Metabolic modeling reveals a multi-level deregulation of host-microbiome metabolic networks in IBD DOI Creative Commons
Jan Taubenheim, A. Samer Kadibalban, Johannes Zimmermann

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Sept. 19, 2024

Abstract Inflammatory bowel diseases (IBDs) are chronic disorders involving dysregulated immune responses. Despite the role of disrupted host-microbial interaction in pathophysiology IBD, underlying metabolic principles not fully understood. We densely profiled microbiome, transcriptome and metabolome signatures from longitudinal IBD cohorts before after advanced drug therapy initiation reconstructed models gut microbiome host intestine to study host-microbiome cross-talk context inflammation. identified concomitant changes activity across data layers NAD, amino acid, one-carbon phospholipid metabolism. In particular on level, elevated tryptophan catabolism depleted circulating tryptophan, thereby impairing NAD biosynthesis. Reduced transamination reactions nitrogen homeostasis polyamine/glutathione The suppressed cycle patient tissues altered profiles due limited choline availability. Simultaneously, shifts acid polyamine metabolism exacerbated these imbalances. Leveraging microbe models, we predicted dietary interventions remodeling restore homeostasis, suggesting novel therapeutic strategies for IBD.

Language: Английский

Mitochondrial function and gastrointestinal diseases DOI

Parsa Haque,

Neeraj Kapur,

Terrence A. Barrett

et al.

Nature Reviews Gastroenterology & Hepatology, Journal Year: 2024, Volume and Issue: 21(8), P. 537 - 555

Published: May 13, 2024

Language: Английский

Citations

20
Metagenome-informed metaproteomics of the human gut microbiome, host, and dietary exposome uncovers signatures of health and inflammatory bowel disease DOI
Rafael Valdés‐Mas, Avner Leshem,

Danping Zheng

et al.

Cell, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 1, 2025

Language: Английский

Citations

4
Integrative analysis of single-cell RNA-seq and gut microbiome metabarcoding data elucidates macrophage dysfunction in mice with DSS-induced ulcerative colitis DOI Creative Commons
Dawon Hong,

Hyo Keun Kim,

Wonhee Yang

et al.

Communications Biology, Journal Year: 2024, Volume and Issue: 7(1)

Published: June 15, 2024

Ulcerative colitis (UC) is a significant inflammatory bowel disease caused by an abnormal immune response to gut microbes. However, there are still gaps in our understanding of how and metabolic changes specifically contribute this disease. Our research aims address gap examining mouse colons after inducing ulcerative colitis-like symptoms. Employing single-cell RNA-seq 16 s rRNA amplicon sequencing analyze distinct cell clusters microbiomes the colon at different time points induction with dextran sodium sulfate. We observe reduction epithelial populations during acute colitis, indicating tissue damage, partial recovery observed chronic inflammation. Analyses cell-cell interactions demonstrate shifts networking patterns among types progression. Notably, macrophage phenotypes exhibit diversity, pronounced polarization towards pro-inflammatory M1 phenotype conditions, suggesting role heterogeneity severity. Increased expression Nampt NOX2 complex subunits UC macrophages contributes processes. The microbiome exhibits reduced taxonomic diversity compared healthy conditions UC. study also highlights T differentiation context dysbiosis its implications progression, emphasizing need for targeted interventions modulate balance colitis.

Language: Английский

Citations

8
Insights into Alkaline Phosphatase Anti-Inflammatory Mechanisms DOI Creative Commons
Larissa Balabanova,

G. I. Bondarev,

Aleksandra Seitkalieva

et al.

Biomedicines, Journal Year: 2024, Volume and Issue: 12(11), P. 2502 - 2502

Published: Nov. 1, 2024

The endogenous ecto-enzyme and exogenously administered alkaline phosphatase (ALP) have been evidenced to significantly attenuate inflammatory conditions, including Toll-like receptor 4 (TLR4)-related signaling cytokine overexpression, barrier tissue dysfunction oxidative stress, metabolic syndrome insulin resistance, in experimental models of colitis, liver failure, renal cardiac ischemia-reperfusion injury. This suggests multiple mechanisms ALP anti-inflammatory action that remain be fully elucidated.

Language: Английский

Citations

6
Novel immune cross-talk between inflammatory bowel disease and IgA nephropathy DOI Creative Commons

Qianqian Yan,

Zihao Zhao, Dongwei Liu

et al.

