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Article: Unsuitability of the Oxidation-Reduction Potential Measurement for the Quantification of Fecal Redox Status in Inflammatory Bowel Disease.

Geertsema, Sem / Jansen, Bernadien H / van Goor, Harry / Dijkstra, Gerard / Faber, Klaas Nico / Bourgonje, Arno R

2023 Volume 11, Issue 12

Abstract: Oxidative stress is a key pathophysiological process associated with the development and progression of inflammatory bowel disease (IBD). Biomarkers for oxidative stress, however, are scarce, as are diagnostic tools that can interrogate an individual's ... ...

Abstract	Oxidative stress is a key pathophysiological process associated with the development and progression of inflammatory bowel disease (IBD). Biomarkers for oxidative stress, however, are scarce, as are diagnostic tools that can interrogate an individual's gut redox status. This proof-of-concept study aimed to evaluate the potential utility of an oxidation-reduction potential (ORP) measurement probe, to quantify redox status in the feces of both patients with IBD and healthy controls. Previous studies using this ORP measurement probe demonstrated promising data when comparing ORP from severely malnourished individuals with that of healthy controls. To date, ORP analyses have not been performed in the context of IBD. We hypothesized that measuring the ORP of fecal water in patients with IBD might have diagnostic value. The current study, however, did not show significant differences in ORP measurement values between patients with IBD (median [IQR] 46.5 [33.0-61.2] mV) and healthy controls (25 [8.0-52.0] mV;
Language	English
Publishing date	2023-11-21
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2720867-9
ISSN	2227-9059
ISSN	2227-9059
DOI	10.3390/biomedicines11123107
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Article ; Online: Mucosal host-microbe interactions associate with clinical phenotypes in inflammatory bowel disease.

Hu, Shixian / Bourgonje, Arno R / Gacesa, Ranko / Jansen, Bernadien H / Björk, Johannes R / Bangma, Amber / Hidding, Iwan J / van Dullemen, Hendrik M / Visschedijk, Marijn C / Faber, Klaas Nico / Dijkstra, Gerard / Harmsen, Hermie J M / Festen, Eleonora A M / Vich Vila, Arnau / Spekhorst, Lieke M / Weersma, Rinse K

Nature communications

2024 Volume 15, Issue 1, Page(s) 1470

Abstract: Disrupted host-microbe interactions at the mucosal level are key to the pathophysiology of IBD. This study aimed to comprehensively examine crosstalk between mucosal gene expression and microbiota in patients with IBD. To study tissue-specific ... ...

Abstract	Disrupted host-microbe interactions at the mucosal level are key to the pathophysiology of IBD. This study aimed to comprehensively examine crosstalk between mucosal gene expression and microbiota in patients with IBD. To study tissue-specific interactions, we perform transcriptomic (RNA-seq) and microbial (16S-rRNA-seq) profiling of 697 intestinal biopsies (645 derived from 335 patients with IBD and 52 from 16 non-IBD controls). Mucosal gene expression patterns in IBD are mainly determined by tissue location and inflammation, whereas the mucosal microbiota composition shows a high degree of individual specificity. Analysis of transcript-bacteria interactions identifies six distinct groups of inflammation-related pathways that are associated with intestinal microbiota (adjusted P < 0.05). An increased abundance of Bifidobacterium is associated with higher expression of genes involved in fatty acid metabolism, while Bacteroides correlates with increased metallothionein signaling. In patients with fibrostenosis, a transcriptional network dominated by immunoregulatory genes is associated with Lachnoclostridium bacteria in non-stenotic tissue (adjusted P < 0.05), while being absent in CD without fibrostenosis. In patients using TNF-α-antagonists, a transcriptional network dominated by fatty acid metabolism genes is linked to Ruminococcaceae (adjusted P < 0.05). Mucosal microbiota composition correlates with enrichment of intestinal epithelial cells, macrophages, and NK-cells. Overall, these data demonstrate the presence of context-specific mucosal host-microbe interactions in IBD, revealing significantly altered inflammation-associated gene-taxa modules, particularly in patients with fibrostenotic CD and patients using TNF-α-antagonists. This study provides compelling insights into host-microbe interactions that may guide microbiota-directed precision medicine and fuels the rationale for microbiota-targeted therapeutics as a strategy to alter disease course in IBD.
MeSH term(s)	Humans ; Host Microbial Interactions/genetics ; Tumor Necrosis Factor-alpha/genetics ; Inflammatory Bowel Diseases/pathology ; Phenotype ; Inflammation/genetics ; Inflammation/pathology ; Fatty Acids ; Intestinal Mucosa/pathology
Chemical Substances	Tumor Necrosis Factor-alpha ; Fatty Acids
Language	English
Publishing date	2024-02-17
Publishing country	England
Document type	Journal Article
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-024-45855-2
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Article ; Online: Faecal metabolome and its determinants in inflammatory bowel disease.

