The Colonic Mucosal MicroRNAs, MicroRNA-219a-5p, and MicroRNA-338-3p Are Downregulated in Irritable Bowel Syndrome and Are Associated With Barrier Function and MAPK Signaling

Mahurkar-Joshi, Swapna; Rankin, Carl R.; Videlock, Elizabeth J.; Soroosh, Artin; Verma, Abhishek; Khandadash, Ariela; Iliopoulos, Dimitrios; Pothoulakis, Charalabos; Mayer, Emeran A.; Chang, Lin

doi:10.1053/j.gastro.2021.02.040

Cited by 32 publications

(43 citation statements)

References 83 publications

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“…The functional role of miRNAs is a complex and tightly regulated task to modulate targets at the posttranscriptional (translational) level [42,48,49]. Previous studies evidenced that loss of functional activity of the GI pacemaking cells including, ICCs, SMCs, enteric neurons, platelet-derived growth factor receptor alpha positive (PDGFRα + ), and immune cells are driving forces contributing to the pathogenesis of DGBIs [10,23,29,31,50]. Cellular dysfunction in GI cells mediated via dysregulation of miRNAs likely regulates a variety of gut physiological and pathophysiological mechanisms leading to the development of diseases such as DGBIs [51,52].…”

Section: Functional Role Of Mirnas In Gut Physiological Mechanismsmentioning

confidence: 99%

“…Approximately 60% of protein coding mRNAs are modulated by miRNAs, including many of the key proteins associated with diseases [41,53]. In recent studies, the impacts of miRNAs have been exhibited to regulate pathophysiological mechanisms of DGBIs, including impaired GI barrier function, gut immune dysfunction, visceral hypersensitivity, and gut dysmotility [26,28,29,31,51]. The identification of precise miRNA targets has been the topic of extensive research.…”

Section: Functional Role Of Mirnas In Gut Physiological Mechanismsmentioning

confidence: 99%

“…Delayed gut transit is result of irregular GI muscular movements, which is a major pathophysiological mechanism of DGBIs [10,23]. Recent studies have elucidated the cellular and molecular alterations underpinning the abnormalities in GI cells, which are crucial for gut homeostasis [23,28,29]. Further exploration of the precise miRNA-mediated pathologies contributing to the cellular plasticity in DGBIs is needed.…”

Section: Mirna Dysregulation In Gi Cells Contribute To the Pathogenesis Of Dgbismentioning

confidence: 99%

“…Recently, miRNA transcriptome data from colonic biopsies showed that miR-363-3p and miR-338-3p were downregulated, whereas miR-106b-5p and miR-532-5p were upregulated in IBS as compared to HCs [29]. miR-219-5p levels were decreased threefold in patients with IBS-D compared with HCs.…”

Section: Mirna Dysregulation In Ibsmentioning

confidence: 99%

“…MicroRNAs (miRNAs) are small non-coding RNAs that regulate gene expression post-transcriptionally and modulate pathophysiological mechanisms of DGBIs [24]. miRNAs have been linked to gut physiological mechanisms such as visceral sensation (miR-200a, -199a/b, -338, and -495), gut immune functions (miR-29, -155, -146a/b, -192, -146a, -155, and -122), GI barrier functions (miR-16, -29a, -219a, and -122a), neuronal cell development and function (miR-375), as well as gut motility (miR-10b, -143, -551b, -222, -145, let-7f, -375, and -128) [23,[25][26][27][28][29][30][31]. These mechanisms are highly relevant to the gut where neuroimmune interactions are key contributors to the control of gut functions and interruptions in these interactions lead to DGBIs [32][33][34][35].…”

Section: Introductionmentioning

confidence: 99%

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Role of microRNAs in Disorders of Gut–Brain Interactions: Clinical Insights and Therapeutic Alternatives

