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- Juan F Burgueño, Hajar Hazime, Julia Fritsch, Gillian E Jacobsen, Henry D Dione, Trevor Cickovski, Eddy E González, Ana M Santander, Irina Fernández, Nivis Brito, Zhen Gao, Yuguang Ban, Lily Wang, Landon Wilson, Stephen Barnes, Judith Pignac-Kobinger, Mark S Sundrud, Maria T Abreu
Local interactions between innate immune signaling, microbiota, and bile acids drive the development of duodenal adenomas
Cell Mol Gastroenterol Hepatol. 2025 Dec 2:101694. doi: 10.1016/j.jcmgh.2025.101694 PMID: 41344439
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Abstract
Background & aims: Duodenal adenomas have malignant potential, yet the drivers of duodenal tumorigenesis remain unclear. Duodenal adenomas robustly develop in villin-TLR4 mice, a transgenic mouse model of increased innate immune signaling in the intestinal epithelium. Here, we sought to test the contributions of the microbiota and bile acids to duodenal adenoma development.
Methods: Duodenal tissue was analyzed for proliferation rate and histology in villin-TLR4 versus WT mice. Mice were rederived into germ-free conditions and administered a diet containing the bile acid sequestering resin cholestyramine or treated with the NADPH oxidase inhibitor apocynin. Chemokine expression and myeloid cell recruitment were measured. Findings from mouse studies were corroborated by RNA sequencing and tissue microarray analyses of human duodenal adenomas.
Results: Constitutive activation of epithelial TLR signaling in the duodenum led to adenomas with an intestinal phenotype. Non-adenomatous duodenal tissue showed increased expression of Cxcl1 and Cxcl2 by intestinal epithelial cells and recruitment of S100A8+ and myeloperoxidase (MPO)+ myeloid cells. Re-deriving villin-TLR4 mice in germ-free conditions or feeding them a cholestyramine-supplemented diet prevented tumor initiation, epithelial expression of CXCR2 ligands, and myeloid cell recruitment. Apocynin supplementation slowed tumor progression without affecting chemokine expression or myeloid cell recruitment. In humans, duodenal adenomas had enriched neutrophil activation pathways, increased chemokine expression, and infiltration of S100A8+ and MPO+ myeloid cells.
Conclusions: Bile acids and the microbiota are necessary for duodenal adenoma development and are potentially modifiable risk factors in humans at risk of duodenal adenomas. The recruitment of myeloid cells may promote tumor progression via the release of reactive oxygen species.
Keywords: Small intestine adenocarcinoma; Toll-like receptor 4; duodenal cancer; mouse model.
Copyright © 2025 The Authors. Published by Elsevier Inc. All rights reserved.
- Jia Li, Phillip G Popovich, Kristina A Kigerl, Dana M McTigue, Jan Schwab, Stephen Barnes, Ceren Yarar-Fisher
Multiomic Analysis of the Gut Microbiome and Serum Metabolome in Response to a Low-Carbohydrate, High-Protein Diet in Individuals With Spinal Cord Injury
Randomized Controlled Trial Top Spinal Cord Inj Rehabil. 2025 Fall;31(4):111-129. Epub 2025 Nov 18. doi: 10.46292/sci24-00061 PMID: 41268133
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Abstract
Background: Dietary interventions play a significant role in preventing and managing cardiometabolic diseases partly through their impact on the gut microbiome and circulating metabolites.
Objectives: To assess the impact of an 8-week low-carbohydrate, high-protein (LC/HP) diet on gut microbiome composition, function, and serum metabolome in individuals with spinal cord injury (SCI).
Methods: Twenty-four adults with chronic SCI were randomized into an LC/HP diet or a control group for 8 weeks. Stool and fasting serum samples were collected at baseline and week 8. The gut microbiome composition and metabolic potential were determined using metagenomic sequencing, while serum metabolome was assessed through untargeted liquid chromatography-tandem mass spectrometry. Statistical analyses focused on diet and time interaction effects, using R (version 4.1.0).
Results: A trend for increased alpha diversity (Gini-Simpson, P = .09) in the diet group indicated a more evenly distributed microbial community. Compared to the control group, several microbiome species (e.g., Fusicatenibacter saccharivorans, Eubacterium siraeum) that are implicated with better intestinal health and reduced inflammation increased, while other species (e.g., Hungatella hathewayi, Clostridium symbiosum) that are associated with colorectal cancer risk decreased in the diet group. Microbial metabolic pathways related to amino acid and purine nucleotides were altered. Increased tryptophan betaine and decreased 8-hydroxy-deoxyguanosine were observed in the serum in the diet group (P interaction < .05), indicating compliance and reduced oxidative stress, respectively.
