expressions of duodenal DcytB, DMT1, Fpn, SFT, and Heph. Similarly, hepatic Tf, TfR1, TfR2, and DMT1 expressions were augmented in Balb/c mice. Interestingly, there was no change in hepatic Hamp expression between the two strains, suggesting that the disparity in their maintenance of iron is independent of hepcidin. Additionally, the basal levels of intracellular labile iron pool in Balb/c intestinal epithelial cells, and bone marrow‐derived macrophages and neutrophils, were higher compared to BL6 mice. When mice were challenged with lipopolysaccharide, the acute inflammatory response in BL6 mice was more pronounced than in Balb/c mice, as indicated by the more rapid development of hypoferremia and upregulation of serum IL‐6 and TNF‐α levels in BL6 mice. In conclusion, this study underscores that iron homeostasis is distinct between BL6 and Balb/c strains under both physiologic and inflammatory conditions. more...
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- 2020
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13. Immunoglobulin A, an Active Liaison for Host-Microbiota Homeostasis
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Ahmed A. Abokor, Grant H. McDaniel, Rachel M. Golonka, Connor Campbell, Sreya Brahmandam, Beng San Yeoh, Bina Joe, Matam Vijay-Kumar, and Piu Saha
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secretory IgA ,gut homeostasis ,IgA deficiency ,polymeric immunoglobulin receptor (pIgR) ,mucosal immunology ,B cells ,Biology (General) ,QH301-705.5 - Abstract
Mucosal surfaces in the gastrointestinal tract are continually exposed to native, commensal antigens and susceptible to foreign, infectious antigens. Immunoglobulin A (IgA) provides dual humoral responses that create a symbiotic environment for the resident gut microbiota and prevent the invasion of enteric pathogens. This review features recent immunological and microbial studies that elucidate the underlying IgA and microbiota-dependent mechanisms for mutualism at physiological conditions. IgA derailment and concurrent microbiota instability in pathological diseases are also discussed in detail. Highlights of this review underscore that the source of IgA and its structural form can dictate microbiota reactivity to sustain a diverse niche where both host and bacteria benefit. Other important studies emphasize IgA insufficiency can result in the bloom of opportunistic pathogens that encroach the intestinal epithelia and disseminate into circulation. The continual growth of knowledge in these subjects can lead to the development of therapeutics targeting IgA and/or the microbiota to treat life threatening diseases. more...
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- 2021
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14. Data on IL-10R neutralization-induced chronic colitis in Lipocalin 2 deficient mice on BALB/c background
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Vishal Singh, Beng San Yeoh, Marit Nilsen-Hamilton, Thorsten Berger, Tak W. Mak, and Matam Vijay-Kumar
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Siderocalin ,Neutrophil gelatinase-associated lipocalin ,Inflammatory bowel disease ,IL-10 ,Computer applications to medicine. Medical informatics ,R858-859.7 ,Science (General) ,Q1-390 - Abstract
The data herein is related to the research article entitled “Microbiota-inducible Innate Immune, Siderophore Binding Protein Lipocalin 2 is Critical for Intestinal Homeostasis” (Singh et al., 2016) [1] where we have demonstrated that C57BL/6 Lipocalin 2 deficient mice (Lcn2KO) developed chronic colitis upon anti-interleukin-10 receptor (αIL-10R) monoclonal antibody administration. In the present article, we evaluated the susceptibility of BALB/c Lcn2KO mice and their WT littermates to the αIL-10R neutralization-induced chronic colitis. Our data showed that αIL-10R mAb-treated BALB/c Lcn2KO mice exhibited severe chronic colitis (i.e., splenomegaly, colomegaly, colonic pathology, and incidence of rectal prolapse) when compared to WT mice. more...
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- 2017
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15. Fermentable fiber-induced hepatocellular carcinoma in mice recapitulates gene signatures found in human liver cancer.
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Darshan Shimoga Chandrashekar, Rachel M Golonka, Beng San Yeoh, David J Gonzalez, Mathias Heikenwälder, Andrew T Gerwirtz, Sooryanarayana Varambally, and Matam Vijay-Kumar
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Medicine ,Science - Abstract
Hepatocellular carcinoma (HCC), the most malignant form of primary liver cancer, is the fourth most prevalent cause of cancer mortality globally. It was recently discovered that the dietary fermentable fiber, inulin, can reprogram the murine liver to favor HCC development in a gut microbiota-dependent manner. Determining the molecular pathways that are either over expressed or repressed during inulin-induced HCC would provide a platform of potential therapeutic targets. In the present study, we have combined analysis of the novel inulin-induced HCC murine model and human HCC samples to identify differentially expressed genes (DEGs) in hepatocarcinogenesis. Hepatic transcriptome profiling revealed that there were 674 DEGs in HCC mice compared to mice safeguarded from HCC. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis uncovered enrichment in ECM-receptor interaction, steroid hormone biosynthesis, PPAR signaling pathway, focal adhesion and protein digestion and absorption during inulin-induced HCC. Tandem mass tag based quantitative, multiplexed proteomic analysis delineated 57 differentially expressed proteins, where the over-expressed proteins were associated with cell adhesion molecules, valine, leucine and isoleucine degradation and ECM-receptor interaction. After obtaining the human orthologs of the mouse genes, we did a comparison analysis to level 3 RNA-seq data found in the Cancer Genome Atlas (TCGA) database, corresponding to human HCC (n = 361) and healthy liver (n = 50) samples. Out of the 549 up-regulated and 68 down-regulated human orthologs identified, 142 genes (137 significantly over-expressed and 5 significantly under-expressed) were associated with human HCC. Using univariate survival analysis, we found 27 over-expressed genes involved in cell-cell adhesion and cell division that were associated with poor HCC patient survival. Overall, the genetic and proteomics signatures highlight potential underlying mechanisms in inulin-induced HCC and support that this murine HCC model is human relevant. more...
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- 2020
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16. Adaptive Immunity Induces Tolerance to Flagellin by Attenuating TLR5 and NLRC4-Mediated Innate Immune Responses
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Beng San Yeoh, Andrew T. Gewirtz, and Matam Vijay-Kumar
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LPS ,innate immunity ,immune tolerance ,antibodies ,salmonella ,infection ,Microbiology ,QR1-502 - Abstract
The host immune system is constantly exposed to diverse microbial ligands, including flagellin (FliC; a ligand for TLR5 and NLRC4) and lipopolysaccharide (LPS; a ligand for TLR4), which could induce immune tolerance to subsequent exposure. Herein, we investigated the extent to which FliC induces self-tolerance in vivo and the role of adaptive immunity in mediating such effect. Mice pre-treated with FliC displayed attenuated serum keratinocyte-derived chemokine (KC), interleukin (IL)-6 and IL-18 responses to secondary challenge of FliC. A negative correlation was observed between high anti-FliC titer and reduced KC, IL-6, and IL-18 responses upon FliC re-challenge in WT mice, but not Rag1KO mice, suggesting that adaptive immunity could tolerize TLR5 and NLRC4. However, administration of LPS during FliC pre-treatment impaired the generation of anti-FliC antibodies and resulted in a partial loss of self-tolerance to FliC re-challenge. These findings may be relevant in the context of bacterial infection, as we observed that anti-FliC response are protective against systemic infection by Salmonella typhimurium. Taken together, our study delineates a distinct co-operative and reciprocal interaction between the innate and adaptive arms of immunity in modulating their responses to a bacterial protein. more...
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- 2019
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17. Data on importance of hematopoietic cell derived Lipocalin 2 against gut inflammation
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Piu Saha, Vishal Singh, Xia Xiao, Beng San Yeoh, and Matam Vijay-Kumar
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Computer applications to medicine. Medical informatics ,R858-859.7 ,Science (General) ,Q1-390 - Abstract
The data herein is related to the research article entitled “Microbiota-inducible innate immune siderophore binding protein Lipocalin 2 is critical for intestinal homeostasis” (Singh et al., 2016) [1]. In the present article, we monitored dextran sodium sulfate (DSS)-induced colitis development upon Lipocalin 2 (Lcn2) neutralization, and examined the survival of Lcn2 deficient (Lcn2KO) mice and their WT littermates upon DSS challenge. To dissect the relative contribution of immune and non-immune cells-derived Lcn2 in mediating protection against gut inflammation, we generated respective bone marrow chimera and evaluated their susceptibility to IL-10 receptor neutralization-induced chronic colitis.Neutralization of Lcn2 in WT mice resulted in exacerbated DSS-induced colitis. Notably, mice lacking Lcn2 exhibited 100% mortality whereas only 20% mortality was observed in WT mice upon DSS challenge. Further, data from bone marrow chimera showed that immune cell-derived Lcn2 is the major contributor in conferring protection against colitis. Keywords: Siderocalin, Gut microbiota, Inflammatory bowel disease, Bone marrow chimeras, Colitis more...