Vich Vila, Arnau / Hu, Shixian / Andreu-Sánchez, Sergio / Collij, Valerie / Jansen, Bernadien H / Augustijn, Hannah E / Bolte, Laura A / Ruigrok, Renate A A A / Abu-Ali, Galeb / Giallourakis, Cosmas / Schneider, Jessica / Parkinson, John / Al-Garawi, Amal / Zhernakova, Alexandra / Gacesa, Ranko / Fu, Jingyuan / Weersma, Rinse K

Gut

2023 Volume 72, Issue 8, Page(s) 1472–1485

Abstract: Objective: Inflammatory bowel disease (IBD) is a multifactorial immune-mediated inflammatory disease of the intestine, comprising Crohn's disease and ulcerative colitis. By characterising metabolites in faeces, combined with faecal metagenomics, host ... ...

Abstract	Objective: Inflammatory bowel disease (IBD) is a multifactorial immune-mediated inflammatory disease of the intestine, comprising Crohn's disease and ulcerative colitis. By characterising metabolites in faeces, combined with faecal metagenomics, host genetics and clinical characteristics, we aimed to unravel metabolic alterations in IBD. Design: We measured 1684 different faecal metabolites and 8 short-chain and branched-chain fatty acids in stool samples of 424 patients with IBD and 255 non-IBD controls. Regression analyses were used to compare concentrations of metabolites between cases and controls and determine the relationship between metabolites and each participant's lifestyle, clinical characteristics and gut microbiota composition. Moreover, genome-wide association analysis was conducted on faecal metabolite levels. Results: We identified over 300 molecules that were differentially abundant in the faeces of patients with IBD. The ratio between a sphingolipid and L-urobilin could discriminate between IBD and non-IBD samples (AUC=0.85). We found changes in the bile acid pool in patients with dysbiotic microbial communities and a strong association between faecal metabolome and gut microbiota. For example, the abundance of Conclusion: In this large-scale analysis, we identified alterations in the metabolome of patients with IBD that are independent of commonly overlooked confounders such as diet and surgical history. Considering the influence of the microbiome on faecal metabolites, our results pave the way for future interventions targeting intestinal inflammation.
MeSH term(s)	Humans ; Genome-Wide Association Study ; Inflammatory Bowel Diseases/metabolism ; Colitis, Ulcerative/metabolism ; Metabolome ; Feces ; Arylamine N-Acetyltransferase/metabolism
Chemical Substances	NAT2 protein, human (EC 2.3.1.5) ; Arylamine N-Acetyltransferase (EC 2.3.1.5)
Language	English
Publishing date	2023-03-23
Publishing country	England
Document type	Journal Article
ZDB-ID	80128-8
ISSN	1468-3288 ; 0017-5749
ISSN (online)	1468-3288
ISSN	0017-5749
DOI	10.1136/gutjnl-2022-328048
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Article ; Online: The gut microbiome across the cardiovascular risk spectrum.