Conclusion: Adopting an LC/HP diet resulted in favorable gut microbiome and metabolome adaptations that may reduce the risk for cardiometabolic disease and colorectal cancer in individuals with SCI.
Keywords: cardiometabolic health; diet; gut microbiome; metabolomics analysis; next-generation sequencing; spinal cord injury.
- Byrne NJ, Koentges C, Pfeil K, Lueg JC, Bakshi S, Tarkhnishvili A, Vosko I, Gollmer J, Birkle LC, Rathner T, Birkle S, Tang S, Rau C, Hoffmann MM, Odening KE, Barnes S, Wilson LS, Ljubojevic-Holzer S, Wallner M, von Lewinski D, Rainer P, Sedej S, Sourij H, Bode C, Wende AR, Zirlik A, Bugger H.
Cardiomyocyte-Specific Deletion of Sirtuin 5 Accelerates the Development of Heart Failure Upon Dysregulating Purine Metabolism.
Acta Physiol (Oxf). 2025 Nov;241(11):e70120. doi: 10.1111/apha.70120 PMID: 41104836
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Abstract
Aim: Sirtuin 5 (SIRT5), a mitochondrial NAD+-dependent deacylase, regulates fundamental cellular pathways, including energy substrate metabolism. The current study is designed to better elucidate the role of SIRT5 in the development of heart failure (HF).
Methods: Mice with cardiomyocyte-specific deletion (cSirt5-/-) or overexpression (cSirt5-Tg) of SIRT5 were generated and subjected to chronic pressure overload by transverse aortic constriction (TAC) or Sham surgery. Cardiac structure and function were assessed by echocardiography, isolated heart perfusions, and histology. MS-based metabolomics and bulk RNA sequencing were used to explore metabolic and molecular signatures.
Results: cSirt5-Tg mice had similar cardiac structure and function compared to control mice, whereas cSirt5-/- mice displayed exacerbated cardiac dilation and dysfunction following TAC, measured both in vivo by echocardiography and ex vivo in isolated heart perfusions. Metabolomics revealed accumulation of inosine and hypoxanthine, and depletion of adenosine, adenine, AMP, and ADP in cSirt5-/- hearts and following TAC, indicating dysregulation of purine metabolism. RNA-sequencing uncovered upregulation of purine-nucleoside phosphorylase and 5′ nucleotidase, and downregulation of adenosine kinase (ADK) in cSirt5-/- hearts following TAC, indicating dysregulation at the interface of adenosine nucleotide salvage and purine degradation in the absence of SIRT5. Analyses of left ventricular tissue of patients with HF revealed reduced SIRT5 expression correlating with reduced ADK expression.
Conclusion: Loss of SIRT5 in cardiomyocytes aggravates cardiac remodeling and dysfunction in response to chronic pressure overload, involving ATP precursor depletion due to transcriptional dysregulation of cardiac purine metabolism.
Keywords: SIRT5; adenosine kinase; heart failure; purine metabolism; sirtuin.
Figure 4
Altered purine and pyrimidine metabolism in cSirt5 −/− hearts following TAC. (A) PLS‐DA plots and (B) VIP scores of top 25 metabolites in cSirt5 −/− hearts compared to control 12 weeks following Sham or TAC surgery (n = 6). Changes in myocardial (C) metabolite level and expression of (D) genes related to purine pathway, (E) ADK protein, and (F) genes related to pyrimidine pathway in control and cSirt5 −/− hearts (n = 6). (G) Schematic illustrating alterations in gene expression and metabolites involved in purine pathway conversion of adenosine to ATP via ADK or to hypoxanthine via ADA and PNP in cSirt5 −/− hearts. VIP scores ≥ 1.0 were considered significant. ADA, adenosine deaminase; ADARB, ADA acting on RNA specific B; ADK, adenosine kinase; ADP, adenosine diphosphate; AMP, adenosine monophosphate; APRT, adenine phosphoribosyl transferase; ATP, adenosine triphosphate; DPYD, dihydropyrimidine dehydrogenase; GNS, glucosamine (N‐acetyl)‐6‐sulfatase; HPRT, hypoxanthine guanine phosphoribosyl transferase; NT5E, 5′ nucleotidase, ecto; PLS‐DA, partial least squares‐discriminant analysis; PNP, purine‐nucleoside phosphorylase; PRPS, phosphoribosyl pyrophosphate synthetase; SIRT5, sirtuin 5; TAC, transverse aortic constriction; UPP, uridine phosphorylase. 2‐Way ANOVA: §, effect of TAC; #, effect of cSirt5‐Tg; % effect of interaction. *p < 0.05, **p < 0.01, ***p < 0.001 using unpaired t test (E) or Fisher’s LSD test (C, D, F).