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- 2016
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18. Microbiota-Inducible Innate Immune Siderophore Binding Protein Lipocalin 2 Is Critical for Intestinal HomeostasisSummary
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Vishal Singh, Beng San Yeoh, Benoit Chassaing, Benyue Zhang, Piu Saha, Xia Xiao, Deepika Awasthi, Rangaiah Shashidharamurthy, Madhu Dikshit, Andrew Gewirtz, and Matam Vijay-Kumar
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Diseases of the digestive system. Gastroenterology ,RC799-869 - Abstract
Background & Aims: Lipocalin 2 (Lcn2) is a multifunctional innate immune protein whose expression closely correlates with the extent of intestinal inflammation. However, whether Lcn2 plays a role in the pathogenesis of gut inflammation is unknown. Herein, we investigated the extent to which Lcn2 regulates inflammation and gut bacterial dysbiosis in mouse models of IBD. Methods: Lcn2 expression was monitored in murine colitis models and upon microbiota ablation/restoration. Wild-type (WT) and Lcn2 knockout (Lcn2KO) mice were analyzed for gut bacterial load, composition by 16S ribosomal RNA gene pyrosequencing, and their colitogenic potential by co-housing with interleukin (Il)10KO mice. Acute (dextran sodium sulfate) and chronic (IL10R neutralization and T-cell adoptive transfer) colitis were induced in WT and Lcn2KO mice with or without antibiotics. Results: Lcn2 expression was dramatically induced on inflammation and was dependent on the presence of a gut microbiota and MyD88 signaling. Use of bone marrowâchimeric mice showed that nonimmune cells are the major contributors of circulating Lcn2. Lcn2KO mice showed increased levels of entA-expressing gut bacteria burden, and, moreover, a broadly distinct bacterial community relative to WT littermates. Lcn2KO mice developed highly colitogenic T cells and showed exacerbated colitis on exposure to DSS or neutralization of IL10. Such exacerbated colitis could be prevented by antibiotic treatment. Moreover, exposure to the microbiota of Lcn2KO mice, via cohousing, resulted in severe colitis in Il10KO mice. Conclusions: Lcn2 is a bacterially induced, MyD88-dependent protein that plays an important role in gut homeostasis and a pivotal role on challenge. Hence, therapeutic manipulation of Lcn2 levels may provide a strategy to help manage diseases driven by alteration of the gut microbiota. Keywords: Gut Microbiota, Innate Immunity, Germ-Free Mice, MyD88, Colitis, NGAL, Siderocalin, Neutrophils, IBD more...
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- 2016
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19. Gut Microbiota Conversion of Dietary Ellagic Acid into Bioactive Phytoceutical Urolithin A Inhibits Heme Peroxidases.
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Piu Saha, Beng San Yeoh, Rajbir Singh, Bhargavi Chandrasekar, Praveen Kumar Vemula, Bodduluri Haribabu, Matam Vijay-Kumar, and Venkatakrishna R Jala
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Medicine ,Science - Abstract
Numerous studies signify that diets rich in phytochemicals offer many beneficial functions specifically during pathologic conditions, yet their effects are often not uniform due to inter-individual variation. The host indigenous gut microbiota and their modifications of dietary phytochemicals have emerged as factors that greatly influence the efficacy of phytoceutical-based intervention. Here, we investigated the biological activities of one such active microbial metabolite, Urolithin A (UA or 3,8-dihydroxybenzo[c]chromen-6-one), which is derived from the ellagic acid (EA). Our study demonstrates that UA potently inhibits heme peroxidases i.e. myeloperoxidase (MPO) and lactoperoxidase (LPO) when compared to the parent compound EA. In addition, chrome azurol S (CAS) assay suggests that EA, but not UA, is capable of binding to Fe3+, due to its catechol-like structure, although its modest heme peroxidase inhibitory activity is abrogated upon Fe3+-binding. Interestingly, UA-mediated MPO and LPO inhibition can be prevented by innate immune protein human NGAL or its murine ortholog lipocalin 2 (Lcn2), implying the complex nature of host innate immunity-microbiota interactions. Spectral analysis indicates that UA inhibits heme peroxidase-catalyzed reaction by reverting the peroxidase back to its inactive native state. In support of these in vitro results, UA significantly reduced phorbol myristate acetate (PMA)-induced superoxide generation in neutrophils, however, EA failed to block the superoxide generation. Treatment with UA significantly reduced PMA-induced mouse ear edema and MPO activity compared to EA treated mice. Collectively, our results demonstrate that microbiota-mediated conversion of EA to UA is advantageous to both host and microbiota i.e. UA-mediated inhibition of pro-oxidant enzymes reduce tissue inflammation, mitigate non-specific killing of gut bacteria, and abrogate iron-binding property of EA, thus providing a competitive edge to the microbiota in acquiring limiting nutrient iron and thrive in the gut. more...
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- 2016
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20. Combating Hypertension Beyond GWAS: Microbiome and Artificial Intelligence as Opportunities for Precision Medicine
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Sachin Aryal, Ishan Manandhar, Xue Mei, Beng San Yeoh, Ramakumar Tummala, Piu Saha, Islam Osman, Jasenka Zubcevic, David J. Durgan, Matam Vijay-Kumar, and Bina Joe
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- 2023
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21. Conjugated bile acids are nutritionally re-programmable antihypertensive metabolites
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Saroj Chakraborty, Anju Lulla, Xi Cheng, Ji-Youn Yeo, Juthika Mandal, Tao Yang, Xue Mei, Piu Saha, Rachel M. Golonka, Beng San Yeoh, Blair Mell, Wei Jia, Vasanta Putluri, Danthasinghe Waduge Badrajee Piyarathna, Nagireddy Putluri, Arun Sreekumar, Katie Meyer, Matam Vijay-Kumar, and Bina Joe more...
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Physiology ,Internal Medicine ,Cardiology and Cardiovascular Medicine - Published
- 2023
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22. Selective IgA Deficiency in Spontaneously Hypertensive Rats With Gut Dysbiosis
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Piu Saha, Blair Mell, Rachel M. Golonka, Venugopal R. Bovilla, Ahmed A. Abokor, Xue Mei, Beng San Yeoh, Peter A. Doris, Andrew T. Gewirtz, Bina Joe, and Matam Vijay-Kumar
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Immunoglobulin M ,Immunoglobulin G ,Rats, Inbred SHR ,Hypertension ,Internal Medicine ,IgA Deficiency ,Animals ,Dysbiosis ,Blood Pressure ,Rats, Inbred WKY ,Immunoglobulin A ,Rats - Abstract
Background:The spontaneously hypertensive rat (SHR) is extensively used to study hypertension. Gut microbiota dysbiosis is a notable feature in SHR for reasons unknown. Immunoglobulin A (IgA) is a major host factor required for gut microbiota homeostasis. We hypothesized that inadequate IgA contributes to gut microbiota dysbiosis in SHR.methods:IgA was measured in feces, cecum, serum, liver, gut-associated lymphoid tissue, and milk from SHR and Wistar Kyoto rats. IgA regulatory factors like IgM, IgG, andpIgR(polymeric immunoglobulin receptor) were analyzed. IgA and IgG antibodies and blood pressure (BP) were measured before and after administrating a bacterial antigen (ie, flagellin).Results:Compared with Wistar Kyoto rats, SHR displayed remarkably near-deficient IgA levels accompanied by compensatory increases in serum IgM and IgG and gut-liverpIgRexpression. Inadequate milk IgA in SHR emphasized this immune defect stemmed from the neonatal stage. Reduced IgA+B cells in circulation and Peyer patches indicated a possible reason for the lower IgA in SHR. Noteworthy, a genetic insufficiency was unlikely because administering flagellin to SHR induced anti-flagellin IgA antibodies. This immune response surprisingly accelerated hypertension development in SHR, suggesting IgA quiescence may help maintain lower BP.Conclusions:This study is the first to reveal IgA deficiency in SHR as one host factor associated with gut microbiota dysbiosis and invigorates future research to determine the pathophysiological role of IgA in hypertension. more...
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- 2023
23. Gut microbiota lends a helping hand to nurse liver regeneration
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Beng San Yeoh and Matam Vijay-Kumar
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Hepatology - Published
- 2023
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24. Eat more natural dietary fiber and whole grains to minimize liver disease risk
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Rachel M, Golonka, Beng San, Yeoh, and Matam, Vijay-Kumar
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Lifestyle modification ,Hepatocellular carcinoma ,Epidemiology ,General Earth and Planetary Sciences ,Nutrition disorders ,Article ,General Environmental Science - Abstract
The relationship between dietary factors and liver disease remains poorly understood. This study evaluated the associations of whole grain and dietary fiber intake with liver cancer risk and chronic liver disease mortality. The National Institutes of Health–American Association of Retired Persons Diet and Health Study cohort recruited 485, 717 retired U.S. participants in 1995–1996. Follow-up through 2011 identified 940 incident liver cancer cases and 993 deaths from chronic liver disease. Compared with the lowest, the highest quintile of whole grain intake was associated with lower liver cancer risk (Hazard ratio [HR]Q5 vs. Q1 = 0.78, 95% confidence interval [CI]: 0.63–0.96) and chronic liver disease mortality (HRQ5 vs. Q1 = 0.44, 95% CI: 0.35–0.55) in multivariable Cox models. Dietary fiber was also associated with lower liver cancer risk (HRQ5 vs. Q1 = 0.69, 95% CI: 0.53–0.90) and chronic liver disease mortality (HRQ5 vs. Q1 = 0.37, 95% CI: 0.29–0.48). Fiber from vegetables, beans and grains showed potential protective effect. Here, we show that higher intake of whole grain and dietary fiber are associated with lower risk of liver cancer and liver disease mortality., Higher intake of dietary fiber and whole grains are associated with reduced risk of various diseases including some cancers. Here, the authors estimate reductions in liver cancer of 22% and 31% and chronic liver disease mortality of 56% and 63% associated with increased whole grain and dietary fiber intake, respectively. more...
