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24 pages, 6320 KiB

Open AccessArticle

Vitamin A Promotes the Fusion of Autophagolysosomes and Prevents Excessive Inflammasome Activation in Dextran Sulfate Sodium-Induced Colitis

by Hiroto Hiraga, Daisuke Chinda, Takato Maeda, Yasuhisa Murai, Kohei Ogasawara, Ryutaro Muramoto, Shinji Ota, Keisuke Hasui, Hirotake Sakuraba, Yoh Ishiguro, Shukuko Yoshida, Krisana Asano, Akio Nakane and Shinsaku Fukuda

Int. J. Mol. Sci. 2023, 24(10), 8684; https://doi.org/10.3390/ijms24108684 - 12 May 2023

Cited by 1 | Viewed by 1575

Abstract

Vitamin A ensures intestinal homeostasis, impacting acquired immunity and epithelial barrier function; however, its role in innate immunity is mostly unknown. Here, we studied the impact of vitamin A in different dextran sulfate sodium (DSS)-induced colitis animal models. Interestingly, more severe DSS-induced colitis [...] Read more.

Vitamin A ensures intestinal homeostasis, impacting acquired immunity and epithelial barrier function; however, its role in innate immunity is mostly unknown. Here, we studied the impact of vitamin A in different dextran sulfate sodium (DSS)-induced colitis animal models. Interestingly, more severe DSS-induced colitis was observed in vitamin A-deficient (VAD) mice than in vitamin A-sufficient (VAS) mice; the same was observed in VAD severe combined immunodeficient mice lacking T/B cells. Remarkably, IL-1β production, LC3B-II expression, and inflammasome activity in the lamina propria were significantly elevated in VAD mice. Electron microscopy revealed numerous swollen mitochondria with severely disrupted cristae. In vitro, non-canonical inflammasome signaling-induced pyroptosis, LC3B-II and p62 expression, and mitochondrial superoxide levels were increased in murine macrophages (RAW 264.7) pretreated with retinoic acid receptor antagonist (Ro41-5253). These findings suggest that vitamin A plays a crucial role in the efficient fusion of autophagosomes with lysosomes in colitis. Full article

(This article belongs to the Special Issue Molecular Advances in Inflammatory Bowel Diseases)

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21 pages, 8928 KiB

Open AccessArticle

Response Variability to Drug Testing in Two Models of Chemically Induced Colitis

by Roger Suau, Anna Garcia, Carla Bernal, Mariona Llaves, Katharina Schiering, Eva Jou-Ollé, Alex Pertegaz, Arce Garcia-Jaraquemada, Ramon Bartolí, Violeta Lorén, Patri Vergara, Míriam Mañosa, Eugeni Domènech and Josep Manyé

Int. J. Mol. Sci. 2023, 24(7), 6424; https://doi.org/10.3390/ijms24076424 - 29 Mar 2023

Cited by 1 | Viewed by 1990

Abstract

The lack of knowledge regarding the pathogenesis of IBD is a challenge for the development of more effective and safer therapies. Although in vivo preclinical approaches are critical for drug testing, none of the existing models accurately reproduce human IBD. Factors that influence [...] Read more.

The lack of knowledge regarding the pathogenesis of IBD is a challenge for the development of more effective and safer therapies. Although in vivo preclinical approaches are critical for drug testing, none of the existing models accurately reproduce human IBD. Factors that influence the intra-individual response to drugs have barely been described. With this in mind, our aim was to compare the anti-inflammatory efficacy of a new molecule (MTADV) to that of corticosteroids in TNBS and DSS-induced colitis mice of both sexes in order to clarify further the response mechanism involved and the variability between sexes. The drugs were administered preventively and therapeutically, and real-time bioluminescence was performed for the in vivo time-course colitis monitoring. Morphometric data were also collected, and colonic cytokines and acute plasma phase proteins were analyzed by qRT-PCR and ELISA, respectively—bioluminescence images correlated with inflammatory markers. In the TNBS model, dexamethasone worked better in females, while MTADV improved inflammation in males. In DSS-colitis, both therapies worked similarly. Based on the molecular profiles, interaction networks were constructed to pinpoint the drivers of therapeutic response that were highly dependent on the sex. In conclusion, our results suggest the importance of considering sex in IBD preclinical drug screening. Full article