Prins, Femke M / Collij, Valerie / Groot, Hilde E / Björk, Johannes R / Swarte, J Casper / Andreu-Sánchez, Sergio / Jansen, Bernadien H / Fu, Jingyuan / Harmsen, Hermie J M / Zhernakova, Alexandra / Lipsic, Erik / van der Harst, Pim / Weersma, Rinse K / Gacesa, Ranko

European journal of preventive cardiology

2023

Abstract: Aims: Despite treatment advancements, cardiovascular disease remains a leading cause of death worldwide. Identifying new targets is crucial for enhancing preventive and therapeutic strategies. The gut microbiome has been associated with coronary artery ... ...

Abstract	Aims: Despite treatment advancements, cardiovascular disease remains a leading cause of death worldwide. Identifying new targets is crucial for enhancing preventive and therapeutic strategies. The gut microbiome has been associated with coronary artery disease (CAD), however our understanding of specific changes during CAD development remains limited. We aimed to investigate microbiome changes in participants without clinically manifest CAD with different cardiovascular risk levels and in patients with ST-elevation myocardial infarction (STEMI). Methods: In this cross-sectional study, we characterized the gut microbiome using metagenomics of 411 faecal samples from individuals with low (n=130), intermediate (n=130) and high (n=125) cardiovascular risk based on the Framingham score, and STEMI patients (n=26). We analysed diversity, and differential abundance of species and functional pathways while accounting for confounders including medication and technical covariates. Results: Collinsella stercoris, Flavonifractor plautii and Ruthenibacterium lactatiformans showed increased abundances with cardiovascular risk, while Streptococcus thermophilus was negatively associated. Differential abundance analysis revealed eight species and 49 predicted metabolic pathways that were differently abundant among the groups. In the gut microbiome of STEMI patients, there was a depletion of pathways linked to vitamin, lipid and amino-acid biosynthesis. Conclusion: We identified four microbial species showing a gradual trend in abundance from low-risk individuals to those with STEMI, and observed differential abundant species and pathways in STEMI patients compared to those without clinically manifest CAD. Further investigation is warranted to gain deeper understanding of their precise role in CAD progression and potential implications, with the ultimate goal of identifying novel therapeutic targets.
Language	English
Publishing date	2023-12-07
Publishing country	England
Document type	Journal Article
ZDB-ID	2626011-6
ISSN	2047-4881 ; 2047-4873
ISSN (online)	2047-4881
ISSN	2047-4873
DOI	10.1093/eurjpc/zwad377
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Zs.A 4686: Show issues

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Article: HIF1α-Dependent Induction of

Fagundes, Raphael R / Bourgonje, Arno R / Hu, Shixian / Barbieri, Ruggero / Jansen, Bernadien H / Sinnema, Nienke / Blokzijl, Tjasso / Taylor, Cormac T / Weersma, Rinse K / Faber, Klaas Nico / Dijkstra, Gerard

Frontiers in physiology

2022 Volume 13, Page(s) 889091

Abstract: Background and Aims: ...

Abstract	Background and Aims:
Language	English
Publishing date	2022-06-08
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2564217-0
ISSN	1664-042X
ISSN	1664-042X
DOI	10.3389/fphys.2022.889091
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Article ; Online: Pirfenidone Inhibits Cell Proliferation and Collagen I Production of Primary Human Intestinal Fibroblasts.

Cui, Yingying / Zhang, Mengfan / Leng, Changsen / Blokzijl, Tjasso / Jansen, Bernadien H / Dijkstra, Gerard / Faber, Klaas Nico

Cells

2020 Volume 9, Issue 3

Abstract: Intestinal fibrosis is a common complication of inflammatory bowel disease. So far, there is no safe and effective drug for intestinal fibrosis. Pirfenidone is an anti-fibrotic compound available for the treatment of idiopathic pulmonary fibrosis. Here, ... ...