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- 2022
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25. Loss of toll-like receptor 5 potentiates spontaneous hepatocarcinogenesis in farnesoid X receptor–deficient mice
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Rachel M. Golonka, Beng San Yeoh, Piu Saha, Amira Gohara, Ramakumar Tummala, Stanislaw Stepkowski, Amit K. Tiwari, Bina Joe, Frank J. Gonzalez, Andrew T. Gewirtz, and Matam Vijay-Kumar
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Hepatology - Published
- 2023
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26. Abstract P109: A Novel Murine Model Of Diet-induced Cholemia For Studies On The Gut-liver-kidney Axis In Blood Pressure Regulation
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Beng San Yeoh, Piu Saha, Rachel M Golonka, Ahmed A Abokor, Bina Joe, and Matam Vijay-Kumar
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Internal Medicine - Abstract
Bile acids (BA) are classically viewed as emulsifiers produced by the liver for aiding the absorption of fats in the gut. Accumulating evidence now recognizes BA as vasoactive agents capable of lowering blood pressure (BP). However, it remains unclear whether the ensuing hypotension can be associated with end-organ damage. To delineate the pathogenic role of BA in the gut-liver-kidney axis, we leveraged our prior finding that a subset of C57BL/6 mice developed cholemia ( i.e. , high circulating BA) when fed a diet supplemented with 7.5% inulin. Briefly, we challenged 4-week-old male mice (n=50) with the inulin diet for one week and identified the subset that developed cholemia (B6 BA ; n=6). Non-cholemic mice (B6; n=6) were maintained as control. Assessment on BP at 6 months of inulin feeding indicated that B6 BA mice (systolic BP: 107.6 ± 2.2 mmHg; diastolic BP: 78.6 ± 3.1 mmHg) are hypotensive relative to non-cholemic B6 mice (systolic BP: 139.8 ± 5.6 mmHg; diastolic BP: 109.0 ± 3.8 mmHg), which was accompanied by polydipsia (7.0 ± 0.4 ml/day in B6 BA vs 4.3 ± 0.2 ml/day water intake in B6), polyuria (2.5 ± 0.1 ml/day in B6 BA vs 1.2 ± 0.1 ml/day urine output in B6), and elevated urinary BA (28.5 ± 1.7 μM in B6 BA vs 3.3 ± 0.6 μM in B6) in B6 BA mice. B6 BA mice also excreted more urinary creatinine (50.4 ± 3.4 mg/dl in B6 BA vs 25.6 ± 1.3 mg/dl in B6), sodium (271.8 ± 20.1 μmol/day in B6 BA vs 103.0 ± 11.0 μmol/day in B6) and potassium (349.2 ± 16.7 μmol/day in B6 BA vs 128.7 ± 7.7 μmol/day in B6), which could be, in part, explained by their higher glomerular filtration rate (1209.0 ± 121.0 in B6 BA vs 681.2 ± 148.7 μl/min/100 g body weight in B6). Of note, B6 BA mice displayed renomegaly, interstitial nephritis, and bile casts in urine, as well as elevated renal transcripts (>2-fold increase relative to B6) for lipocalin 2, kidney injury molecule-1, tumor necrosis factor alpha, collagen type I α1 and endothelin-1. Taken together, these findings demonstrate that our mouse model of diet-induced cholemia presents with low BP and renal pathology. We envision that this model has notable advantages ( e.g. , ease in inducing cholemia, no early morbidity and tractable for long-term study), in lieu of the conventional bile duct ligation approach, for studying how BA regulate BP. more...
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- 2022
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27. Abstract P077: Targeting Neutrophilia Is A Therapeutic Strategy To Regulate Blood Pressure
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Piu Saha, Blair Mell, Xue Mei, Rachel Golonka, Saroj Chakraborty, Beng San Yeoh, Bina Joe, and Matam Vijay-Kumar
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Internal Medicine - Abstract
Neutrophils are important innate immune cells that are relatively understudied for their contributions to blood pressure (BP) regulation. As neutrophilia is a clinical marker for various pathologies, we hypothesized that neutrophilia is also a feature of hypertension and curtailing neutrophilia is beneficial for lowering BP. Peripheral neutrophil levels were quantitated in Dahl salt-sensitive (S) and Dahl salt-resistant (R) rats consuming either a low salt (0.3% NaCl) or high salt (2% NaCl) diet. Compared to R rats, S rats on a low-salt diet already exhibited neutrophilia (% neutrophils, 33.51±1.6 vs. 39.74±1.2, pi.e., generation of reactive oxygen species (ROS) and neutrophil extracellular traps (NETs, web-like structures of expelled neutrophil DNA). Peripheral neutrophils stimulated with either PMA or LPS showed a ~ 3-fold induction of ROS and NETs, respectively, in S rats compared to R rats on a low-salt diet. Introducing a high-salt diet increased ROS and NETs (~2-fold), the extent of elevation being higher in S rats. Impressively, treatment of S rats on a high-salt diet with 1,3-butandiol [(β - hydroxybutyrate (βOHB, a ketone body) precursor] in the drinking water (20% v/v, 4 weeks) significantly lowered neutrophilia (vehicle: 1.74±0.5 vs βOHB: 0.73±0.3 x 10 9 cells/l, p9 cells/l), albeit to a lesser degree than S rats. Importantly, βOHB administration to S and R rats also reduced NETs and ROS (~2-fold), predominantly in S rats. Collectively, our data are the first to demonstrate that an exaggerated innate immune response via neutrophilia is pathological in hypertension, whereby curbing the neutrophilic response ( e.g., βOHB) could present therapeutic potential in lowering BP. more...
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- 2022
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28. Bacterial Swarmers Enriched During Intestinal Stress Ameliorate Damage
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Christian Jobin, Libusha Kelly, Arjun Byju, Dana J. Lukin, Thomas B. Bartnikas, Weijie Chen, Subho Ghosh, Matam Vijay-Kumar, Regina Lamendella, Jay X. Tang, Milankumar Prajapati, Katherine Sun, Beng San Yeoh, Shirshendu Chatterjee, Justin P. Wright, Wendy Szymczak, Hao Li, Zhen He, Sridhar Mani, Xiaoping Luo, Daniel B. Kearns, and Arpan De more...
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Adult ,Male ,0301 basic medicine ,Movement ,Enterobacter ,Swarming (honey bee) ,Swarming motility ,Inflammation ,Biology ,Inflammatory bowel disease ,Article ,Microbiology ,Feces ,Mice ,Young Adult ,03 medical and health sciences ,0302 clinical medicine ,Re-Epithelialization ,medicine ,Animals ,Humans ,Intestinal Mucosa ,Colitis ,Aged ,Specific-pathogen-free ,Aged, 80 and over ,Bacteriological Techniques ,Wound Healing ,Microbial Viability ,Hepatology ,Probiotics ,Gastroenterology ,Middle Aged ,Inflammatory Bowel Diseases ,medicine.disease ,biology.organism_classification ,Gastrointestinal Microbiome ,Mice, Inbred C57BL ,Disease Models, Animal ,030104 developmental biology ,Dysbiosis ,Female ,030211 gastroenterology & hepatology ,medicine.symptom ,Bacteria - Abstract
Background and Aims Bacterial swarming, a collective movement on a surface, has rarely been associated with human pathophysiology. This study aims to define a role for bacterial swarmers in amelioration of intestinal stress. Methods We developed a polymicrobial plate agar assay to detect swarming and screened mice and humans with intestinal stress and inflammation. From chemically induced colitis in mice, as well as humans with inflammatory bowel disease, we developed techniques to isolate the dominant swarmers. We developed swarm-deficient but growth and swim-competent mutant bacteria as isogenic controls. We performed bacterial reinoculation studies in mice with colitis, fecal 16S, and meta-transcriptomic analyses, as well as in vitro microbial interaction studies. Results We show that bacterial swarmers are highly predictive of intestinal stress in mice and humans. We isolated a novel Enterobacter swarming strain, SM3, from mouse feces. SM3 and other known commensal swarmers, in contrast to their mutant strains, abrogated intestinal inflammation in mice. Treatment of colitic mice with SM3, but not its mutants, enriched beneficial fecal anaerobes belonging to the family of Bacteroidales S24-7. We observed SM3 swarming associated pathways in the in vivo fecal meta-transcriptomes. In vitro growth of S24-7 was enriched in presence of SM3 or its mutants; however, because SM3, but not mutants, induced S24-7 in vivo, we concluded that swarming plays an essential role in disseminating SM3 in vivo. Conclusions Overall, our work identified a new but counterintuitive paradigm in which intestinal stress allows for the emergence of swarming bacteria; however, these bacteria act to heal intestinal inflammation. more...