(This article belongs to the Special Issue Molecular Advances in Inflammatory Bowel Diseases)

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20 pages, 4690 KiB

Open AccessArticle

Molecular Docking Identifies 1,8-Cineole (Eucalyptol) as A Novel PPARγ Agonist That Alleviates Colon Inflammation

by Balaji Venkataraman, Saeeda Almarzooqi, Vishnu Raj, Bhoomendra A. Bhongade, Rajesh B. Patil, Veedamali S. Subramanian, Samir Attoub, Tahir A. Rizvi, Thomas E. Adrian and Sandeep B. Subramanya

Int. J. Mol. Sci. 2023, 24(7), 6160; https://doi.org/10.3390/ijms24076160 - 24 Mar 2023

Cited by 7 | Viewed by 1942

Abstract

Inflammatory bowel disease, comprising Crohn’s disease (CD) and ulcerative colitis (UC), is often debilitating. The disease etiology is multifactorial, involving genetic susceptibility, microbial dysregulation, abnormal immune activation, and environmental factors. Currently, available drug therapies are associated with adverse effects when used long-term. Therefore, [...] Read more.

Inflammatory bowel disease, comprising Crohn’s disease (CD) and ulcerative colitis (UC), is often debilitating. The disease etiology is multifactorial, involving genetic susceptibility, microbial dysregulation, abnormal immune activation, and environmental factors. Currently, available drug therapies are associated with adverse effects when used long-term. Therefore, the search for new drug candidates to treat IBD is imperative. The peroxisome proliferator-activated receptor-γ (PPARγ) is highly expressed in the colon. PPARγ plays a vital role in regulating colonic inflammation. 1,8-cineole, also known as eucalyptol, is a monoterpene oxide present in various aromatic plants which possess potent anti-inflammatory activity. Molecular docking and dynamics studies revealed that 1,8-cineole binds to PPARγ and if it were an agonist, that would explain the anti-inflammatory effects of 1,8-cineole. Therefore, we investigated the role of 1,8-cineole in colonic inflammation, using both in vivo and in vitro experimental approaches. Dextran sodium sulfate (DSS)-induced colitis was used as the in vivo model, and tumor necrosis factor-α (TNFα)-stimulated HT-29 cells as the in vitro model. 1,8-cineole treatment significantly decreased the inflammatory response in DSS-induced colitis mice. 1,8-cineole treatment also increased nuclear factor erythroid 2-related factor 2 (Nrf2) translocation into the nucleus to induce potent antioxidant effects. 1,8-cineole also increased colonic PPARγ protein expression. Similarly, 1,8-cineole decreased proinflammatory chemokine production and increased PPARγ protein expression in TNFα-stimulated HT-29 cells. 1,8-cineole also increased PPARγ promoter activity time-dependently. Because of its potent anti-inflammatory effects, 1,8-cineole may be valuable in treating IBD. Full article

(This article belongs to the Special Issue Molecular Advances in Inflammatory Bowel Diseases)

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18 pages, 5505 KiB

Open AccessArticle

Ameliorating Effects of Vitamin K2 on Dextran Sulfate Sodium-Induced Ulcerative Colitis in Mice

by Shouna Hu, Yan Ma, Ke Xiong, Yanrong Wang, Yajun Liu, Yongye Sun, Yuexin Yang and Aiguo Ma

Int. J. Mol. Sci. 2023, 24(3), 2986; https://doi.org/10.3390/ijms24032986 - 03 Feb 2023

Cited by 14 | Viewed by 2448

Abstract

Ulcerative colitis (UC) is a chronic recurrent inflammatory illness of the gastrointestinal system. The purpose of this study was to explore the alleviating effect of vitamin K2 (VK2) on UC, as well as its mechanism. C57BL/6J mice were given 3% DSS for seven [...] Read more.