Abstract	Intestinal fibrosis is a common complication of inflammatory bowel disease. So far, there is no safe and effective drug for intestinal fibrosis. Pirfenidone is an anti-fibrotic compound available for the treatment of idiopathic pulmonary fibrosis. Here, we explored the anti-proliferative and anti-fibrotic properties of pirfenidone on primary human intestinal fibroblasts (p-hIFs). p-hIFs were cultured in the absence and presence of pirfenidone. Cell proliferation was measured by a real-time cell analyzer (xCELLigence) and BrdU incorporation. Cell motility was monitored by live cell imaging. Cytotoxicity and cell viability were analyzed by Sytox green, Caspase-3 and Water Soluble Tetrazolium Salt-1 (WST-1) assays. Gene expression of fibrosis markers was determined by quantitative reverse transcription PCR (RT-qPCR). The mammalian target of rapamycin (mTOR) signaling was analyzed by Western blotting and type I collagen protein expression additionally by immunofluorescence microscopy. Pirfenidone dose-dependently inhibited p-hIF proliferation and motility, without inducing cell death. Pirfenidone suppressed mRNA levels of genes that contribute to extracellular matrix production, as well as basal and TGF-β1-induced collagen I protein production, which was associated with inhibition of the rapamycin-sensitive mTOR/p70S6K pathway in p-hIFs. Thus, pirfenidone inhibits the proliferation of intestinal fibroblasts and suppresses collagen I production through the TGF-β1/mTOR/p70S6K signaling pathway, which might be a novel and safe anti-fibrotic strategy to treat intestinal fibrosis.
MeSH term(s)	Cell Death/drug effects ; Cell Proliferation/drug effects ; Cells, Cultured ; Collagen Type I/biosynthesis ; Extracellular Matrix Proteins/metabolism ; Fibroblasts/cytology ; Fibroblasts/drug effects ; Fibroblasts/metabolism ; Humans ; Intestines/cytology ; Phosphorylation/drug effects ; Pyridones/pharmacology ; RNA, Messenger/genetics ; RNA, Messenger/metabolism ; Ribosomal Protein S6 Kinases, 70-kDa/metabolism ; Signal Transduction/drug effects ; TOR Serine-Threonine Kinases/metabolism ; Transforming Growth Factor beta1/pharmacology
Chemical Substances	Collagen Type I ; Extracellular Matrix Proteins ; Pyridones ; RNA, Messenger ; Transforming Growth Factor beta1 ; pirfenidone (D7NLD2JX7U) ; TOR Serine-Threonine Kinases (EC 2.7.1.1) ; Ribosomal Protein S6 Kinases, 70-kDa (EC 2.7.11.1)
Language	English
Publishing date	2020-03-22
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2661518-6
ISSN	2073-4409 ; 2073-4409
ISSN (online)	2073-4409
ISSN	2073-4409
DOI	10.3390/cells9030775
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Article ; Online: The Composition and Metabolic Potential of the Human Small Intestinal Microbiota Within the Context of Inflammatory Bowel Disease.

Ruigrok, Renate A A A / Collij, Valerie / Sureda, Paula / Klaassen, Marjolein A Y / Bolte, Laura A / Jansen, Bernadien H / Voskuil, Michiel D / Fu, Jingyuan / Wijmenga, Cisca / Zhernakova, Alexandra / Weersma, Rinse K / Vich Vila, Arnau

Journal of Crohn's & colitis

2021 Volume 15, Issue 8, Page(s) 1326–1338

Abstract: Background and aims: The human gastrointestinal tract harbours distinct microbial communities essential for health. Little is known about small intestinal communities, despite the small intestine playing a fundamental role in nutrient absorption and ... ...