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- 2021
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29. Activation of CD81+skin ILC2s by cold-sensing TRPM8+neuron-derived signals maintains cutaneous thermal homeostasis
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Ming Xu, Chao Li, Jie Yang, Amy Ye, Liping Yan, Beng San Yeoh, Lai Shi, Yu Shin Kim, Joonsoo Kang, Matam Vijay-Kumar, and Na Xiong
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Inflammation ,Neurons ,Mice ,Immunology ,Animals ,Homeostasis ,TRPM Cation Channels ,Lymphocytes ,General Medicine ,Article ,Immunity, Innate - Abstract
As the outermost barrier tissue of the body, the skin harbors a large number of innate lymphoid cells (ILCs) that help maintain local homeostasis in the face of changing environments. How skin-resident ILCs are regulated and function in local homeostatic maintenance is poorly understood. We here report the discovery of a cold-sensing neuron-initiated pathway that activates skin group 2 ILCs (ILC2s) to help maintain thermal homeostasis. In stearoyl-CoA desaturase 1 (SCD1) knockout mice whose skin is defective in heat maintenance, chronic cold stress induced excessive activation of CCR10−CD81+ST2+skin ILC2s and associated inflammation. Mechanistically, stimulation of the cold-sensing receptor TRPM8 expressed in sensory neurons of the skin led to increased production of IL-18, which, in turn, activated skin ILC2s to promote thermogenesis. Our findings reveal a neuroimmune link that regulates activation of skin ILC2s to support thermal homeostasis and promotes skin inflammation after hyperactivation. more...
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- 2022
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30. Loss of toll-like receptor 5 potentiates spontaneous hepatocarcinogenesis in farnesoid X receptor-deficient mice.
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Golonka, Rachel M., Beng San Yeoh, Saha, Piu, Gohara, Amira, Tummala, Ramakumar, Stepkowski, Stanislaw, Tiwari, Amit K., Joe, Bina, Gonzalez, Frank J., Gewirtz, Andrew T., and Vijay-Kumar, Matam
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- 2023
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31. Microbiota Introduced to Germ-Free Rats Restores Vascular Contractility and Blood Pressure
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Xi Cheng, Cameron G. McCarthy, Saroj Chakraborty, Tao Yang, Matam Vijay-Kumar, Jiyoun Yeo, Camilla F Wenceslau, Jonnelle M Edwards, Nicole R. Bearss, Piu Saha, Bina Joe, Rachel M. Golonka, Beng San Yeoh, Blair Mell, and Janara Furtado more...
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Male ,0301 basic medicine ,medicine.medical_specialty ,Hemodynamics ,Blood Pressure ,030204 cardiovascular system & hematology ,Gut flora ,Article ,Polymerization ,Rats, Sprague-Dawley ,03 medical and health sciences ,0302 clinical medicine ,Cell Movement ,Internal medicine ,Internal Medicine ,medicine ,Animals ,Germ-Free Life ,Actin ,Cell Proliferation ,biology ,Microbiota ,Cofilin ,biology.organism_classification ,Gastrointestinal Microbiome ,Mesenteric Arteries ,Specific Pathogen-Free Organisms ,Actin Cytoskeleton ,030104 developmental biology ,Endocrinology ,Blood pressure ,Phosphorylation ,Hypotension ,medicine.symptom ,Vasoconstriction ,Homeostasis - Abstract
Commensal gut microbiota are strongly correlated with host hemodynamic homeostasis, but only broadly associated with cardiovascular health. This includes a general correspondence of quantitative and qualitative shifts in intestinal microbial communities found in hypertensive rat models and human patients. However, the mechanisms by which gut microbes contribute to the function of organs important for blood pressure control remain unanswered. To examine the direct effects of microbiota on blood pressure, we conventionalized germ-free (GF) rats with specific pathogen free rats for a short-term period of 10 days, which served as a model system to observe the dynamic responses when reconstituting the holobiome. The absence of microbiota in GF rats resulted with relative hypotension compared to their conventionalized counterparts, suggesting an obligatory role of microbiota in blood pressure homeostasis. Hypotension observed in GF rats was accompanied by a marked reduction in vascular contractility. Both blood pressure and vascular contractility were restored by the introduction of microbiota to GF rats, indicating that microbiota could be impacting blood pressure through a vascular-dependent mechanism. This is further supported by the decrease in actin polymerization in arteries from GF rats. Improved vascular contractility in conventionalized GF rats, as indicated through stabilized actin filaments, was associated with an increase in cofilin phosphorylation. These data indicate that the vascular system senses the presence (or lack of) microbiota to maintain vascular tone via actin polymerization. Taken together, these results constitute a fundamental discovery of the essential nature of microbiota in blood pressure regulation. more...
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- 2020
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32. Diurnal Timing Dependent Alterations in Gut Microbial Composition Are Synchronously Linked to Salt-Sensitive Hypertension and Renal Damage
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Saroj Chakraborty, Sarah Galla, Xi Cheng, Blair Mell, Tao Yang, Juthika Mandal, Matam Vijay-Kumar, Beng San Yeoh, Anay Hindupur, Piu Saha, Bina Joe, and Jiyoun Yeo
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Male ,0301 basic medicine ,medicine.medical_specialty ,Firmicutes ,Blood Pressure ,030204 cardiovascular system & hematology ,Lipocalin ,Gut flora ,Kidney ,Article ,Actinobacteria ,Feces ,03 medical and health sciences ,0302 clinical medicine ,Downregulation and upregulation ,RNA, Ribosomal, 16S ,Internal medicine ,Internal Medicine ,medicine ,Animals ,Circadian rhythm ,Sodium Chloride, Dietary ,Rats, Inbred Dahl ,3-Hydroxybutyric Acid ,Base Sequence ,biology ,Bacteroidetes ,Metabolism ,Diet, Sodium-Restricted ,biology.organism_classification ,Circadian Rhythm ,Gastrointestinal Microbiome ,Rats ,RNA, Bacterial ,030104 developmental biology ,Endocrinology ,Genes, Bacterial ,Hypertension ,Energy Metabolism - Abstract
Alterations of diurnal rhythms of blood pressure (BP) and reshaping of gut microbiota are both independently associated with hypertension. However, the relationships between biorhythms of BP and gut microbial composition are unknown. We hypothesized that diurnal timing-associated alterations of microbial compositions are synchronous with diurnal rhythmicity, dip in BP, and renal function. To test this hypothesis, Dahl salt-sensitive (S) rats on low- and high-salt diets were examined for time of day effects on gut microbiota, BP, and indicators of renal damage. Major shifts in night and day patterns of specific groups of microbiota were observed between the dark (active) and light (rest) phases, which correlated with diurnal rhythmicity of BP. The diurnal abundance of Firmicutes, Bacteroidetes, and Actinobacteria were independently associated with BP. Discrete bacterial taxa were observed to correlate independently or interactively with one or more of the following 3 factors: (1) BP rhythm, (2) dietary salt, and (3) dip in BP. Phylogenetic Investigation of Communities revealed diurnal timing effects on microbial pathways, characterized by upregulated biosynthetic processes during the active phase of host, and upregulated degradation pathways of metabolites in the resting phase. Additional metagenomics functional pathways with rhythm variations were noted for aromatic amino acid metabolism and taurine metabolism. These diurnal timing dependent changes in microbiota, their functional pathways, and BP dip were associated with concerted effects of the levels of renal lipocalin 2 and kidney injury molecule-1 expression. These data provide evidence for a firm and concerted diurnal timing effects of BP, renal damage, and select microbial communities. more...
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- 2020
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33. Low-dose 1,3-butanediol reverses age-associated vascular dysfunction independent of ketone body β-hydroxybutyrate
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Cameron G. McCarthy, Emily W. Waigi, Beng San Yeoh, Blair Mell, Matam Vijay-Kumar, Camilla F. Wenceslau, and Bina Joe
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3-Hydroxybutyric Acid ,Physiology ,Physiology (medical) ,Quality of Life ,Animals ,Ketone Bodies ,Cardiology and Cardiovascular Medicine ,Butylene Glycols ,Rats, Inbred WKY ,Research Article ,Rats - Abstract
With an aging global population, identifying novel therapeutics are necessary to increase longevity and decrease the deterioration of essential end organs such as the vasculature. Secondary alcohol, 1,3-butanediol (1,3-BD), is commonly administered to stimulate the biosynthesis of the most abundant ketone body β-hydroxybutyrate (βHB), in lieu of nutrient deprivation. However, suprapharmacological concentrations of 1,3-BD are necessary to significantly increase systemic βHB, and 1,3-BD per se can cause vasodilation at nanomolar concentrations. Therefore, we hypothesized that 1,3-BD could be a novel antiaging therapeutic, independent of βHB biosynthesis. To test this hypothesis, we administered a low-dose (5%) 1,3-BD to young and old Wistar-Kyoto (WKY) rats via drinking water for 4 wk and measured indices of vascular function and metabolism posttreatment. We observed that low-dose 1,3-BD was sufficient to reverse age-associated endothelial-dependent and -independent dysfunction, and this was not associated with increased βHB bioavailability. Further analysis of the direct vasodilator mechanisms of 1,3-BD revealed that it is predominantly an endothelium-dependent vasodilator through activation of potassium channels and nitric oxide synthase. In summary, we report that 1,3-BD, at a concentration that does not stimulate βHB biosynthesis, could be a nutraceutical that can reverse the age-associated decline in vascular function. These results emphasize that 1,3-BD has multiple, concentration-dependent mechanisms of action. Therefore, we suggest alternative approaches to study the physiological and cardiovascular effects of βHB. NEW & NOTEWORTHY 1,3-Butanediol (1,3-BD) is often administered to stimulate the biosynthesis of the most abundant ketone body, β-hydroxybutyrate (βHB), and its purported salubrious effects. Here, we report that a low dose of 1,3-BD (5%) is sufficient to reverse age-associated vascular dysfunction, independent of βHB. Therefore, low-dose 1,3-BD could be a novel therapeutic to increase blood flow and improve the quality of life in the elderly. more...