Singh

Zogg

2021

JPM

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Disorders of gut–brain interactions (DGBIs) are heterogeneous in nature and intertwine with diverse pathophysiological mechanisms. Regular functioning of the gut requires complex coordinated interplay between a variety of gastrointestinal (GI) cell types and their functions are regulated by multiple mechanisms at the transcriptional, post-transcriptional, translational, and post-translational levels. MicroRNAs (miRNAs) are small non-coding RNA molecules that post-transcriptionally regulate gene expression by binding to specific mRNA targets to repress their translation and/or promote the target mRNA degradation. Dysregulation of miRNAs might impair gut physiological functions leading to DGBIs and gut motility disorders. Studies have shown miRNAs regulate gut functions such as visceral sensation, gut immune response, GI barrier function, enteric neuronal development, and GI motility. These biological processes are highly relevant to the gut where neuroimmune interactions are key contributors in controlling gut homeostasis and functional defects lead to DGBIs. Although extensive research has explored the pathophysiology of DGBIs, further research is warranted to bolster the molecular mechanisms behind these disorders. The therapeutic targeting of miRNAs represents an attractive approach for the treatment of DGBIs because they offer new insights into disease mechanisms and have great potential to be used in the clinic as diagnostic markers and therapeutic targets. Here, we review recent advances regarding the regulation of miRNAs in GI pacemaking cells, immune cells, and enteric neurons modulating pathophysiological mechanisms of DGBIs. This review aims to assess the impacts of miRNAs on the pathophysiological mechanisms of DGBIs, including GI dysmotility, impaired intestinal barrier function, gut immune dysfunction, and visceral hypersensitivity. We also summarize the therapeutic alternatives for gut microbial dysbiosis in DGBIs, highlighting the clinical insights and areas for further exploration. We further discuss the challenges in miRNA therapeutics and promising emerging approaches.

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Section: Functional Role Of Mirnas In Gut Physiological Mechanismsmentioning

confidence: 99%

Section: Functional Role Of Mirnas In Gut Physiological Mechanismsmentioning

confidence: 99%

Section: Mirna Dysregulation In Gi Cells Contribute To the Pathogenesis Of Dgbismentioning

confidence: 99%

Section: Mirna Dysregulation In Ibsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Role of microRNAs in Disorders of Gut–Brain Interactions: Clinical Insights and Therapeutic Alternatives

Singh

Zogg

2021

JPM

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Comparison of Geqingpi and Sihuaqingpi based on ultra‐high‐performance liquid chromatography‐tandem mass spectrometry combined with multivariate statistics, network pharmacology analysis, and molecular docking

Wang

Cui

Yang

et al. 2022

J of Separation Science

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Citri Reticulatae Pericarpium Viride is used in traditional Chinese medicine as Geqingpi and Sihuaqingpi varieties. We used the ultra‐high‐performance liquid chromatography‐quadrupole‐Exactive Orbitrap‐mass spectrometry method and high‐performance liquid chromatography‐triple quadrupole‐tandem mass spectrometry to analyze the chemical compounds in these varieties. Principal components analysis and orthogonal partial least squares discriminant analysis were used to analyze the quantitative results. Network pharmacology and molecular docking technology were used to forecast Citri Reticulatae Pericarpium Viride treatment mechanisms in irritable bowel syndrome. We identified 44 main compounds in Citri Reticulatae Pericarpium Viride. Compared to Sihuaqingpi, Geqingpi had higher narirutin, didymin, naringenin, and hesperetin, and lower hesperidin, isosinensetin, nobiletin, 3,5,6,7,8,3′,4′‐hexamethoxyflavone, tangeretin. Tangeretin, nobiletin, narirutin, didymin, and isosinensetin were the main compounds distinguishing Geqingpi from Sihuaqingpi. We found that the MAPK signaling pathway, which is closely related to irritable bowel syndrome, was an important target pathway. TP53, HRAS, MAPK1, AKT1, and EGFR were important targets in this pathway. Eriodictyol‐7‐O‐rutinoside, narirutin, limonin, and hesperidin showed a good binding ability to the five targets. Orientin, unique to Sihuaqingpi, bound well to TP53, MAPK1, AKT1, and EGFR, while rhoifolin bound well to TP53, HRAS, MAPK1, AKT1, and EGFR. Hesperetin, unique to Geqingpi, bound well to TP53, HRAS, and MAPK1, while naringenin bound well to HRAS. Hesperidin and didymin bound well to TP53, MAPK1, AKT1, and EGFR.