- llis G, Nowak MK, Kronenberger WG, Recht GO, Ogbeide O, Klemsz LM, Quinn PD, Wilson L, Berryhill T, Barnes S, Newman SD, Kawata K.
Alterations in mitochondrial energy metabolites following acute subconcussive head impacts among athletes with and without ADHD.
iScience. 2025 May 28;28(6):112776. doi: 10.1016/j.isci.2025.112776 eCollection 2025 Jun 20.PMID: 40568316 Free PMC article.
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ABSTRACT
Attention-deficit/hyperactivity disorder (ADHD) is prevalent among contact sports athletes, who may regularly incur repetitive head impacts. This study investigated the effects of acute head impacts on mitochondrial function by analyzing tricarboxylic acid (TCA) cycle metabolites and the potential modulatory role of ADHD. Fifty adult soccer players (ADHD n = 25; non-ADHD n = 25) participated, undergoing ten soccer headers using a controlled heading model. TCA metabolites were assessed at pre-heading baseline, and 2 and 24 h post-heading. Baseline analysis revealed elevated levels of TCA metabolites, including oxaloacetate, citrate, and isocitrate, in the ADHD group. Following head impacts, both groups exhibited significant decreases in these metabolites, yet the magnitude of decrease was more pronounced in the ADHD group. Pyruvate, alpha-ketoglutarate, and fumarate levels increased after headers in both groups. These findings suggest that ADHD is associated with elevated baseline metabolites initiating the TCA cycle, while acute head impacts induce mitochondrial dysfunction, regardless of ADHD.
- Sedaka R, Huang J, Yamaguchi S, Hallit E, Moran-Reyna A, Shan Hsu J, Lovelady C, Fujihashi A, Sako M, Kasztan M, Benavides G, Wilson L, Darley-Usmar V, Barnes S, Saigusa T.
Wheat-based protein slows disease progression in Pkd1 knockout mice.
Function (Oxf). 2025 Jun 10:zqaf026. doi: 10.1093/function/zqaf026. Online ahead of print.PMID: 40493450 No abstract available.
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Abstract
Dietary load and composition are known contributors that accelerate cyst growth in polycystic kidney disease (PKD). High protein intake, which increases amino acid burden in the kidneys, is one such factor. Despite identical protein load, a plant-based wheat-gluten (WG) diet was recently reported to blunt the inflammatory response of animal-based casein diet in a hypertensive model. Considering the importance of pro-inflammatory signals on cystogenesis in PKD, we therefore sought to determine whether a WG compared to casein diet would decelerate cyst progression. Tamoxifen-inducible, global Pkd1 knockout mice were fed either a low casein (6%), high casein (60%), or high wheat-gluten (60%) protein diet for 6 wk. In a separate cohort, mice were gavaged daily with vehicle, lysine, or glutamine for 4 wk while maintained on a normal protein (18%) diet. Tissues were used for histology, flow cytometry, mitochondrial function, metabolomics, and various biochemical assays. WG-fed mice had better kidney function and reduced kidney macrophage percentages, proinflammatory cytokine expression, and cyst growth compared to casein-fed mice. Protein source did not alter kidney mitochondria function. Supplementation with lysine, the highest amino acid in casein versus WG diet, increased kidney cyst growth, acid production, and metabolic disarray. This did not occur with glutamine supplementation, the highest amino acid in WG versus casein diet, despite increased glomerular filtration rate with both amino acids. Neither supplementation mounted an inflammatory response. A plant-based, low-lysine diet slows disease burden in a murine model of PKD. This easily modifiable diet may be a beneficial intervention for PKD patients.
- Hazime H, Ducasa GM, Santander AM, Brito N, Gonzalez-Horta EE, Quintero MA, Barnes S, Wilson L, Zhang Y, Yu F, Gharaibeh RZ, Jobin C, Faust KM, Damas OM, Deshpande A, Kerman DH, Proksell S, Pignac-Kobinger J, Fernández I, Burgueño JF, Abreu MT.
DUOX2 activation drives bacterial translocation and subclinical inflammation in IBD-associated dysbiosis.
