Elevated miR‐124‐3p in the aging colon disrupts mucus barrier and increases susceptibility to colitis by targeting T‐synthase

Huang, Li; Sun, Tingyi; Hu, Liang-Jun; Hu, Shi-Long; Sun, Hongxia; Zhao, Fu-qian; Wu, Bo; Yang, Shu; Ji, Fengqing; Zhou, Dujin

doi:10.1111/acel.13252

Cited by 24 publications

(36 citation statements)

References 40 publications

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“…The procedure used to generate the DSS colitis model is shown in Supplementary Figure 1A . Our published data 12 demonstrated that miR-1-3p expression in the distal colon mucosa of 24-mo-old mice was 1.6 times higher than that of miR-124-3p . These previous data provide a reference for the miRNA agomir dose required in the animal model.…”

Section: Methodsmentioning

confidence: 70%

“…8 , 9 As one of the hallmarks of health, 10 the intestinal barrier is progressively damaged during senescence. 11 Our recent work 12 demonstrated that age-related changes in mucus properties increase the susceptibility to colitis in elderly populations. However, research on the underlying regulatory mechanism is far from comprehensive.…”

Section: Introductionmentioning

confidence: 99%

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MiR-1-3p and MiR-124-3p Synergistically Damage the Intestinal Barrier in the Ageing Colon

Sun

Zhao

et al. 2021

Journal of Crohn's and Colitis

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Background and Aims Disruption of the intestinal barrier of the digestive tract is a common pathophysiological change in the elderly, which may partly contribute to gut dysfunction and inflammatory bowel disease. This study aimed to discover new interactive epigenetic regulation patterns involved in intestinal barrier dysfunction and colitis in elderly populations. Methods Intestinal barrier function and structure were evaluated in naturally aging mice and elderly people. High-throughput analysis was performed on colonic tissues from humans and mice. The synergistic roles of miR-1-3p and miR-124-3p were identified using microRNA mimic/agomirs. Related genes were examined in biopsies of old IBD patients. Results A defective mucus barrier was observed before mucosal microstructural damage during aging. Elevated miR-1-3p expression in the colons of older individuals impaired mucus barrier by directly targeting T-synthase, similar to the mechanism of miR-124-3p, which we reported previously. Importantly, the synergistic effect of a half dose of each microRNA supplement on T-synthase and CDK4/6 was stronger than that of a full dose of miR-1-3p or miR-124-3p alone, and mice cotreated with two microRNAs showed greater susceptibility to chemical-induced colitis than mice treated with either microRNA alone. These two microRNAs were up-expressed in old IBD patients. Conclusions The slight increases in miR-1-3p and miR-124-3p expression with aging may be important contributors to the breakdown of intestinal homeostasis by targeting divergent genes in different cells. These data reveal the potential ability of multiple microRNAs to exert synergistic effects to damage the intestinal barrier and promote inflammatory bowel disease development in elderly populations.

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Section: Methodsmentioning

confidence: 70%

Section: Introductionmentioning

confidence: 99%

MiR-1-3p and MiR-124-3p Synergistically Damage the Intestinal Barrier in the Ageing Colon

Sun

Zhao

et al. 2021

Journal of Crohn's and Colitis

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“…The intestinal mucosal barrier integrity is necessary to maintain normal intestinal functions ( Huang et al, 2020 ). The thick mucus covering the epithelium is the primary defensive layer separating microbiota from epithelial cells, which is synthesized by goblet cells ( Johansson and Hansson, 2016 ).…”

Section: Discussionmentioning

confidence: 99%

“…Gel-forming mucin2 (Muc-2) is the major building block of mucus, which accounts for up to 80% of the mass of mucin molecules, and Muc-2 is the reason for the gel-like properties of mucus ( Johansson et al, 2008 ; Fu et al, 2011 ). Moreover, the intestinal gel-forming mucins are mainly from goblet cells ( Huang et al, 2020 ). In our study, a fewer goblet cells number, thinner AB/PAS mucus layer, and lower Muc-2 protein expression in the colonic tissue of STC rats were observed.…”

Section: Discussionmentioning

confidence: 99%

Effects of Maren Pills on the Intestinal Microflora and Short-Chain Fatty Acid Profile in Drug-Induced Slow Transit Constipation Model Rats

Wen

et al. 2022

Front. Pharmacol.