Ulcerative colitis (UC) is a chronic recurrent inflammatory illness of the gastrointestinal system. The purpose of this study was to explore the alleviating effect of vitamin K2 (VK2) on UC, as well as its mechanism. C57BL/6J mice were given 3% DSS for seven days to establish UC, and they then received VK2 (15, 30, or 60 mg/kg·bw) and 5-aminosalicylic acid (100 mg/kg·bw) for two weeks. We recorded the clinical signs, body weights, colon lengths, and histological changes during the experiment. We detected the inflammatory factor expressions using enzyme-linked immunosorbent assay (ELISA) kits, and we detected the tight junction proteins using Western blotting. We analyzed the intestinal microbiota alterations and short-chain fatty acids (SCFAs) using 16S rRNA sequencing and targeted metabolomics. According to the results, VK2 restored the colon lengths, improved the colonic histopathology, reduced the levels of proinflammatory cytokines (such as IL-1β, TNF-α, and IL-6), and boosted the level of the immunosuppressive cytokine IL-10 in the colon tissues of the colitis mice. Moreover, VK2 promoted the expression of mucin and tight junction proteins (such as occludin and zonula occludens-1) in order to preserve the intestinal mucosal barrier function and prevent UC in mice. Additionally, after the VK2 intervention, the SCFAs and SCFA-producing genera, such as Eubacterium_ruminantium_group and Faecalibaculum, were elevated in the colon. In conclusion, VK2 alleviated the DSS-induced colitis in the mice, perhaps by boosting the dominant intestinal microflora, such as Faecalibaculum, by reducing intestinal microflora dysbiosis, and by modulating the expression of SCFAs, inflammatory factors, and intestinal barrier proteins. Full article

(This article belongs to the Special Issue Molecular Advances in Inflammatory Bowel Diseases)

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15 pages, 703 KiB

Open AccessArticle

The Genetic Diversity and Dysfunctionality of Catalase Associated with a Worse Outcome in Crohn’s Disease

by Marisa Iborra, Inés Moret, Enrique Busó, José Luis García-Giménez, Elena Ricart, Javier P. Gisbert, Eduard Cabré, Maria Esteve, Lucía Márquez-Mosquera, Esther García-Planella, Jordi Guardiola, Federico V. Pallardó, Carolina Serena, Francisco Algaba-Chueca, Eugeni Domenech, Pilar Nos and Belén Beltrán

Int. J. Mol. Sci. 2022, 23(24), 15881; https://doi.org/10.3390/ijms232415881 - 14 Dec 2022

Cited by 3 | Viewed by 1897

Abstract

Chronic gut inflammation in Crohn’s disease (CD) is associated with an increase in oxidative stress and an imbalance of antioxidant enzymes. We have previously shown that catalase (CAT) activity is permanently inhibited by CD. The purpose of the study was to determine whether [...] Read more.

Chronic gut inflammation in Crohn’s disease (CD) is associated with an increase in oxidative stress and an imbalance of antioxidant enzymes. We have previously shown that catalase (CAT) activity is permanently inhibited by CD. The purpose of the study was to determine whether there is any relationship between the single nucleotide polymorphisms (SNPs) in the CAT enzyme and the potential risk of CD associated with high levels of oxidative stress. Additionally, we used protein and regulation analyses to determine what causes long-term CAT inhibition in peripheral white mononuclear cells (PWMCs) in both active and inactive CD. We first used a retrospective cohort of 598 patients with CD and 625 age-matched healthy controls (ENEIDA registry) for the genotype analysis. A second human cohort was used to study the functional and regulatory mechanisms of CAT in CD. We isolated PWMCs from CD patients at the onset of the disease (naïve CD patients). In the genotype-association SNP analysis, the CAT SNPs rs1001179, rs475043, and rs525938 showed a significant association with CD (p < 0.001). Smoking CD patients with the CAT SNP rs475043 A/G genotype had significantly more often penetrating disease (p = 0.009). The gene expression and protein levels of CAT were permanently reduced in the active and inactive CD patients. The inhibition of CAT activity in the PWMCs of the CD patients was related to a low concentration of CAT protein caused by the downregulation of CAT-gene transcription. Our study suggests an association between CAT SNPs and the risk of CD that may explain permanent CAT inhibition in CD patients together with low CAT gene and protein expression. Full article

(This article belongs to the Special Issue Molecular Advances in Inflammatory Bowel Diseases)