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- 2022
34. Reconstitution of the host holobiont in germ-free born male rats acutely increases bone growth and affects marrow cellular content
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Yuan Tian, Jiyoun Yeo, Sudipta Baroi, Xi Cheng, Beng San Yeoh, Andrew D. Patterson, Matam Vijay-Kumar, Beata Lecka-Czernik, Piu Saha, Bina Joe, Saroj Chakraborty, Rachel M. Golonka, Blair Mell, Piotr J. Czernik, and Ahmed A. Abokor more...
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Male ,medicine.medical_specialty ,Physiology ,Bone Marrow Cells ,Butyrate ,Biology ,Gut flora ,Bone tissue ,Bone Lengthening ,Muscle hypertrophy ,Rats, Sprague-Dawley ,Feces ,Chondrocytes ,Bone Density ,Osteogenesis ,Internal medicine ,RNA, Ribosomal, 16S ,Genetics ,medicine ,Adipocytes ,Coprophagia ,Animals ,Germ-Free Life ,Cell Proliferation ,Bone growth ,Bone Development ,Bacteria ,Host Microbial Interactions ,biology.organism_classification ,Fatty Acids, Volatile ,Gastrointestinal Microbiome ,Rats ,Endocrinology ,medicine.anatomical_structure ,Alkaline phosphatase ,Dysbiosis ,Bone marrow ,Research Article - Abstract
Integration of microbiota in a host begins at birth and progresses during adolescence, forming a multidirectional system of physiological interactions. Here, we present an instantaneous effect of natural, bacterial gut colonization on the acceleration of longitudinal and radial bone growth in germ-free born, 7-wk-old male rats. Changes in bone mass and structure were analyzed after 10 days following the onset of colonization through cohousing with conventional rats and revealed unprecedented acceleration of bone accrual in cortical and trabecular compartments, increased bone tissue mineral density, improved proliferation and hypertrophy of growth plate chondrocytes, bone lengthening, and preferential deposition of periosteal bone in the tibia diaphysis. In addition, the number of small in size adipocytes increased, whereas the number of megakaryocytes decreased, in the bone marrow of conventionalized germ-free rats indicating that not only bone mass but also bone marrow environment is under control of gut microbiota signaling. The changes in bone status paralleled with a positive shift in microbiota composition toward short-chain fatty acids (SCFA)-producing microbes and a considerable increase in cecal SCFA concentrations, specifically butyrate. Furthermore, reconstitution of the host holobiont increased hepatic expression of IGF-1 and its circulating levels. Elevated serum levels of 25-hydroxy vitamin D and alkaline phosphatase pointed toward an active process of bone formation. The acute stimulatory effect on bone growth occurred independently of body mass increase. Overall, the presented model of conventionalized germ-free rats could be used to study microbiota-based therapeutics for combatting dysbiosis-related bone disorders. more...
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- 2021
35. Immunoglobulin A, an Active Liaison for Host-Microbiota Homeostasis
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Matam Vijay-Kumar, Beng San Yeoh, Connor Campbell, Sreya Brahmandam, Grant H. McDaniel, Ahmed A. Abokor, Rachel M. Golonka, Piu Saha, and Bina Joe
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Microbiology (medical) ,Immunoglobulin A ,Gastrointestinal tract ,B cells ,biology ,Host (biology) ,QH301-705.5 ,Review ,Gut flora ,polymeric immunoglobulin receptor (pIgR) ,biology.organism_classification ,Microbiology ,gut homeostasis ,Mucosal immunology ,Antigen ,secretory IgA ,mucosal immunology ,Virology ,Immunology ,biology.protein ,IgA deficiency ,Biology (General) ,Homeostasis - Abstract
Mucosal surfaces in the gastrointestinal tract are continually exposed to native, commensal antigens and susceptible to foreign, infectious antigens. Immunoglobulin A (IgA) provides dual humoral responses that create a symbiotic environment for the resident gut microbiota and prevent the invasion of enteric pathogens. This review features recent immunological and microbial studies that elucidate the underlying IgA and microbiota-dependent mechanisms for mutualism at physiological conditions. IgA derailment and concurrent microbiota instability in pathological diseases are also discussed in detail. Highlights of this review underscore that the source of IgA and its structural form can dictate microbiota reactivity to sustain a diverse niche where both host and bacteria benefit. Other important studies emphasize IgA insufficiency can result in the bloom of opportunistic pathogens that encroach the intestinal epithelia and disseminate into circulation. The continual growth of knowledge in these subjects can lead to the development of therapeutics targeting IgA and/or the microbiota to treat life threatening diseases. more...
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- 2021
36. 'Western Diet'-Induced Adipose Inflammation Requires a Complex Gut Microbiota
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Andrew T. Gewirtz, Jun Zou, Benoit Chassaing, Aneseh Adeshirlarijaney, Matam Vijay-Kumar, Timothy L. Denning, Hao Q. Tran, Alexis Bretin, and Beng San Yeoh
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0301 basic medicine ,Adipose tissue ,AST, aspartate aminotransferase ,Gut flora ,Germ-Free ,0302 clinical medicine ,WSD, Western-style diet ,Antibiotics ,DC, dendritic cells ,CXCL1, chemokine (C-X-C motif) ligand 1 ,TNF-α, tumor necrosis factor α ,Original Research ,Adiposity ,2. Zero hunger ,Metabolic Syndrome ,Microbiota ,Gastroenterology ,High-Fat Diet ,M2 Macrophage ,MyD88, myeloid differentiation primary response 88 ,3. Good health ,LPS, lipopolysaccharide ,030211 gastroenterology & hepatology ,medicine.symptom ,TLR, Toll-like receptor ,ASF, altered Schaedler flora ,Inflammation ,Biology ,Proinflammatory cytokine ,03 medical and health sciences ,FBS, fetal bovine serum ,ALT, alanine aminotransferase ,SVC, stromal vascular cells ,medicine ,Humans ,Obesity ,lcsh:RC799-869 ,Innate immune system ,KO, knockout ,Hepatology ,Altered Schaedler Flora ,HBSS, Hank’s balanced salt solution ,Dendritic cell ,biology.organism_classification ,MyD88 ,Altered Schaedler flora ,IL, interleukin ,Gastrointestinal Microbiome ,GF, germ-free ,PP, Peyer’s patches ,030104 developmental biology ,Diet, Western ,Immunology ,lcsh:Diseases of the digestive system. Gastroenterology - Abstract
Background & Aims Consumption of a low-fiber, high-fat, Western-style diet (WSD) induces adiposity and adipose inflammation characterized by increases in the M1:M2 macrophage ratio and proinflammatory cytokine expression, both of which contribute to WSD-induced metabolic syndrome. WSD-induced adipose inflammation might result from endoplasmic reticulum stress in lipid-overloaded adipocytes and/or dissemination of gut bacterial products, resulting in activation of innate immune signaling. Hence, we aimed to investigate the role of the gut microbiota, and its detection by innate immune signaling pathways, in WSD-induced adipose inflammation. Methods Mice were fed grain-based chow or a WSD for 8 weeks, assessed metabolically, and intestinal and adipose tissue were analyzed by flow cytometry and quantitative reverse transcription polymerase chain reaction. Microbiota was ablated via antibiotics and use of gnotobiotic mice that completely lacked microbiota (germ-free mice) or had a low-complexity microbiota (altered Schaedler flora). Innate immune signaling was ablated by genetic deletion of Toll-like receptor signaling adaptor myeloid differentiation primary response 88. Results Ablation of microbiota via antibiotic, germ-free, or altered Schaedler flora approaches did not significantly impact WSD-induced adiposity, yet dramatically reduced WSD-induced adipose inflammation as assessed by macrophage populations and cytokine expression. Microbiota ablation also prevented colonic neutrophil and CD103- dendritic cell infiltration. Such reduced indices of inflammation correlated with protection against WSD-induced dysglycemia, hypercholesterolemia, and liver dysfunction. Genetic deletion of myeloid differentiation primary response 88 also prevented WSD-induced adipose inflammation. Conclusions These results indicate that adipose inflammation, and some aspects of metabolic syndrome, are not purely a consequence of diet-induced adiposity per se but, rather, may require disturbance of intestine-microbiota interactions and subsequent activation of innate immunity., Graphical abstract more...