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A starch‐ and sucrose‐reduced dietary intervention in irritable bowel syndrome patients produced a shift in gut microbiota composition along with changes in phylum, genus, and amplicon sequence variant abundances, without affecting the micro‐RNA levels

et al. 2022

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Background/Aim A randomized clinical trial with a starch‐ and sucrose‐reduced diet (SSRD) in irritable bowel syndrome (IBS) patients has shown clear improvement of participants' symptoms. The present study aimed to explore the effects of the SSRD on the gut microbiota and circulating micro‐RNA in relation to nutrient intake and gastrointestinal symptoms. Methods IBS patients were randomized to a 4‐week SSRD intervention (n = 80) or control group (n = 25); habitual diet). At baseline and 4 weeks, blood and fecal samples, 4 day‐dietary records, and symptom questionnaires were collected, that is, Rome IV questionnaires, IBS‐symptom severity score (IBS‐SSS) and visual analog scale for IBS (VAS‐IBS). Micro‐RNA was analyzed in blood and microbiota in faeces by 16S rRNA from regions V1–V2. Results The alpha diversity was unaffected, whereas beta diversity was decreased (p < 0.001) along with increased abundance of Proteobacteria (p = 0.0036) and decreased abundance of Bacteroidetes phyla (p < 0.001) in the intervention group at 4 weeks. Few changes were noted in the controls. The shift in beta diversity and phyla abundance correlated with decreased intakes of carbohydrates, disaccharides, and starch and increased fat and protein intakes. Proteobacteria abundance also correlated positively (R2 = 0.07, p = 0.0016), and Bacteroidetes negatively (R2 = 0.07, p = 0.0017), with reduced total IBS‐SSS. Specific genera, for example, Eubacterium eligens, Lachnospiraceae UCG‐001, Victivallis, and Lachnospira increased significantly in the intervention group (p < 0.001 for all), whereas Marvinbryantia, DTU089 (Ruminoccocaceae family), Enterorhabdus, and Olsenella decreased, together with changes in amplicon sequence variant (ASV) levels. Modest changes of genus and ASV abundance were observed in the control group. No changes were observed in micro‐RNA expression in either group. Conclusion The SSRD induced a shift in beta diversity along with several bacteria at different levels, associated with changes in nutrient intakes and reduced gastrointestinal symptoms. No corresponding changes were observed in the control group. Neither the nutrient intake nor the microbiota changes affected micro‐RNA expression. The study was registered at ClinicalTrials.gov data base (NCT03306381).

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The Colonic Mucosal MicroRNAs, MicroRNA-219a-5p, and MicroRNA-338-3p Are Downregulated in Irritable Bowel Syndrome and Are Associated With Barrier Function and MAPK Signaling

Cited by 32 publications

References 83 publications

Role of microRNAs in Disorders of Gut–Brain Interactions: Clinical Insights and Therapeutic Alternatives

Role of microRNAs in Disorders of Gut–Brain Interactions: Clinical Insights and Therapeutic Alternatives

Comparison of Geqingpi and Sihuaqingpi based on ultra‐high‐performance liquid chromatography‐tandem mass spectrometry combined with multivariate statistics, network pharmacology analysis, and molecular docking

A starch‐ and sucrose‐reduced dietary intervention in irritable bowel syndrome patients produced a shift in gut microbiota composition along with changes in phylum, genus, and amplicon sequence variant abundances, without affecting the micro‐RNA levels

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