Abstract	Background and aims: The human gastrointestinal tract harbours distinct microbial communities essential for health. Little is known about small intestinal communities, despite the small intestine playing a fundamental role in nutrient absorption and host-microbe immune homeostasis. We aimed to explore the small intestine microbial composition and metabolic potential, in the context of inflammatory bowel disease [IBD]. Methods: Metagenomes derived from faecal samples and extensive phenotypes were collected from 57 individuals with an ileostomy or ileoanal pouch, and compared with 1178 general population and 478 IBD faecal metagenomes. Microbiome features were identified using MetaPhAn2 and HUMAnN2, and association analyses were performed using multivariate linear regression. Results: Small intestinal samples had a significantly lower bacterial diversity, compared with the general population and, to a lesser extent, IBD samples. Comparing bacterial composition, small intestinal samples clustered furthest from general population samples and closest to IBD samples with intestinal resections. Veillonella atypica, Streptococcus salivarius, and Actinomyces graevenitzii were among the species significantly enriched in the small intestine. Predicted metabolic pathways in the small intestine are predominantly involved in simple carbohydrate and energy metabolism, but also suggest a higher pro-inflammatory potential. Conclusions: We described the bacterial composition and metabolic potential of the small intestinal microbiota. The colonic microbiome of IBD patients, particularly with intestinal resections, showed resemblance to that of the small intestine. Moreover, several features characterising the small intestinal microbiome have been previously associated with IBD. These results highlight the importance of studying the small intestinal microbiota to gain new insight into disease pathogenesis.
MeSH term(s)	Cohort Studies ; Feces/microbiology ; Female ; Gastrointestinal Microbiome ; Humans ; Inflammatory Bowel Diseases ; Intestine, Small/microbiology ; Male ; Middle Aged
Language	English
Publishing date	2021-01-29
Publishing country	England
Document type	Comparative Study ; Journal Article
ZDB-ID	2390120-2
ISSN	1876-4479 ; 1873-9946
ISSN (online)	1876-4479
ISSN	1873-9946
DOI	10.1093/ecco-jcc/jjab020
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Article ; Online: Inflammation status modulates the effect of host genetic variation on intestinal gene expression in inflammatory bowel disease.

Hu, Shixian / Uniken Venema, Werna T / Westra, Harm-Jan / Vich Vila, Arnau / Barbieri, Ruggero / Voskuil, Michiel D / Blokzijl, Tjasso / Jansen, Bernadien H / Li, Yanni / Daly, Mark J / Xavier, Ramnik J / Dijkstra, Gerard / Festen, Eleonora A / Weersma, Rinse K

Nature communications

2021 Volume 12, Issue 1, Page(s) 1122

Abstract: More than 240 genetic risk loci have been associated with inflammatory bowel disease (IBD), but little is known about how they contribute to disease development in involved tissue. Here, we hypothesized that host genetic variation affects gene expression ...

Abstract	More than 240 genetic risk loci have been associated with inflammatory bowel disease (IBD), but little is known about how they contribute to disease development in involved tissue. Here, we hypothesized that host genetic variation affects gene expression in an inflammation-dependent way, and investigated 299 snap-frozen intestinal biopsies from inflamed and non-inflamed mucosa from 171 IBD patients. RNA-sequencing was performed, and genotypes were determined using whole exome sequencing and genome wide genotyping. In total, 28,746 genes and 6,894,979 SNPs were included. Linear mixed models identified 8,881 independent intestinal cis-expression quantitative trait loci (cis-eQTLs) (FDR < 0.05) and interaction analysis revealed 190 inflammation-dependent intestinal cis-eQTLs (FDR < 0.05), including known IBD-risk genes and genes encoding immune-cell receptors and antibodies. The inflammation-dependent cis-eQTL SNPs (eSNPs) mainly interact with prevalence of immune cell types. Inflammation-dependent intestinal cis-eQTLs reveal genetic susceptibility under inflammatory conditions that can help identify the cell types involved in and the pathways underlying inflammation, knowledge that may guide future drug development and profile patients for precision medicine in IBD.
MeSH term(s)	Adult ; Cohort Studies ; Female ; Gene Expression Regulation ; Genetic Predisposition to Disease ; Genetic Variation ; Humans ; Inflammation/genetics ; Inflammatory Bowel Diseases/genetics ; Inflammatory Bowel Diseases/pathology ; Intestines/pathology ; Male ; Polymorphism, Single Nucleotide/genetics ; Quantitative Trait Loci/genetics
Language	English
Publishing date	2021-02-18
Publishing country	England
Document type	Journal Article
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-021-21458-z
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Article ; Online: Donor genetic variants as risk factors for thrombosis after liver transplantation: A genome-wide association study.