- Published
- 2019
37. Enterobactin, an iron chelating bacterial siderophore, arrests cancer cell proliferation
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Rachel M. Golonka, Beng San Yeoh, Piu Saha, Xia Xiao, Sivarajan Kumarasamy, and Matam Vijay-Kumar
- Subjects
0301 basic medicine ,Siderophore ,Cell Survival ,Iron ,Siderophores ,Antineoplastic Agents ,Apoptosis ,Mitochondrion ,Biochemistry ,Article ,Enterobactin ,Mice ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Lipocalin-2 ,Escherichia coli ,medicine ,Animals ,Homeostasis ,Cell Proliferation ,Pharmacology ,chemistry.chemical_classification ,Reactive oxygen species ,Chemistry ,Mitochondria ,Cell biology ,Mice, Inbred C57BL ,Deferoxamine ,RAW 264.7 Cells ,030104 developmental biology ,Cell culture ,030220 oncology & carcinogenesis ,Cancer cell ,Reactive Oxygen Species ,Intracellular ,medicine.drug - Abstract
Iron is essential for many biological functions, including being a cofactor for enzymes involved in cell proliferation. In line, it has been shown that cancer cells can perturb their iron metabolism towards retaining an abundant iron supply for growth and survival. Accordingly, it has been suggested that iron deprivation through the use of iron chelators could attenuate cancer progression. While they have exhibited anti-tumor properties in vitro, the current therapeutic iron chelators are inadequate due to their low efficacy. Therefore, we investigated whether the bacterial catecholate-type siderophore, enterobactin (Ent), could be used as a potent anti-cancer agent given its strong iron chelation property. We demonstrated that iron-free Ent can exert cytotoxic effects specifically towards monocyte-related tumor cell lines (RAW264.7 and J774A.1), but not primary cells, i.e. bone marrow-derived macrophages (BMDMs), through two mechanisms. First, we observed that RAW264.7 and J774A.1 cells preserve a bountiful intracellular labile iron pool (LIP), whose homeostasis can be disrupted by Ent. This may be due, in part, to the lower levels of lipocalin 2 (Lcn2; an Ent-binding protein) in these cell lines, whereas the higher levels of Lcn2 in BMDMs could prevent Ent from hindering their LIP. Secondly, we observed that Ent could dose-dependently impede reactive oxygen species (ROS) generation in the mitochondria. Such disruption in LIP balance and mitochondrial function may in turn promote cancer cell apoptosis. Collectively, our study highlights Ent as an anti-cancer siderophore, which can be exploited as an unique agent for cancer therapy. more...
- Published
- 2019
- Full Text
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38. Dietary Additives and Supplements Revisited: the Fewer, the Safer for Gut and Liver Health
- Author
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Rachel M. Golonka, Matam Vijay-Kumar, and Beng San Yeoh
- Subjects
0301 basic medicine ,Enterocyte ,Physiology ,Disease ,Gut flora ,Biochemistry ,03 medical and health sciences ,0302 clinical medicine ,Drug Discovery ,Genetics ,medicine ,Ingestion ,Pharmacology ,biology ,High-fructose corn syrup ,business.industry ,digestive, oral, and skin physiology ,Fatty liver ,medicine.disease ,biology.organism_classification ,030104 developmental biology ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Metabolic syndrome ,business ,Dysbiosis - Abstract
The supplementation of dietary additives into processed foods has exponentially increased in the past few decades. Similarly, the incidence rates of various diseases, including metabolic syndrome, gut dysbiosis, and hepatocarcinogenesis, have been elevating. Current research reveals that there is a positive association between food additives and these pathophysiological diseases. This review highlights the research published within the past 5 years that elucidate and update the effects of dietary supplements on liver and intestinal health. Some of the key findings include: enterocyte dysfunction of fructose clearance causes non-alcoholic fatty liver disease (NAFLD); non-caloric sweeteners are hepatotoxic; dietary emulsifiers instigate gut dysbiosis and hepatocarcinogenesis; and certain prebiotics can induce cholestatic hepatocellular carcinoma (HCC) in gut dysbiotic mice. Overall, multiple reports suggest that the administration of purified, dietary supplements could cause functional damage to both the liver and gut. The extraction of bioactive components from natural resources was considered a brilliant method to modulate human health. However, current research highlights that such purified components may negatively affect individuals with microbiotal dysbiosis, resulting in a deeper break of the symbiotic relationship between the host and gut microbiota, which can lead to repercussions on gut and liver health. Therefore, ingestion of these dietary additives should not go without some caution! more...
- Published
- 2019
- Full Text
- View/download PDF
39. PAD4-dependent NETs generation are indispensable for intestinal clearance of Citrobacter rodentium
- Author
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Vishal Singh, Rachel M. Golonka, Yanming Wang, Matam Vijay-Kumar, Piu Saha, Beng San Yeoh, and Xia Xiao
- Subjects
0301 basic medicine ,Infectious colitis ,Arginine ,Colon ,Hydrolases ,Neutrophils ,Immunology ,Inflammation ,Biology ,Neutrophil extracellular traps ,Extracellular Traps ,Article ,Microbiology ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Protein-Arginine Deiminase Type 4 ,Immunity ,medicine ,Citrobacter rodentium ,Immunology and Allergy ,Deoxyribonuclease I ,Animals ,PAD4 ,Mice, Knockout ,Goblet cell ,Innate immune system ,Enterobacteriaceae Infections ,NETs ,Hyperplasia ,medicine.disease ,Bacterial Load ,Immunity, Innate ,3. Good health ,Intestines ,Mice, Inbred C57BL ,030104 developmental biology ,medicine.anatomical_structure ,medicine.symptom ,030215 immunology - Abstract
Peptidyl arginine deiminase-4 (PAD4) is indispensable for generation of neutrophil extracellular traps (NETs), which can provide antimicrobial effects during host innate immune response; however, the role of PAD4 against gastrointestinal infection is largely unknown. Herein, we challenged PAD4-deficient (Pad4-/-) mice and wild-type (WT) littermates with Citrobacter rodentium (CR), and investigated bacteria clearance and gut pathology. Luminal colonization of CR in Pad4-/- mice peaked between 11-14 days post-infection, whereas WT mice suppressed the infection by 14 days. We demonstrated that Pad4-/- mice were unable to form NETs, whereas WT mice showed increased NETs formation in the colon during infection. Pad4-/- mice showed aggravated CR-associated inflammation as indicated by elevated systemic and colonic pro-inflammatory markers. Histological analysis revealed that transmissible colonic hyperplasia, goblet cell depletion, and apoptotic cell death were more pronounced in the colon of CR-infected Pad4-/- mice. Treating WT mice with deoxyribonuclease I, which can disrupt NETs generation, recapitulated the exacerbated CR infection and gut pathology associated with the loss of PAD4. Administration of the PAD4 inhibitor, Cl-amidine also aggravated CR infection, but to a lesser extent. Taken together, our findings highlight the importance of PAD4 in the mucosal clearance of CR and in resolving gut-associated inflammation. more...
- Published
- 2019
40. Psyllium fiber protects mice against western diet-induced metabolic syndrome via the gut microbiota-dependent mechanism.
- Author
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Bretin, Alexis, Beng San Yeoh, Ngo, Vu L., Reddivari, Lavanya, Pellizzon, Michael, Vijay-Kumar, Matam, and Gewirtz, Andrew T.
- Published
- 2023
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41. Gut Microbiota Accelerates Bone Growth and Marrow Adiposity of the Adolescent Gnotobiotic Rat
- Author
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Xi Cheng, Piotr J. Czernik, Matam Vijay-Kumar, Ahmed A. Abokor, Saroj Chakraborty, Jiyoun Yeo, Yuan Tian, Piu Saha, Bina Joe, Sudipta Baroi, Beata Lecka-Czernik, Beng San Yeoh, Andrew D. Patterson, Rachel M. Golonka, and Blair Mell more...
- Subjects
Bone growth ,medicine.medical_specialty ,Endocrinology ,Internal medicine ,Genetics ,medicine ,Biology ,Gut flora ,biology.organism_classification ,Molecular Biology ,Biochemistry ,Biotechnology - Published
- 2021
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42. Metabolomics reveal dynamic host responses in lipid, amino acid, and energy metabolism after acute exposure of gut microbiota in germ‐free rats
- Author
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Matam Vijay-Kumar, Beng San Yeoh, Piu Saha, Bina Joe, Xi Cheng, Rachel M. Golonka, Yuan Tian, Andrew D. Patterson, Blair Mell, Jiyoun Yeo, Ahmed A. Abokor, and Saroj Chakraborty
- Subjects
chemistry.chemical_classification ,Host (biology) ,Energy metabolism ,Biology ,Gut flora ,biology.organism_classification ,Biochemistry ,Amino acid ,Metabolomics ,chemistry ,Acute exposure ,Genetics ,Germ ,Molecular Biology ,Biotechnology - Published
- 2021
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43. Ketone body β-hydroxybutyrate is an autophagy-dependent vasodilator
- Author
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Xi Cheng, Nicole R. Bearss, Cameron G. McCarthy, Camilla F Wenceslau, Saroj Chakraborty, Tao Yang, Matam Vijay-Kumar, Beng San Yeoh, Zachary J Schreckenberger, Blair Mell, Avinash Singh, Bina Joe, and Gagandeep Singh more...