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15 pages, 2543 KiB

Open AccessArticle

Anti-TNF Therapies Suppress Adipose Tissue Inflammation in Crohn’s Disease

by Albert Boronat-Toscano, Diandra Monfort-Ferré, Margarita Menacho, Aleidis Caro, Ramon Bosch, Beatriz Espina, Francisco Algaba-Chueca, Alfonso Saera-Vila, Alicia Moliné, Marc Marti, Eloy Espin, Mónica Millan and Carolina Serena

Int. J. Mol. Sci. 2022, 23(19), 11170; https://doi.org/10.3390/ijms231911170 - 22 Sep 2022

Cited by 3 | Viewed by 2261

Abstract

Anti-TNF biologics have been shown to markedly improve the quality of life for patients with Crohn’s disease (CD), yet one-third of patients fail to benefit from this treatment. Patients with CD develop a characteristic wrapping of visceral adipose tissue (VAT) in the inflamed [...] Read more.

Anti-TNF biologics have been shown to markedly improve the quality of life for patients with Crohn’s disease (CD), yet one-third of patients fail to benefit from this treatment. Patients with CD develop a characteristic wrapping of visceral adipose tissue (VAT) in the inflamed intestinal area, termed creeping fat, and it is known that adipose tissue expansion influences the efficacy of anti-TNF drugs. We questioned whether anti-TNF therapies impact the creeping fat in CD, which might affect the outcome of the disease. Adipose tissue biopsies were obtained from a cohort of 14 patients with CD that received anti-TNF drugs and from 29 non-anti-TNF-treated patients (control group) matched by sex, age, and body mass index undergoing surgical interventions for symptomatic complications. We found that anti-TNF therapies restored adipose tissue morphology and suppressed immune cell infiltration in the creeping fat. Additionally, anti-TNF treatments appeared to markedly improve the pro-inflammatory phenotype of adipose-tissue macrophages and adipose-tissue-derived stem cells. Our study provides evidence that anti-TNF medications influence immune cells and progenitor cells in the creeping of patients with CD, suppressing inflammation. We propose that perilesional VAT should be considered when administering anti-TNF therapy in patients with CD. Full article

(This article belongs to the Special Issue Molecular Advances in Inflammatory Bowel Diseases)

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15 pages, 2294 KiB

Open AccessArticle

Intercontinental Gut Microbiome Variances in IBD

by Luis Mayorga, Gerard Serrano-Gómez, Zixuan Xie, Natalia Borruel and Chaysavanh Manichanh

Int. J. Mol. Sci. 2022, 23(18), 10868; https://doi.org/10.3390/ijms231810868 - 17 Sep 2022

Cited by 3 | Viewed by 1931

Abstract

The development of biomarkers for inflammatory bowel disease (IBD) diagnosis would be relevant in a generalized context. However, intercontinental investigation on these microbial biomarkers remains scarce. We examined taxonomic microbiome variations in IBD using published DNA shotgun metagenomic data. For this purpose, we [...] Read more.

The development of biomarkers for inflammatory bowel disease (IBD) diagnosis would be relevant in a generalized context. However, intercontinental investigation on these microbial biomarkers remains scarce. We examined taxonomic microbiome variations in IBD using published DNA shotgun metagenomic data. For this purpose, we used sequenced data from our previous Spanish Crohn’s disease (CD) and ulcerative colitis (UC) cohort, downloaded sequence data from a Chinese CD cohort, and downloaded taxonomic and functional profiling tables from a USA CD and UC cohort. At the global level, geographical location and disease phenotype were the main explanatory covariates of microbiome variations. In healthy controls (HC) and UC, geography turned out to be the most important factor, while disease intestinal location was the most important one in CD. Disease severity correlated with lower alpha-diversity in UC but not in CD. Across geography, alpha-diversity was significantly different independently of health status, except for CD. Despite recruitment from different countries and with different disease severity scores, CD patients may harbor a very similar microbial taxonomic profile. Our study pointed out that geographic location, disease activity status, and other environmental factors are important contributing factors in microbiota changes in IBD. We therefore strongly recommend taking these factors into consideration for future IBD studies to obtain globally valid and reproducible biomarkers. Full article

(This article belongs to the Special Issue Molecular Advances in Inflammatory Bowel Diseases)