Renal Failure, Journal Year: 2024, Volume and Issue: 46(1)

Published: April 17, 2024

The mechanisms underlying the complex correlation between immunoglobulin A nephropathy (IgAN) and inflammatory bowel disease (IBD) remain unclear. This study aimed to identify optimal cross-talk genes, potential pathways, mutual immune-infiltrating microenvironments IBD IgAN elucidate linkage patients with IgAN. datasets were obtained from Gene Expression Omnibus (GEO). Three algorithms, CIBERSORTx, ssGSEA, xCell, used evaluate similarities in infiltrating microenvironment two diseases. Weighted gene co-expression network analysis (WGCNA) was implemented dataset major immune infiltration modules, Boruta algorithm, RFE LASSO regression applied filter genes. Next, multiple machine learning models confirm Finally, relevant findings validated using histology immunohistochemistry of mice. Immune showed no significant differences samples most cells. three algorithms identified 10 diagnostic MAPK3, NFKB1, FDX1, EPHX2, SYNPO, KDF1, METTL7A, RIDA, HSDL2, RIPK2; FDX1 NFKB1 enhanced kidney Kyoto Encyclopedia Genes Genomes 15 pathways diseases, lipid metabolism playing a vital role cross-talk. Our offer insights into shared IBD. These common cell-mediated abnormal immunity may inform further experimental studies.

Language: Английский

Citations

5
Dysregulation of CD4+and CD8+resident memory T, myeloid, and stromal cells in steroid-experienced, checkpoint inhibitor colitis DOI Creative Commons
Jun He,

Yang-Joon Kim,

Elvira Mennillo

et al.

Journal for ImmunoTherapy of Cancer, Journal Year: 2024, Volume and Issue: 12(4), P. e008628 - e008628

Published: April 1, 2024

Background Colitis caused by checkpoint inhibitors (CPI) is frequent and treated with empiric steroids, but CPI colitis mechanisms in steroid-experienced or refractory disease are unclear. Methods Using colon biopsies blood from predominantly patients, we performed multiplexed single-cell transcriptomics proteomics to nominate contributing populations. Results showed enrichment of CD4 + resident memory (RM) T cells addition CD8 RM cytotoxic cells. Matching cell receptor (TCR) clonotypes suggested that both RMs progenitors yield effectors. Activated, CD38 HLA-DR were enriched a validation data set steroid-naïve colitis, underscoring their pathogenic potential across steroid exposure. Distinct ulcerative exhibited perturbed stromal metabolism (NAD , tryptophan) impacting epithelial survival inflammation. Endothelial after anti-TNF anti-cytotoxic T-lymphocyte-associated antigen 4 (anti-CTLA-4) upregulated the integrin α4β7 ligand molecular vascular addressin adhesion molecule 1 (MAdCAM-1), which may preferentially respond vedolizumab (anti-α4β7). Conclusions These findings MAdCAM-1 endothelial for targeting specific subsets patients.

Language: Английский

Citations

4
Explainable AI-prioritized plasma and fecal metabolites in inflammatory bowel disease and their dietary associations DOI Creative Commons

Serena Onwuka,

Laura Bravo-Merodio, Georgios V. Gkoutos

et al.

iScience, Journal Year: 2024, Volume and Issue: 27(7), P. 110298 - 110298

Published: June 18, 2024

Fecal metabolites effectively discriminate inflammatory bowel disease (IBD) and show differential associations with diet. Metabolomics AI-based models, including explainable AI (XAI), play crucial roles in understanding IBD. Using datasets from the UK Biobank Human Microbiome Project Phase II IBD Multi'omics Database (HMP2 IBDMDB), this study uses multiple machine learning (ML) classifiers Shapley additive explanations (SHAP)-based XAI to prioritize plasma fecal analyze their diet correlations. Key findings include identification of discriminative like glycoprotein acetyl albumin plasma, as well nicotinic acid andurobilin feces. provided a more robust predictor model (AUC [95%]: 0.93 [0.87-0.99]) compared 0.74 [0.69-0.79]), stronger group-differential diet-metabolite The validates known metabolite highlights impact on interplay between gut microbial

Language: Английский

Citations

4
Interactions between NAD+ metabolism and immune cell infiltration in ulcerative colitis: subtype identification and development of novel diagnostic models DOI Creative Commons

Linglin Tian,

Huiyang Gao,

Yao Tian

et al.