- Subjects
Vasodilator Agents ,Inflammation ,Endogeny ,Ketone Bodies ,medicine.disease_cause ,Mice ,Downregulation and upregulation ,Vascular Biology ,medicine ,Autophagy ,Animals ,Humans ,Endothelial dysfunction ,Receptor ,Pharmacology ,3-Hydroxybutyric Acid ,Chemistry ,Microcirculation ,General Medicine ,medicine.disease ,Cardiovascular disease ,Cell biology ,Rats ,Models, Animal ,Ketone bodies ,medicine.symptom ,Oxidative stress ,Research Article - Abstract
Autophagy has long been associated with longevity, and it is well established that autophagy reverts and prevents vascular deterioration associated with aging and cardiovascular diseases. Currently, our understanding of how autophagy benefits the vasculature is centered on the premise that reduced autophagy leads to the accumulation of cellular debris, resulting in inflammation and oxidative stress, which are then reversed by reconstitution or upregulation of autophagic activity. Evolutionarily, autophagy also functions to mobilize endogenous nutrients in response to starvation. Therefore, we hypothesized that the biosynthesis of the most physiologically abundant ketone body, β-hydroxybutyrate (βHB), would be autophagy dependent and exert vasodilatory effects via its canonical receptor, Gpr109a. To the best of our knowledge, we have revealed for the first time that the biosynthesis of βHB can be impaired by preventing autophagy. Subsequently, βHB caused potent vasodilation via potassium channels but not Gpr109a. Finally, we observed that chronic consumption of a high-salt diet negatively regulates both βHB biosynthesis and hepatic autophagy and that reconstitution of βHB bioavailability prevents high-salt diet-induced endothelial dysfunction. In summary, this work offers an alternative mechanism to the antiinflammatory and antioxidative stress hypothesis of autophagy-dependent vasculoprotection. Furthermore, it reveals a direct mechanism by which ketogenic interventions (e.g., intermittent fasting) improve vascular health. more...
- Published
- 2021
44. Sterile neutrophilia induced via CXCR4 antagonism ameliorates colonic inflammation by increasing immunosuppressive regulatory T cells
- Author
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Piu Saha, Beng San Yeoh, Rachel Golonka, Ahmed Abokor, and Matam Vijay-Kumar
- Subjects
Immunology ,Immunology and Allergy - Abstract
Sterile neutrophilia (SN) is commonly associated with chronic disease, but its role in inflammatory bowel diseases (IBD) is largely unknown. AMD3100 (plerixafor; AMD) is a CXCR4 antagonist that promotes neutrophil egress from bone marrow resulting in SN. To study the role of SN in IBD, we induced chronic intestinal inflammation in C57BL6 mice via 4 weekly injections of IL-10R neutralizing antibody and administered AMD (10 mg/kg bw, i.p., twice weekly) or vehicle. As expected, AMD-treated control and colitic mice had increased peripheral and splenic neutrophils. AMD treatment remarkably reduced epithelial damage and hyperplasia, immune cell infiltration, and disease activity index. To elucidate the protective mechanism, we analyzed immune cells in peripheral circulation, spleen and lamina propria. In circulation, colitic mice with AMD treatment had elevated % CD3+CD4+ helper T cells (Th) but reduced % CD3+CD8+ cytotoxic T (Tc) cells. Yet, the % CD3+CD4+FoxP3+ cells (Tregs) and % CD3+CD4+RORγt+ cells (Th17) remained unchanged. In spleen, AMD treatment significantly increased Tregs, but decreased Th and Tc cells. In lamina propria, AMD treatment markedly elevated Tregs, including RORγt+ Tregs and tolerogenic IL-10+ Tregs. Conversely, the inflammatory IL-17+ Th cells were decreased in AMD-treated colitic mice. In addition to the immunosuppressive milieu, AMD-treated colitic mice had increased ileal expression of the antimicrobial peptide angiogenin 4, which further suggests SN to be important in maintaining gut microbiota homeostasis. Collectively, our results demonstrate that SN could be an adaptive and beneficial immune response during chronic intestinal inflammation. This research was funded by R01 grant from the National Institutes of Health (NIH) [grant number CA219144] and Crohn’s and Colitis Foundation (CCF) [grant number 855256]. more...
- Published
- 2022
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45. Dynamics of antimicrobial protein secretion in mouse milk
- Author
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Ahmed Abokor, Piu Saha, Beng San Yeoh, Rachel Golonka, and Matam Vijay-Kumar
- Subjects
Immunology ,Immunology and Allergy - Abstract
Breast milk is the preferred food for the newborns and considered as complete ‘edible immune system’. In addition, breast milk is a source of innate and adaptive proteins which not only protects the naïve infant gastrointestinal tract from enteropathogens but also aid in the appropriate initial colonization of gut microbiota. In this study, we analyzed antimicrobial immune proteins in the milk from C57BL/6 dams at several time points, and observed distinctive patterns in the immune protein levels throughout the lactation period. The presence of innate immune proteins serum amyloid A (SAA), CD14, and notably lipocalin-2 (Lcn2) were observed in high quantities with Lcn2 and SAA present at microgram levels suggesting a potential niche for these proteins during neonatal immune development. Moreover, low dose LPS administration to dams significantly increased some of these proteins in the milk. In addition, adaptive immune proteins immunoglobulins (Ig) A and G with IgG were present in milk at higher quantities compared to IgA at day 5 post-delivery. Interestingly, class-switching occurs by day 15 indicating a selective adaptive immune preference towards IgA, which could be due to gut colonization of newborns with more complex gut microbiota with aging and IgA being a major gut homeostatic factor. Additionally, milk from IgA-deficient dams allowed for robust proliferation of E. coli compared to wild-type milk further signifying the potential involvement of IgA during the early colonization of microbes in the neonatal gut. Collectively, our findings provide insight in the various immune proteins with antimicrobial activity may play a major role in the initial microbial colonization in the gut, which has long-lasting consequences on the host. Supported by NIH R01-CA219144, NCI Diversity Supplement (CA219144-05S1) more...
- Published
- 2022
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46. Abstract P150: Concerted Diurnal Rhythms Of Gut Microbiota With Salt-sensitive Hypertension And Renal Damage
- Author
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Anay Hindupur, Beng San Yeoh, Sarah Galla, Saroj Chakraborty, Blair Mell, Jiyoun Yeo, Xi Cheng, Tao Yang, Matam Vijay Kumar, Piu Saha, Bina Joe, and Juthika Mandal
- Subjects
Kidney ,Renal damage ,Physiology ,Biology ,Gut flora ,biology.organism_classification ,Diurnal rhythms ,Holobiont ,medicine.anatomical_structure ,Salt sensitivity ,Internal Medicine ,medicine ,Microbiome ,Circadian rhythm - Abstract
Circadian, diurnal rhythm is a vital physiological feature of life forms, which enables holobionts to adapt to the day and night cycles. Evidence suggests that both factions of the holobiont, i.e, the host and its microbiota demonstrate physiological circadian rhythms. Blood pressure is a good example of a host physiological feature with a well-defined diurnal rhythm. In a healthy human, blood pressure (BP) rises to its peak during awakening morning hours and declines to the lowest level during night. In salt-sensitive hypertension, aberrant diurnal rhythms of BP and gut dysbiosis have been demonstrated. Given the critical role of gut microbiota in BP regulation, our current objective was to investigate whether there are synchronous rhythms of holobiont in rodents on low salt and high salt diets and if inflammation pattern also changes diurnally. We examined Dahl Salt-Sensitive (S) rats on low (0.3%) and high (2%) salt diets and BP and inflammation pattern was checked. As hypothesized, both microbiota and kidney inflammation showed diurnal rhythm in response to low salt and high salt diet. Major shifts in diurnal patterns of specific groups of microbiota were observed between the dark (active) and light (rest) phases, which correlated with the diurnal rhythmicity of BP. Diurnal rhythms of Firmicutes, Bacteroidetes and Actinobacteria were independently associated with BP. Discrete bacterial taxa were observed to correlate independently or interactively with one or more of the following 3 factors- 1) BP rhythm, 2) dietary salt, 3) amplitude of BP. PICRUSt analysis revealed diurnal rhythmicity of microbial pathways, characterized by microbiota upregulated biosynthetic processes during active phase and upregulated degradation pathways of metabolites in resting phase. These diurnal changes in microbiota, their functional pathways and BP amplitude were associated with concerted rhythmicity of renal Lipocalin 2 and Kim1 expression and circulating β-hydroxybutyrate in high salt S rats. Such concerted rhythmicity of holobiont with peak of changes at active phase of salt hypertension suggests that targeting this timepoint to reshape microbiota and/or intervene with medication could efficiently benefit the hypertensives more...