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20 pages, 4687 KiB

Open AccessArticle

The P2X7 Receptor Promotes Colorectal Inflammation and Tumorigenesis by Modulating Gut Microbiota and the Inflammasome

by Claudio Bernardazzi, Morgana Teixeira Lima Castelo-Branco, Beatriz Pêgo, Beatriz Elias Ribeiro, Siane Lopes Bittencourt Rosas, Patrícia Teixeira Santana, João Carlos Machado, Camille Leal, Fabiano Thompson, Robson Coutinho-Silva and Heitor Siffert Pereira de Souza

Int. J. Mol. Sci. 2022, 23(9), 4616; https://doi.org/10.3390/ijms23094616 - 21 Apr 2022

Cited by 20 | Viewed by 3092

Abstract

Background: Given the role of the P2X7 receptor (P2X7R) in inflammatory bowel diseases (IBD), we investigated its role in the development and progression of colitis-associated colorectal cancer (CA-CRC). Methods: CA-CRC was induced in P2X7R^+/+ and P2X7R^−/− mice with azoxymethane (AOM) combined [...] Read more.

Background: Given the role of the P2X7 receptor (P2X7R) in inflammatory bowel diseases (IBD), we investigated its role in the development and progression of colitis-associated colorectal cancer (CA-CRC). Methods: CA-CRC was induced in P2X7R^+/+ and P2X7R^−/− mice with azoxymethane (AOM) combined with dextran sodium sulfate (DSS). In a therapeutic protocol, P2X7R^+/+ mice were treated with a P2X7R-selective inhibitor (A740003). Mice were evaluated with follow-up video endoscopy with endoluminal ultrasound biomicroscopy. Colon tissue was analyzed for histological changes, densities of immune cells, expression of transcription factors, cytokines, genes, DNA methylation, and microbiome composition of fecal samples by sequencing for 16S rRNA. Results: The P2X7R^+/+ mice displayed more ulcers, tumors, and greater wall thickness, than the P2X7R^−/− and the P2X7R^+/+ mice treated with A740003. The P2X7R^+/+ mice showed increased accumulation of immune cells, production of proinflammatory cytokines, activation of intracellular signaling pathways, and upregulation of NLRP3 and NLRP12 genes, stabilized after the P2X7R-blockade. Microbial changes were observed in the P2X7R^−/− and P2X7R^+/+-induced mice, partially reversed by the A740003 treatment. Conclusions: Regulatory mechanisms activated downstream of the P2X7R in combination with signals from a dysbiotic microbiota result in the activation of intracellular signaling pathways and the inflammasome, amplifying the inflammatory response and promoting CA-CRC development. Full article

(This article belongs to the Special Issue Molecular Advances in Inflammatory Bowel Diseases)

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13 pages, 3983 KiB

Open AccessArticle

Aconitate Decarboxylase 1 Deficiency Exacerbates Mouse Colitis Induced by Dextran Sodium Sulfate

by Ho Won Kim, A-Reum Yu, Ji Won Lee, Hoe Sun Yoon, Byung Soo Lee, Hwan-Woo Park, Sung Ki Lee, Young Ik Lee, Jake Whang and Jong-Seok Kim

Int. J. Mol. Sci. 2022, 23(8), 4392; https://doi.org/10.3390/ijms23084392 - 15 Apr 2022

Cited by 7 | Viewed by 2518

Abstract

Ulcerative colitis is a complex inflammatory bowel disorder disease that can induce rectal and colonic dysfunction. Although the prevalence of IBD in Western countries is almost 0.5% of the general population, genetic causes are still not fully understood. In a recent discovery, itaconate [...] Read more.