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Background: Slow transit constipation (STC) is becoming a common and frequently occurring disease in today’s society, and it is necessary to explore the safe and effective treatment of STC.Method: Our study aimed to investigate whether the laxative effect of Maren pills (MRW) is associated with the regulation of intestinal microflora and intestinal metabolism in the colon. Loperamide hydrochloride-induced STC rats received MRW intragastrically for two consecutive weeks to evaluate the laxative effect of MRW involving the regulation of intestinal microflora, intestinal metabolism, and 5-HT signaling pathway. Intestinal microflora was detected by 16s rDNA sequencing, intestinal metabolism of short-chain fatty acids (SCFAs) was detected by HPLC, and the 5-HT signaling pathway was detected by WB, ELISA, immunofluorescence, and immunohistochemical analysis.Results: Our results revealed that the treatments with MRW increased not only the body weight, 24-h fecal number, 24-h wet fecal weight, 24-h dry fecal weight, fecal water content, and the intestinal propulsion rate but also the colonic goblet cell number, colonic Muc-2 protein expression, and colonic mucus layer thickness in the STC model rats. Moreover, MRW activated the 5-HT pathway by increasing the levels of 5-HT, 5-HIAA, 5-HT4R, CFTR, cAMP, and PKA in the colon tissue of STC rats. The 16S rDNA sequencing results showed that MRW improved the colonic microflora structure in colonic contents of STC rats, mainly by increasing Lactobacillus and decreasing Prevotella. Finally, we found that MRW regulated the SCFA metabolism in the colonic contents of the STC rats, mainly by increasing the contents of acetic acid, propionic acid, and butyric acid; the relative abundance of Lactobacillus was positively correlated with either contents of acetic acid, propionic acid, and butyric acid, and the relative abundance of Clostridium was negatively correlated.Conclusion: Our study further showed that MRW could improve constipation in STC rats, and the mechanism may be by regulating the intestinal microflora structure and improving the metabolism of SCFAs.

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“…Indeed, miR-124-3p was reported to target T-synthase, also known as C1GALT1, which catalyses the core-1 O-glycosylation of mucins. The miR-124-3p-mediated downregulation of T-synthase interferes with mucin O-glycosylation, leading to a predisposition for senile colitis [ 140 ]. The expression of C1GALT1 is dependent on a specific molecular chaperon, C1GALT1C1 (Cosmc).…”

Section: Permeability Of the Gut Epithelial Barriermentioning

confidence: 99%

The Impact of MicroRNAs during Inflammatory Bowel Disease: Effects on the Mucus Layer and Intercellular Junctions for Gut Permeability

Stiegeler

Mercurio

Iancu

et al. 2021

Cells

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Research on inflammatory bowel disease (IBD) has produced mounting evidence for the modulation of microRNAs (miRNAs) during pathogenesis. MiRNAs are small, non-coding RNAs that interfere with the translation of mRNAs. Their high stability in free circulation at various regions of the body allows researchers to utilise miRNAs as biomarkers and as a focus for potential treatments of IBD. Yet, their distinct regulatory roles at the gut epithelial barrier remain elusive due to the fact that there are several external and cellular factors contributing to gut permeability. This review focuses on how miRNAs may compromise two components of the gut epithelium that together form the initial physical barrier: the mucus layer and the intercellular epithelial junctions. Here, we summarise the impact of miRNAs on goblet cell secretion and mucin structure, along with the proper function of various junctional proteins involved in paracellular transport, cell adhesion and communication. Knowledge of how this elaborate network of cells at the gut epithelial barrier becomes compromised as a result of dysregulated miRNA expression, thereby contributing to the development of IBD, will support the generation of miRNA-associated biomarker panels and therapeutic strategies that detect and ameliorate gut permeability.

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Elevated miR‐124‐3p in the aging colon disrupts mucus barrier and increases susceptibility to colitis by targeting T‐synthase

Cited by 24 publications

References 40 publications

MiR-1-3p and MiR-124-3p Synergistically Damage the Intestinal Barrier in the Ageing Colon

MiR-1-3p and MiR-124-3p Synergistically Damage the Intestinal Barrier in the Ageing Colon

Effects of Maren Pills on the Intestinal Microflora and Short-Chain Fatty Acid Profile in Drug-Induced Slow Transit Constipation Model Rats

The Impact of MicroRNAs during Inflammatory Bowel Disease: Effects on the Mucus Layer and Intercellular Junctions for Gut Permeability

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