Gut. 2025 Apr 29:gutjnl-2024-334346. doi: 10.1136/gutjnl-2024-334346 Online ahead of print. PMID: 40301115 Free article.
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Abstract
Background: Inflammatory bowel diseases (IBDs) are characterised by dysbiosis and a leaky gut. The NADPH oxidase dual oxidase 2 (DUOX2) is upregulated in patients with IBD, yet its role in driving the disease remains unclear.
Objective: We interrogated the functional consequences of epithelial DUOX2 activity for the host and microbiome.
Design: DUOX2 function was studied in mice with epithelial-specific DUOX2 overactivation (vTLR4), inactivation (vTLR4 DUOXA IEC-KO) and wild-type controls. We assessed the effect of dysbiosis on DUOX2 signalling and intestinal permeability (FITC-dextran, serum zonulin, bacterial translocation) with germ-free (GF) mice engrafted with IBD or healthy microbiota. RNA sequencing of colonic mucosa and microbiota and faecal metabolomics were used to characterise the host-microbe interface. Mechanistic studies were conducted in mouse colonoids, IBD biopsies and patient serum samples.
Results: DUOX2 activity increased permeability and bacterial translocation and induced subclinical inflammation in vTLR4 mice. GF vTLR4 mice had increased DUOX2 activity and permeability but no subclinical inflammation. In patients with IBD, DUOX2 expression was positively associated with plasma zonulin levels and negatively associated with ZO-1 expression. Engraftment of GF mice with IBD stool increased DUOX2 activity and triggered low-grade inflammation and permeability defects in mice. DUOX2 activity functionally altered the microbiome, reduced butyrate metabolism and promoted proinflammatory and pro-oncogenic bacterial metabolites. Butyrate and histone deacetylase (HDAC) inhibitors blocked DUOX2 activation and reversed its effects.
Conclusions: Elevated DUOX2 signalling contributes to epithelial barrier dysfunction, microbiome alterations and subclinical inflammation. Butyrate and HDAC inhibitors reversed these effects, indicating that DUOX2 may be a therapeutic target in IBD.
- Lu Y, Osis G, Zmijewska AA, Traylor A, Thukral S, Wilson L, Barnes S, George JF, Agarwal A.
Macrophage-Specific Lactate Dehydrogenase Expression Modulates Inflammatory Function In Vitro
Kidney360. 2025 Feb 1;6(2):197-207. doi: 10.34067/KID.0000000630 Epub 2024 Nov 12.PMID: 39531318 Free PMC article.
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Abstract
Key Points:
- Lactate dehydrogenase A deletion alters macrophage function.
- Lactate dehydrogenase A could serve as a potential therapeutic target in AKI.
Background: In AKI, macrophages play a major role in regulating inflammation. Classically activated macrophages (M1) undergo drastic metabolic reprogramming during their differentiation and upregulate the aerobic glycolysis pathway to fulfill their proinflammatory functions. NAD+ regeneration is crucial for the maintenance of glycolysis, and the most direct pathway by which this occurs is through the fermentation of pyruvate to lactate, catalyzed by lactate dehydrogenase A (LDHA). Our previous study determined that LDHA is predominantly expressed in the proximal segments of the nephron in the mouse kidney and increases with hypoxia. This study investigates the potential of LDHA as a therapeutic target for inflammation by exploring its role in macrophage function in vitro.
Methods: Bone marrow–derived macrophages (BMDMs) were isolated from myeloid-specific LDHA knockout mice derived from crossbreeding LysM-Cre transgenic mice and LDHA floxed mice. RNA sequencing and LC-MS/MS metabolomics analyses were used in this study to determine the effect of LDHA deletion on BMDMs after stimulation with IFN-γ.
Results: LDHA deletion in IFN-γ BMDMs resulted in a significant alteration of the macrophage activation and functional pathways and change in glycolytic, cytokine, and chemokine gene expression. Metabolite concentrations associated with proinflammatory macrophage profiles were diminished, whereas anti-inflammatory–associated ones were increased in LDHA knockout BMDMs. Glutamate and amino sugar metabolic pathways were significantly affected by the LDHA deletion. A combined multiomics analysis highlighted changes in Rap1 signaling, cytokine–cytokine receptor interaction, focal adhesion, and mitogen-activated protein kinase signaling metabolism pathways.
Conclusions: Deletion of LDHA in macrophages results in a notable reduction in the proinflammatory profile and concurrent upregulation of anti-inflammatory pathways. These findings suggest that LDHA could serve as a promising therapeutic target for inflammation, a key contributor to the pathogenesis of AKI.