Ulcerative colitis is a complex inflammatory bowel disorder disease that can induce rectal and colonic dysfunction. Although the prevalence of IBD in Western countries is almost 0.5% of the general population, genetic causes are still not fully understood. In a recent discovery, itaconate was found to function as an immune-modulating metabolite in mammalian immune cells, wherein it is synthesized as an antimicrobial compound from the citric acid cycle intermediate cis-aconitic acid. However, the association between the Acod1 (Aconitate decarboxylase 1)-itaconate axis and ulcerative colitis has rarely been studied. To elucidate this, we established a DSS-induced colitis model with Acod1-deficient mice and then measured the mouse body weights, colon lengths, histological changes, and cytokines/chemokines in the colon. We first confirmed the upregulation of Acod1 RNA and protein expression levels in DSS-induced colitis. Then, we found that colitis symptoms, including weight loss, the disease activity index, and colon shortening, were worsened by the depletion of Acod1. In addition, the extent of intestinal epithelial barrier breakdown, the extent of immune cell infiltration, and the expression of proinflammatory cytokines and chemokines in Acod1-deficient mice were higher than those in wild-type mice. Finally, we confirmed that 4-octyl itaconate (4-OI) alleviated DSS-induced colitis in Acod1-deficient mice and decreased the expression of inflammatory cytokines and chemokines. To our knowledge, this study is the first to elucidate the role of the Acod1-itaconate axis in colitis. Our data clearly showed that Acod1 deletion resulted in severe DSS-induced colitis and substantial increases in inflammatory cytokine and chemokine levels. Our results suggest that Acod1 may normally play an important regulatory role in the pathogenesis of colitis, demonstrating the potential for novel therapies using 4-OI. Full article

(This article belongs to the Special Issue Molecular Advances in Inflammatory Bowel Diseases)

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Review

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29 pages, 982 KiB

Open AccessReview

Impact of Probiotics on the Prevention and Treatment of Gastrointestinal Diseases in the Pediatric Population

by José Antonio García-Santos, Ana Nieto-Ruiz, María García-Ricobaraza, Tomás Cerdó and Cristina Campoy

Int. J. Mol. Sci. 2023, 24(11), 9427; https://doi.org/10.3390/ijms24119427 - 29 May 2023

Cited by 2 | Viewed by 2045

Abstract

Despite the high prevalence of gastrointestinal disorders (GIDs) in infants and children, especially those categorized as functional GIDs (FGIDs), insufficient knowledge about their pathophysiology has limited both symptomatic diagnosis and the development of optimal therapies. Recent advances in the field of probiotics have [...] Read more.

Despite the high prevalence of gastrointestinal disorders (GIDs) in infants and children, especially those categorized as functional GIDs (FGIDs), insufficient knowledge about their pathophysiology has limited both symptomatic diagnosis and the development of optimal therapies. Recent advances in the field of probiotics have made their potential use as an interesting therapeutic and preventive strategy against these disorders possible, but further efforts are still needed. In fact, there is great controversy surrounding this topic, generated by the high variety of potential probiotics strains with plausible therapeutic utility, the lack of consensus in their use as well as the few comparative studies available on probiotics that record their efficacy. Taking into account these limitations, and in the absence of clear guidelines about the dose and timeframe for successful probiotic therapy, our review aimed to evaluate current studies on potential use of probiotics for the prevention and treatment of the most common FGIDs and GIDs in the pediatric population. Furthermore, matters referring to know major action pathways and key safety recommendations for probiotic administration proposed by major pediatric health agencies shall also be discussed. Full article

(This article belongs to the Special Issue Molecular Advances in Inflammatory Bowel Diseases)

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24 pages, 2737 KiB

Open AccessReview

Interplay between Serotonin, Immune Response, and Intestinal Dysbiosis in Inflammatory Bowel Disease

by Samantha González Delgado, Idalia Garza-Veloz, Fabiola Trejo-Vazquez and Margarita L Martinez-Fierro

Int. J. Mol. Sci. 2022, 23(24), 15632; https://doi.org/10.3390/ijms232415632 - 09 Dec 2022

Cited by 9 | Viewed by 3326

Abstract

Inflammatory Bowel Disease (IBD) is a chronic gastrointestinal disorder characterized by periods of activity and remission. IBD includes Crohn’s disease (CD) and ulcerative colitis (UC), and even though IBD has not been considered as a heritable disease, there are genetic variants associated with [...] Read more.