Li, Yanni / Nieuwenhuis, Lianne M / Voskuil, Michiel D / Gacesa, Ranko / Hu, Shixian / Jansen, Bernadien H / Venema, Werna T U / Hepkema, Bouke G / Blokzijl, Hans / Verkade, Henkjan J / Lisman, Ton / Weersma, Rinse K / Porte, Robert J / Festen, Eleonora A M / de Meijer, Vincent E

American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons

2021 Volume 21, Issue 9, Page(s) 3133–3147

Abstract: Thrombosis after liver transplantation substantially impairs graft- and patient survival. Inevitably, heritable disorders of coagulation originating in the donor liver are transmitted by transplantation. We hypothesized that genetic variants in donor ... ...

Abstract	Thrombosis after liver transplantation substantially impairs graft- and patient survival. Inevitably, heritable disorders of coagulation originating in the donor liver are transmitted by transplantation. We hypothesized that genetic variants in donor thrombophilia genes are associated with increased risk of posttransplant thrombosis. We genotyped 775 donors for adult recipients and 310 donors for pediatric recipients transplanted between 1993 and 2018. We determined the association between known donor thrombophilia gene variants and recipient posttransplant thrombosis. In addition, we performed a genome-wide association study (GWAS) and meta-analyzed 1085 liver transplantations. In our donor cohort, known thrombosis risk loci were not associated with posttransplant thrombosis, suggesting that it is unnecessary to exclude liver donors based on thrombosis-susceptible polymorphisms. By performing a meta-GWAS from children and adults, we identified 280 variants in 55 loci at suggestive genetic significance threshold. Downstream prioritization strategies identified biologically plausible candidate genes, among which were AK4 (rs11208611-T, p = 4.22 × 10
MeSH term(s)	Adult ; Child ; Genome-Wide Association Study ; Graft Survival ; Humans ; Liver Transplantation/adverse effects ; Living Donors ; Retrospective Studies ; Risk Factors ; Thrombosis/genetics ; Tissue Donors
Language	English
Publishing date	2021-02-11
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2060594-8
ISSN	1600-6143 ; 1600-6135
ISSN (online)	1600-6143
ISSN	1600-6135
DOI	10.1111/ajt.16490
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Zs.A 5542: Show issues

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Article ; Online: Health-related quality of life is linked to the gut microbiome in kidney transplant recipients.

Nature communications

2023 Volume 14, Issue 1, Page(s) 7968

Abstract: Kidney transplant recipients (KTR) have impaired health-related quality of life (HRQoL) and suffer from intestinal dysbiosis. Increasing evidence shows that gut health and HRQoL are tightly related in the general population. Here, we investigate the ... ...

Abstract	Kidney transplant recipients (KTR) have impaired health-related quality of life (HRQoL) and suffer from intestinal dysbiosis. Increasing evidence shows that gut health and HRQoL are tightly related in the general population. Here, we investigate the association between the gut microbiome and HRQoL in KTR, using metagenomic sequencing data from fecal samples collected from 507 KTR. Multiple bacterial species are associated with lower HRQoL, many of which have previously been associated with adverse health conditions. Gut microbiome distance to the general population is highest among KTR with an impaired physical HRQoL (R = -0.20, P = 2.3 × 10
MeSH term(s)	Humans ; Quality of Life ; Gastrointestinal Microbiome/genetics ; Kidney Transplantation/adverse effects ; Feces/microbiology ; Dysbiosis/microbiology
Language	English
Publishing date	2023-12-02
Publishing country	England
Document type	Review ; Journal Article
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-023-43431-8
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