Frontiers in Immunology, Journal Year: 2025, Volume and Issue: 16

Published: Feb. 5, 2025

Ulcerative colitis (UC) is a chronic inflammatory disease of the colonic mucosa with increasing incidence worldwide. Growing evidence highlights pivotal role nicotinamide adenine dinucleotide (NAD+) metabolism in UC pathogenesis, prompting our investigation into subtype-specific molecular underpinnings and diagnostic potential NAD+ metabolism-related genes (NMRGs). Transcriptome data from patients healthy controls were downloaded GEO database, specifically GSE75214 GSE87466. We performed unsupervised clustering based on differentially expressed (DE-NMRGs) to classify cases distinct subtypes. GSEA GSVA identified biological pathways active within these subtypes, while CIBERSORT algorithm assessed differential immune cell infiltration. Weighted gene co-expression network analysis (WGCNA) combined expression was used pinpoint specific NMRGs UC. Robust features for subtyping diagnosis selected using two machine learning algorithms. Nomograms constructed their effectiveness evaluated receiver operating characteristic (ROC) curves. Reverse transcription quantitative polymerase chain reaction (RT-qPCR) conducted verify lines. In study, classified subtypes DE-NMRGs levels, Cluster A exhibiting enhanced self-repair capabilities during responses B showing greater inflammation tissue damage. Through comprehensive bioinformatics analyses, we four key biomarkers (AOX1, NAMPT, NNMT, PTGS2) subtyping, (NNMT, PARP9) its diagnosis. These are closely linked various cells microenvironment, particularly NAMPT PTGS2, which strongly associated neutrophil developed demonstrated high predictive accuracy, achieving area under curve (AUC) values up 0.989 0.997 training set 0.998 0.988 validation sets. RT-qPCR showed significant upregulation NNMT PARP9 inflamed versus normal epithelia, underscoring relevance. Our study reveals UC, identifying findings could suggest therapeutic targets contribute advancing personalized treatment strategies potentially improving patient outcomes.

Language: Английский

Citations

0
Lactobacillus rhamnosus GG Stimulates Dietary Tryptophan-Dependent Production of Barrier-Protecting Methylnicotinamide DOI Creative Commons
Panan Suntornsaratoon, Jayson M. Antonio, Juan Flores

et al.

Cellular and Molecular Gastroenterology and Hepatology, Journal Year: 2024, Volume and Issue: 18(2), P. 101346 - 101346

Published: Jan. 1, 2024

BACKGROUND & AIMS: Lacticaseibacillus rhamnosus GG (LGG) is the world's most consumed probiotic but its mechanism of action on intestinal permeability and differentiation along with interactions an essential source signaling metabolites, dietary tryptophan, are unclear.METHODS: Untargeted metabolomic transcriptomic analyses were performed in LGG monocolonized germ-free (GF) mice fed tryptophan (trp)-free or -sufficient diets.LGG-derived metabolites profiled vitro under anaerobic aerobic conditions.Multiomic correlations using a newly developed algorithm discovered novel tightly linked to tight junction (TJ) cell genes whose abundances regulated by trp.Barrier-modulation these functionally tested Caco2 cells, mouse enteroids, dextran sulfate sodium (DSS) experimental colitis.The contribution barrier protection delineated at specific TJ proteins enterocyte-promoting factors gain loss function approaches. RESULTS:LGG, strictly trp, promotes enterocyte program expression genes, particularly Ocln.Functional evaluations fecal serum synergistically stimulated byLGG trp revealed Vitamin B3 metabolism pathway, methylnicotinamide (MNA) unexpectedly being robust barrier-protective metabolite vivo.Reduced MNA significantly associated increased disease activity IBD patients.Exogenous enhances gut homeostasis robustly colonic healing DSS colitis.MNA sufficient promote epithelial Ocln RNF43, master inhibitor Wnt.Blocking absorption abolishes recovery vivo.CONCLUSIONS: Our study uncovers LGG-regulated trp-dependent production that protects against colitis.

Language: Английский

Citations

3
NAD+ modulation of intestinal macrophages renders anti-inflammatory functionality and ameliorates gut inflammation DOI
Young‐In Kim, Inseok Ko,

Eun-Je Yi

et al.

Biomedicine & Pharmacotherapy, Journal Year: 2025, Volume and Issue: 185, P. 117938 - 117938

Published: Feb. 28, 2025

Language: Английский

Citations

0