The stress polarity signaling (SPS) pathway serves as a marker and a target in the leaky gut barrier: implications in aging and cancer

Ghosh, Pradipta; Swanson, Lee; Sayed, Ibrahim M.; Mittal, Yash; Lim, Blaze B. C.; Ibeawuchi, Stella‐Rita; Foretz, Marc; Viollet, Benoı̂t; Sahoo, Debashis; Das, Soumita

doi:10.26508/lsa.201900481

Cited by 33 publications

(41 citation statements)

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“…Findings indicate a significant increase in paracellular permeability upon exposure to e-cig when compared to untreated (p = 0.0002) and air-treated (p = 0.0004) controls (Fig 1E). In e-cig exposed EDMs, confocal microscopy showed significantly increased "burst" tricellular TJs [these are specialized regions of the TJ where three or more cells come in contact (32), are also the regions where TJdisruption can be visualized/assessed first (33)] by ~60.1±8.1% when compared to untreated (p = 0.0010) and air-treated (p = 0.0015) controls (Fig 1F-G). These findings show that chemicals contained within the most basic e-cigarette aerosols disrupt the epithelial barrier.…”

Section: E-cigarette Use Disrupts the Integrity Of The Gut Barriermentioning

confidence: 98%

“…Intestinal crypts, comprised of crypt-base columnar (CBC) cells, were isolated from both colonic and ileal tissue specimens using the previously published paper (33,57). EDMs were generated on either 24-well or 96well transwells with a 0.4 µm pore polyester membrane (Corning) as described previously (33,57,58). Immunofluorescence staining: After the final TEER measurement of all EDM treatments, the media was removed from apical and basolateral compartments.…”

Section: Isolation Of Organoids and Preparation Of Enteroid-derived Mmentioning

confidence: 99%

“…Immunofluorescence staining: After the final TEER measurement of all EDM treatments, the media was removed from apical and basolateral compartments. The exposed EDMs were fixed, permeabilized and stained for occluding and ZO-1 and imaged using a Leica TCS SP5 Confocal Microscope as done previously (33). Z-slices of a Z-stack were overlaid to create maximum intensity projection images; all images were processed using FIJI (Image J) software.…”

Section: Isolation Of Organoids and Preparation Of Enteroid-derived Mmentioning

confidence: 99%

“…For automated assessments, TEER was measured in 96-well transwell plates with EDMs was measured using WPI automated TEER Measurement System (REMS AutoSampler, Version 6.02).Co-cultures of EDMs with invasive E. coli: Adherent Invasive Escherichia coli strain LF82 (AIEC-LF82), isolated from the specimens of Crohn's disease patient, was obtained from Arlette Darfeuille-Michaud(59). Co-cultures were carried out as done previously and expanded in SI(33,57).Measurement of DNA/RNA oxidative damage:The level of DNA damage in EDMs following exposure to air and e-cigarette vapor infused media was quantified with the DNA/RNA Oxidative Damage ELISA Kit (Cayman Chemical, USA) according to the manufacturer's instruction and previous papers(60,61).…”

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confidence: 99%

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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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Section: E-cigarette Use Disrupts the Integrity Of The Gut Barriermentioning

confidence: 98%

Section: Isolation Of Organoids and Preparation Of Enteroid-derived Mmentioning

confidence: 99%

Section: Isolation Of Organoids and Preparation Of Enteroid-derived Mmentioning

confidence: 99%

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confidence: 99%

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E-cigarettes compromise the gut barrier and trigger gut inflammation

Sharma

Lee

Fonseca

et al. 2020

Preprint

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“…Colon organoids were isolated from the colonic tissue specimens of WT C57BL/6, Neil2 KO mice, CPC-APC Min mice, healthy human subjects and colorectal cancer (CRC) patients as described previously (37)(38)(39)(40)(41). Briefly, colon tissues were digested by Collagenase type I [2 mg/ml; Life Technologies Corporation, NY) containing gentamicin (50 µg/ml, Life Technologies Corporation, NY).…”

Section: Isolation and Maintenance Of Colonic Organoidsmentioning

confidence: 99%

DNA glycosylase NEIL2 preventsFusobacterium-mediated inflammation and DNA damage in colonic epithelial cells

Sayed

Chakraborty

Ali

et al. 2020

Preprint

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Colorectal cancer (CRC) is the third most prevalent and deadly cancer. Approximately, 15-20 % of CRCs display microsatellite instability (MSI); however, the majority (80-85%) of cases are sporadic and known as microsatellite stable (MSS). Several recent studies indicated that infection and uncontrolled inflammation initiate DNA damage and lead to cancer progression. One of the major microbes, Fusobacterium nucleatum (Fn) is highly associated with CRC, but the role of DNA repair in microbe-associated CRC has been largely unknown. Here we show that NEIL2, an oxidized base-specific DNA glycosylase, is significantly downregulated among all the key DNA repair proteins involved in various DNA repair pathways, after infection of Fn with stemcell-based enteroid-derived monolayers (EDMs) of murine and human healthy subjects. Furthermore, following Fn infection, NEIL2-null mouse-derived EDMs showed significantly higher level of DNA damage, including double strand breaks, and inflammatory cytokines..Murine CRC model also showed downregulation of the NEIL2 transcript and accumulation of DNA damage. Importantly, analysis of publicly available transcriptomic data showed that the downregulation of NEIL2 is specific for MSS compared to MSI CRCs. We thus conclude that the pathogenic bacterial infection-induced downregulation of NEIL2, and consequent accumulation of DNA damage, play critical roles in the progression of CRC.

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Functions of LKB1 in neural crest development: The story unfolds

Thibert

Lucas

Billaud

et al. 2023

Developmental Dynamics

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Neural crest cells (NCCs) are highly motile, multipotent, embryonic cells that delaminate from the dorsal edges of the neural tube. NCCs follow stereotypical long‐range migratory pathways to reach target organs during development, where they give rise to multiple derivatives. The identification of reservoirs of neural crest stem cells that persist to adulthood has recently aroused renewed interest in the biology of NCCs. In this context, several recent studies have demonstrated the essential role of the metabolic kinase LKB1 in NCC establishment. This review surveys how LKB1 governs the formation and maintenance of several neural crest derivatives, including facial bones, melanocytes, Schwann cells, and the enteric nervous system. We also detail the underlying molecular mechanisms that involve downstream effectors of LKB1, in particular the contribution of the AMPK‐mTOR signaling pathway to both polarity and metabolic processes. Collectively, these recent discoveries open promising perspectives for new therapeutic applications for the treatment of neural crest disorders.

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The stress polarity signaling (SPS) pathway serves as a marker and a target in the leaky gut barrier: implications in aging and cancer

Cited by 33 publications

References 83 publications

E-cigarettes compromise the gut barrier and trigger gut inflammation

E-cigarettes compromise the gut barrier and trigger gut inflammation

DNA glycosylase NEIL2 preventsFusobacterium-mediated inflammation and DNA damage in colonic epithelial cells

Functions of LKB1 in neural crest development: The story unfolds

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