Inflammatory Bowel Disease (IBD) is a chronic gastrointestinal disorder characterized by periods of activity and remission. IBD includes Crohn’s disease (CD) and ulcerative colitis (UC), and even though IBD has not been considered as a heritable disease, there are genetic variants associated with increased risk for the disease. 5-Hydroxytriptamine (5-HT), or serotonin, exerts a wide range of gastrointestinal effects under both normal and pathological conditions. Furthermore, Serotonin Transporter (SERT) coded by Solute Carrier Family 6 Member 4 (SLC6A4) gene (located in the 17q11.1-q12 chromosome), possesses genetic variants, such as Serotonin Transporter Gene Variable Number Tandem Repeat in Intron 2 (STin2-VNTR) and Serotonin-Transporter-linked promoter region (5-HTTLPR), which have an influence over the functionality of SERT in the re-uptake and bioavailability of serotonin. The intestinal microbiota is a crucial actor in normal human gut physiology, exerting effects on serotonin, SERT function, and inflammatory processes. As a consequence of abnormal serotonin signaling and SERT function under these inflammatory processes, the use of selective serotonin re-uptake inhibitors (SSRIs) has been seen to improve disease activity and extraintestinal manifestations, such as depression and anxiety. The aim of this study is to integrate scientific data linking the intestinal microbiota as a regulator of gut serotonin signaling and re-uptake, as well as its role in the pathogenesis of IBD. We performed a narrative review, including a literature search in the PubMed database of both review and original articles (no date restriction), as well as information about the SLC6A4 gene and its genetic variants obtained from the Ensembl website. Scientific evidence from in vitro, in vivo, and clinical trials regarding the use of selective serotonin reuptake inhibitors as an adjuvant therapy in patients with IBD is also discussed. A total of 194 articles were used between reviews, in vivo, in vitro studies, and clinical trials. Full article

(This article belongs to the Special Issue Molecular Advances in Inflammatory Bowel Diseases)

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51 pages, 1367 KiB

Open AccessReview

Impact of the Exposome on the Epigenome in Inflammatory Bowel Disease Patients and Animal Models

by Sophie Vieujean, Bénédicte Caron, Vincent Haghnejad, Jean-Yves Jouzeau, Patrick Netter, Anne-Charlotte Heba, Ndeye Coumba Ndiaye, David Moulin, Guillermo Barreto, Silvio Danese and Laurent Peyrin-Biroulet

Int. J. Mol. Sci. 2022, 23(14), 7611; https://doi.org/10.3390/ijms23147611 - 09 Jul 2022

Cited by 15 | Viewed by 5045

Abstract

Inflammatory bowel diseases (IBD) are chronic inflammatory disorders of the gastrointestinal tract that encompass two main phenotypes, namely Crohn’s disease and ulcerative colitis. These conditions occur in genetically predisposed individuals in response to environmental factors. Epigenetics, acting by DNA methylation, post-translational histones modifications [...] Read more.

Inflammatory bowel diseases (IBD) are chronic inflammatory disorders of the gastrointestinal tract that encompass two main phenotypes, namely Crohn’s disease and ulcerative colitis. These conditions occur in genetically predisposed individuals in response to environmental factors. Epigenetics, acting by DNA methylation, post-translational histones modifications or by non-coding RNAs, could explain how the exposome (or all environmental influences over the life course, from conception to death) could influence the gene expression to contribute to intestinal inflammation. We performed a scoping search using Medline to identify all the elements of the exposome that may play a role in intestinal inflammation through epigenetic modifications, as well as the underlying mechanisms. The environmental factors epigenetically influencing the occurrence of intestinal inflammation are the maternal lifestyle (mainly diet, the occurrence of infection during pregnancy and smoking); breastfeeding; microbiota; diet (including a low-fiber diet, high-fat diet and deficiency in micronutrients); smoking habits, vitamin D and drugs (e.g., IBD treatments, antibiotics and probiotics). Influenced by both microbiota and diet, short-chain fatty acids are gut microbiota-derived metabolites resulting from the anaerobic fermentation of non-digestible dietary fibers, playing an epigenetically mediated role in the integrity of the epithelial barrier and in the defense against invading microorganisms. Although the impact of some environmental factors has been identified, the exposome-induced epimutations in IBD remain a largely underexplored field. How these environmental exposures induce epigenetic modifications (in terms of duration, frequency and the timing at which they occur) and how other environmental factors associated with IBD modulate epigenetics deserve to be further investigated. Full article

(This article belongs to the Special Issue Molecular Advances in Inflammatory Bowel Diseases)

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