Critical role of Keratin 1 in maintaining epithelial barrier and correlation of its down-regulation with the progression of inflammatory bowel disease

Xiao, Dong; Liu, Zichao; Lan, Danfeng; Niu, Junkun; Miao, Jiarong; Yang, Gang; Zhang, Fengrui; Sun, Yuhao; Wang, Kunhua; Miao, Yi

doi:10.1016/j.gene.2017.01.015

Cited by 16 publications

(13 citation statements)

References 27 publications

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“…An intact monolayer of intestinal epithelial cells protects the body from pathogens and other toxic luminal substances. To keep the IEB intact, it is important for prevention and treatment of IBD (26). The TJs are important components of IEB, which are composed of multiple proteins including trans-membrane proteins and intracellular proteins, such as occludin and ZO-1 (27).…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Rho kinase protects against colitis in mice by attenuating intestinal epithelial barrier dysfunction via MLC and the NF-κB pathway

Zou

Zhao

et al. 2017

Int J Mol Med

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The aim of the present study was to investigate the role of Rho kinase (also known as ROCK) inhibitor in 2,4,6-trinitrobenzene sulfonic acid induced mouse colitis; and to elucidate the underlying mechanism of ROCK1/ROCK2 inhibition in enhancing intestinal epithelial barrier (IEB) function. A specific inhibitor of ROCK, Y-27632, was used to examine the role of ROCK in mouse colitis models. ROCK1 and ROCK2 were silenced respectively using RNA interference in Caco-2 cells. The expression of tight junction proteins and the downstream molecules of ROCK were assessed. Y-27632 alleviated colonic inflammation and decreased intestinal permeability. ROCK-myosin light chain (MLC) and ROCK-NF-κB pathway were activated in colitis and inhibited by Y-27632. In vitro, ROCK1 RNAi primarily downregulated the phosphorylation of myosin phosphatase-targeting subunit-1 (MYPT-1) and MLC, while ROCK2 RNAi inhibited phosphorylation of nuclear factor-κB (NF-κB). In conclusion, the results suggested that the ROCK inhibitor alleviated colitis and IEB dysfunction. Inhibition of phospho-MYPT-1 and MLC by ROCK1 knockout or inhibition of NF-κB phosphorylation by ROCK2 knockout may be the underlying mechanisms.

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Section: Discussionmentioning

confidence: 99%

Inhibition of Rho kinase protects against colitis in mice by attenuating intestinal epithelial barrier dysfunction via MLC and the NF-κB pathway

Zou

Zhao

et al. 2017

Int J Mol Med

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“…Because, a sufficient amount of keratin is needed for efficient stress protection in the colonic epithelia and because keratins play an essential role of maintaining epithelial barrier and its down-regulation in intestinal tissue has been correlated with the progression of IBD(41,42), our findings suggest that the three themes of altered gene expression may be interrelated consequences of epithelial stress response to chronic stimuli (simultaneous exposure to e-cig and microbes) and inflammation. E-liquid, not nicotine, is the culprit: Our RNAseq studies using murine models of vaping unexpectedly but decisively revealed that it is the e-liquid component in e-cigarettes that induces broad and sweeping changes on gene expression in the gut.…”