- Published
- 2020
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47. Abstract P149: Germ-free Rats Reveal An Obligatory Role Of Microbiota In Blood Pressure
- Author
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Jiyoun Yeo, Tao Yang, Juthika Mandal, Matam Vijay Kumar, Camilla F Wenceslau, Piu Saha, Rachel M. Golonka, Bina Joe, Blair Mell, Cam McCarthy, Beng San Yeoh, Xi Cheng, and Saroj Chakraborty
- Subjects
Blood pressure ,business.industry ,Internal Medicine ,Medicine ,Physiology ,Microbiome ,Risk factor ,business ,digestive system ,Elevated blood - Abstract
Elevated blood pressure or hypertension is the single largest risk factor for cardiovascular diseases which are the leading cause of human deaths. Current clinical management of blood pressure is focused on restoring homeostasis of the host alone, without accounting for commensal gut microbiota. Recent evidence from the CARDIA study in humans and multiple studies using animal models suggest that development of hypertension in the host is associated with alterations in microbiotal communities. Here we examined whether microbiota is necessary for blood pressure and vascular homeostasis by functional evaluation of the gut homeostasis, hemodynamic, and vascular function of gnotobiotic rats reconstituted with microbiota to represent the complete holobiont. Gnotobiotic rats were used to represent incomplete holobionts. To reconstitute complete holobionts, gnotobiotic rats were co-housed with conventionally-raised rats. Acquisition of microbiota was evaluated through monitoring of gross ceca and fecal samples by metagenomic 16S sequencing. BP was recorded and vascular, renal, hepatic, cardiac and gut features were assessed using histology and ex vivo myography. Markers of innate immune effectors (Immune cell population, level of Lcn2, Gut permeability) were used to examine the nature and extent of host immune cell processes concomitantly occurring along with observations of host hemodynamics. Compared to the reconstituted holobiont represented by the animals exposed to microbiota, the incomplete-holobiont represented by gnotobiotic rats, had significantly lower BP (SBP of germ free:109±8 mmHg, SBP of conventionalized:138±10mmHg * ) and vascular contractility responses to phenylephrine (Emax (mN): germ-free: 6.9±1.3, GFC: 11.7±0.7*). Acute exposure of the host to microbiota reconstituted gut microbiotal communities, significantly boosted their gut epithelial cell proliferation, innate immune function and restored vascular contractility. These data indicate that in addition to the dependency of the host on microbiota for essential bodily functions such as digestion of plant-derived complex carbohydrates, the host is also dependent on microbiota for maintaining blood pressure and vascular function more...
- Published
- 2020
- Full Text
- View/download PDF
48. Abstract P238: Bile Acid Metabolites Modulate Hypertension
- Author
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Juthika Mandal, Cam McCarthy, Camilla F Wenceslau, Katie A. Meyer, Wei Jia, Vasanta Putluri, Matam Vijay Kumar, Jiyoun Yeo, Nagireddy Putluri, Piu Saha, Bina Joe, Anju Lulla, Blair Mell, Arun Sreekumar, Beng San Yeoh, Ahmad Alimadadi, Saroj Chakraborty, and Xi Cheng more...
- Subjects
Blood pressure ,Bile acid ,medicine.drug_class ,business.industry ,Internal Medicine ,medicine ,Physiology ,Disease ,Microbiome ,Risk factor ,medicine.disease ,business ,Stroke - Abstract
Hypertension is the single prominent risk factor of epidemic proportions leading to cardiovascular disease and stroke, which comprise the top two reasons for mortality of humans in the modern age. Much of the attention for the unknown causes of hypertension was focused on genetics and dietary salt, but in recent years, host-microbiotal interaction is gaining importance. Host-microbiotal partnership is key for the generation of many bioactive molecules including bile acid (BA) metabolites. Primary bile acids are synthesized and conjugated by the host but deconjugated and further modified to secondary BA by gut commensal bacteria. BA metabolites serve as important ligands for host nuclear receptors and/or G-protein-coupled receptors. These receptors have pivotal roles in blood pressure regulation. However, the effect of the host-microorganism biliary network on blood pressure (BP) remains poorly characterized. Here we report that both dietary salt and genetic factors rewire the composition of bile acids and BP. Specific reductions in conjugated bile acids were noted in human hypertensives as well as in rats with hypertension. Conjugation of bile acids by the host alone, devoid of the deconjugation step by microbiota, was sufficient to decrease BP of germ-free rats compared to germ-free conventionalized rats. Nutritional restoration of the conjugation of bile acids with Taurine increased the availability of circulating conjugated bile acids as ligands and ameliorated host susceptibility to hypertension via BA nuclear receptors and G-protein-coupled receptors. Thus, hosts and their bacterial symbionts can control host BP homeostasis via the resulting pool of bile acid metabolites. Sources of funding: National Institutes of Health (R01HL143082). more...
- Published
- 2020
- Full Text
- View/download PDF
49. Dietary Additives and Supplements Revisited: The Fewer, the Safer for Liver and Gut Health
- Author
-
Rachel, Golonka, Beng San, Yeoh, and Matam, Vijay-Kumar
- Subjects
digestive, oral, and skin physiology ,Article - Abstract
PURPOSE OF REVIEW: The supplementation of dietary additives into processed foods has exponentially increased in the past few decades. Similarly, the incidence rates of various diseases, including metabolic syndrome, gut dysbiosis and hepatocarcinogenesis, have been elevating. Current research reveals that there is a positive association between food additives and these pathophysiological diseases. This review highlights the research published within the past 5 years that elucidate and update the effects of dietary supplements on liver and intestinal health. RECENT FINDINGS: Some of the key findings include: enterocyte dysfunction of fructose clearance causes non-alcoholic fatty liver disease (NAFLD); non-caloric sweeteners are hepatotoxic; dietary emulsifiers instigate gut dysbiosis and hepatocarcinogenesis; and certain prebiotics can induce cholestatic hepatocellular carcinoma (HCC) in gut dysbiotic mice. Overall, multiple reports suggest that the administration of purified, dietary supplements could cause functional damage to both the liver and gut. SUMMARY: The extraction of bioactive components from natural resources was considered a brilliant method to modulate human health. However, current research highlights that such purified components may negatively affect individuals with microbiotal dysbiosis, resulting in a deeper break of the symbiotic relationship between the host and gut microbiota, which can lead to repercussions on gut and liver health. Therefore, ingestion of these dietary additives should not go without some caution! more...
- Published
- 2020
50. Abstract P112: Elevated Blood Pressure In Conventionalized Germ-free Rats Is Coupled With Upregulation Of Kynurenic Pathway Metabolites And Central Immune Responses
- Author
-
Vasanta Putluri, Jiyoun Yeo, Guannan Zhou, Arun Sreekumar, Camilla F Wenceslau, Nagireddy Putluri, Tao Yang, Xue Mei, Rachel M. Golonka, Danthasinghe Waduge Badrajee Piyarathna, Xi Cheng, Piu Saha, Bina Joe, Blair Mell, Juthika Mandal, Beng San Yeoh, Matam Vijay-Kumar, Saroj Chakraborty, and Cameron G. McCarthy more...
- Subjects
medicine.medical_specialty ,Chemistry ,Metabolite ,Tryptophan ,Metabolism ,Kynurenate ,chemistry.chemical_compound ,Endocrinology ,Immune system ,medicine.anatomical_structure ,nervous system ,Downregulation and upregulation ,Internal medicine ,Internal Medicine ,medicine ,Microbiome ,Nucleus - Abstract
Background: Recent evidence supports that metabolic dysfunction underlies hypertension. Injection of kynurenate, a metabolite of tryptophan pathway, into the paraventricular nucleus of the hypothalamus (PVN) lowers blood pressure (BP). Intestinal absorption and metabolism of tryptophan are impacted by gut microbiota. Since gut-brain axis contributes to gut dysbiosis-inducd hypertension, we hypothesized that gut microbiota modulates the levels of kynurenic pathway metabolites that have central impact on BP regulation. Methods: We, for the first time, used 7 weeks old male Germ-free (GF) Spague Dawley (SD) rats (n=5) and GF rats co-housed with conventional SD rats for 10 days (GFC) (n=6). BP was measured by tail-cuff. Serum metabolites were quantified by 6495 triple quandrople mass spectrometryand data was normalized using isotoplic labelled compounds. The nucleus of the solitary tract (NTS), the principal sensory nucleus for peripheral changes, and the PVN, a relay center projecting sympathetic output based on the integrated afferent inputs from brain regions including NTS, were analyzed by microarray hybridization for mRNA expression. Results: Compared to the GF rats, GFC rats had significantly higher systolic (139 mmHg vs 115 mmHg, p p p p Cd74, Il1b, Cxcl1, Mmp14 ) in the PVN (gene ontology analysis, p Sox11, Tp53, Cdk6, Hoxb4, Foxo4, Cyr61 ) in the NTS (gene ontology analysis, p Conclusion: Colonization of gut microbiota in GF rats induced increased cell differentiation and synaptic plasticity in the NTS and immune responses in the PVN, indicating the restructured sensory neurons of the NTS and enhanced sympathetic output from the PVN. These are in line with increased levels of kynurenic acid and 3-hydroxy kynurenine, and BP, respectively, suggesting that BP regulation by the gut-brain axis may be mediated by kynurenic pathway. more...
- Published
- 2020
- Full Text
- View/download PDF
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