mentioning

confidence: 83%

E-cigarettes compromise the gut barrier and trigger gut inflammation

Sharma

Lee

Fonseca

et al. 2020

Preprint

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E-cigarette and vaping device use continue to rise, particularly in adolescents and young adults, but the safety of inhaling the multitude of chemicals within e-cigarette aerosols has been questioned. While several studies have evaluated vaping effects on the lungs and heart; effects on the gastrointestinal tract remain unknown. Using established murine models of acute (1 week) and chronic (3 month) daily e-cigarette aerosol inhalation, both with nicotine-containing and vehicle control e-liquids, murine colon transcriptomics and organoid co-culture models, we assessed the effects of e-cigarette use on the gut barrier and mucosal health. Histologic analyses revealed that chronic exposure to nicotine-free e-cigarette aerosols induced mucosal inflammation. Transcriptome analyses revealed that chronic, but not acute, nicotine-free e-cigarette use significantly reduced expression of tight junction markers, including occluding, and drove expression of pro-inflammatory cytokines. Exposure of murine and human enteroid-derived monolayers (EDMs) to nicotine-free e-cigarette aerosols alone, or in co-culture with invasive E. coli, confirmed that repetitive exposure was sufficient to recapitulate the key findings observed in vivo, i.e., barrier-disruption, downregulation of occludin, inflammation, and an accentuated risk of and response to bacterial infection. These data highlight an unexpected harmful effect of e-cigarette use on the gut barrier and pinpoint non-nicotine chemical components common across >90% of e-cigarette e-liquids as the source of harm. Given the ever-expanding importance of the integrity of the gut barrier for host fitness, and impact of gut mucosal inflammation on a multitude of chronic diseases, these findings are broadly relevant to medicine and public health.SIGNIFICANCEThe safety of electronic cigarettes has been questioned amidst emerging evidence that they may derail our immune system and increase our susceptibility to infections. Despite these insights, their impact on the most critical entity that separates trillions of microbes from the largest immune system in our body, i.e., the gut barrier, remains unexplored. Using a combination of mouse models, gut transcriptomics, and murine and human gut-derived organoids, here we show that chronic exposure to aerosols of electronic-cigarette disrupts the gut barrier, increases its susceptibility to bacterial infections and triggers inflammation. Given the importance of the gut barrier in the maintenance of immune homeostasis, these findings provide valuable insights into the potential long-term harmful effects of electronic cigarettes on health.

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“…18 Importantly, clinical and laboratory researches have demonstrated the significant role for KRTs in the protection of the epithelial integrity in the small intestine, 19,20 and the down-regulation of KRT1 is correlated with the progression of inflammatory bowel disease (IBD). 21 Our previous studies have shown that radiation could cause intestinal injury, covering elevated levels of inflammation and the destruction of intestinal integrity. However, whether KRT1 contributes to radioprotection remains an enigma.…”

Section: Introductionmentioning

confidence: 99%

Gut commensal derived-valeric acid protects against radiation injuries

et al. 2020

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Background: Hematopoietic and intestinal systems side effects are frequently found in patients who suffered from accidental or medical radiation exposure. In this case, we investigated the effects of gut microbiota produced-valeric acid (VA) on radiation-induced injuries. Methods: Mice were exposed to total body irradiation (TBI) or total abdominal irradiation (TAI) to mimic accidental or clinical scenarios. High-performance liquid chromatography (HPLC) was performed to assess short-chain fatty acids (SCFAs) in fecal pellets. Oral gavage with VA was used to mitigate radiation-induced toxicity. Gross examination was performed to assess tissue injuries of thymus, spleen and small intestine. High-throughput sequencing was used to characterize the gut microbiota profile. Isobaric tags for relative and absolute quantitation (iTRAQ) were performed to analyze the difference of protein profile. Hydrodynamic-based gene delivery assay was performed to silence KRT1 in vivo. Results: VA exerted the most significant radioprotection among the SCFAs. In detail, VA replenishment elevated the survival rate of irradiated mice, protected hematogenic organs, improved gastrointestinal (GI) tract function and intestinal epithelial integrity in irradiated mice. Highthroughput sequencing and iTRAQ showed that oral gavage of VA restored the enteric bacteria taxonomic proportions, reprogrammed the small intestinal protein profile of mice following TAI exposure. Importantly, keratin 1 (KRT1) played a pivotal role in the radioprotection of VA. Conclusions: Our findings provide new insights into gut microbiota-produced VA and underpin that VA might be employed as a therapeutic option to mitigate radiation injury in pre-clinical settings.

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Critical role of Keratin 1 in maintaining epithelial barrier and correlation of its down-regulation with the progression of inflammatory bowel disease

Cited by 16 publications

References 27 publications

Inhibition of Rho kinase protects against colitis in mice by attenuating intestinal epithelial barrier dysfunction via MLC and the NF-κB pathway

Inhibition of Rho kinase protects against colitis in mice by attenuating intestinal epithelial barrier dysfunction via MLC and the NF-κB pathway

E-cigarettes compromise the gut barrier and trigger gut inflammation

Gut commensal derived-valeric acid protects against radiation injuries

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