Role of Autophagy in the Maintenance of Intestinal Homeostasis

Baxt, Leigh A.; Xavier, Ramnik J.

doi:10.1053/j.gastro.2015.06.046

Cited by 84 publications

(69 citation statements)

References 89 publications

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“…Both macrophage differentiation and leukocyte recruitment are important elements of innate immunity and involves autophagy (38,39). Thus, the observation that genes involved directly and indirectly in autophagy were candidates for Paneth cell defect supports the notion that autophagy is a central pathway that controls the intestinal homeostasis (68).…”

Section: L I N I C a L M E D I C I N Ementioning

confidence: 57%

LRRK2 but not ATG16L1 is associated with Paneth cell defect in Japanese Crohn’s disease patients

Liu¹,

Naito²,

Liu³

et al. 2017

JCI Insight

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IntroductionCrohn's disease (CD) and ulcerative colitis are 2 main classical types of inflammatory bowel disease (IBD) (1, 2). The etiology of IBD involves genetic susceptibility and environmental triggers. Over 200 single nucleotide polymorphisms (SNPs) have been associated with susceptibility to IBD (3-7). This complex genetic network indicates that IBD likely encompasses more than the 2 classical subtypes. Therefore, novel, rationally designed biomarkers that can lead to disease stratification and personalized treatments are needed (8). One candidate method to subtype CD is to define the morphological patterns of small intestinal Paneth cells based on the intracellular distribution of granules containing antimicrobial proteins (Paneth cell phenotypes) (7). Paneth cells are specialized secretory cells located at the bases of the crypts of Lieberkühn in the small intestine (9-11). These cells produce a wide repertoire of antimicrobial BACKGROUND. Morphological patterns of Paneth cells are a prognostic biomarker in Western Crohn's disease (CD) patients, and are associated with autophagy-associated ATG16L1 and NOD2 variants. We hypothesized that genetic determinants of Paneth cell phenotype in other ethnic CD cohorts are distinct but also involved in autophagy.

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Section: L I N I C a L M E D I C I N Ementioning

confidence: 57%

LRRK2 but not ATG16L1 is associated with Paneth cell defect in Japanese Crohn’s disease patients

Liu¹,

Naito²,

Liu³

et al. 2017

JCI Insight

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“…These results suggest that SCFAs protect intestinal barrier function from the disruption by LPS in Caco-2 monolayers. [26,27], therefore, we further investigated autophagy in the present study. Microtubule-associated protein light chain (LC3), which is lipidated and incorporated into the autophagosomal membrane, is widely used as a marker for autophagy [15].…”

Section: Scfas Alleviate Intestinal Barrier Dysfunction Induced By Lpsmentioning

confidence: 99%

Short-Chain Fatty Acids Manifest Stimulative and Protective Effects on Intestinal Barrier Function Through the Inhibition of NLRP3 Inflammasome and Autophagy

Feng

Wang

et al. 2018

Cell Physiol Biochem

307

200

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Background/Aims: Short-chain fatty acids (SCFAs) are the major energy resources of intestinal epithelial cells. It has been reported that SCFAs can repair the dysfunction of intestinal barrier, however, the underlying mechanisms are still not fully understood. Here, we investigated the stimulative and protective effects of SCFAs on intestinal barrier function and the possible mechanisms. Methods: To investigate the effects of SCFAs on intestinal barrier function, the Caco-2 monolayers were exposed to acetate, propionate, butyrate respectively or simultaneously without or with lipopolysaccharide (LPS). Next, Caco-2 cells were treated with trichostatin A and etomoxir to identify whether SCFAs act as HDAC inhibitors or energy substances. To activate NLRP3 inflammasome and autophagy, Caco-2 cells were treated with LPS+ATP and rapamycin respectively without or with SCFAs. The transepithelial electrical resistance (TER) and paracellular permeability were respectively detected with a Millicell-ERS voltohmmeter and fluorescein isothiocyanate-labeled dextran. Immunoblotting and immunofluorescence were applied to analyze the expression and distribution of tight junction proteins, and the activation of NLRP3 inflammasome and autophagy. Results: Acetate (0.5mM), propionate(0.01mM) and butyrate (0.01mM) alone or in combination significantly increased TER, and stimulated the formation of tight junction. SCFAs also dramatically attenuated the LPS-induced TER reduction and paracellular permeability increase, accompanying significantly alleviated morphological disruption of ZO-1 and occludin. Meanwhile, the activation of NLRP3 inflammasome and autophagy induced by LPS were significantly inhibited by SCFAs. Trichostatin A imitated the inhibiting action of SCFAs on NLRP3 inflammasome, whereas etomoxir blocked the action of SCFAs on protecting intestinal barrier and inhibiting autophagy. In addition, the activation of autophagy and NLRP3 inflammasome by rapamycin and LPS+ATP resulted in TER reduction, paracellular permeability increase and morphological disruption of both ZO-1 and occludin, which was alleviated by SCFAs. Conclusion: It is suggested that SCFAs stimulate the formation of intestinal barrier, and protect the intestinal barrier from the disruption of LPS through inhibiting NLRP3 inflammasome and autophagy. In addition, SCFAs act as energy substances to protect intestinal barrier and inhibit autophagy, but act as HDAC inhibitors to suppress NLRP3 inflammasome. Furthermore, the mutual promoting action between NLRP3 inflammasome and autophagy would destroy intestinal barrier function, which could be alleviated by SCFAs.

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“…Autophagy is a highly conserved catabolic process in eukaryotes required for the maintenance of cellular and tissue homeostasis [24]. It was initially characterized as a pathway required for starvation survival in yeast, but autophagy has since been recognized to be critical for fundamental processes including programmed cell death, proliferation, as well as cell mediated and innate immunity [25].…”

Section: Autophagy Overviewmentioning

confidence: 99%

“…Autophagosomes are trafficked to and fuse with lysosomes to form an autolysosome resulting in subsequent degradation of cargo and liberation of amino acids from digested proteins [26]. This catabolic process liberates energy from degraded cargo including aged or damaged organelles and protein aggregates, thereby promoting cellular homeostasis [24]. Autophagy is required for maintaining intestinal cell survival and a normal colonic mucosa, as well as regulating inflammatory responses.…”

Section: Autophagy Overviewmentioning

confidence: 99%

“…Traditional genetic linkage and positional cloning strategies, as well as genome wide association studies, have identified loss-of-function mutations and polymorphisms in NOD2 as enhancing the susceptibility for the development of CD [24,58]. Polymorphisms in both the ATG16L1 and NOD2 genes are linked to Paneth cell dysfunction [52].…”

Section: Pattern Recognition Receptors: Critical Inducers Of Autophagymentioning

confidence: 99%

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The role of barrier function, autophagy, and cytokines in maintaining intestinal homeostasis

Elshaer

Begun

2017

Seminars in Cell & Developmental Biology

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Please cite this article as: Elshaer Dana, Begun Jakob.The role of barrier function, autophagy, and cytokines in maintaining intestinal homeostasis.Seminars in Cell and Developmental Biology http://dx.doi.org/10. 1016/j.semcdb.2016.08.018 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Abstract:Intestinal homeostasis is maintained through the interplay of the intestinal mucosa, local and systemic immune factors, and the microbial content of the gut. The cellular processes of autophagy, endoplasmic reticulum stress, the unfolded protein response and regulation of reactive oxygen species production are required to maintain a balance between proinflammatory responses against potential pathogens and a tolerogenic response towards commensal bacteria. Intestinally active cytokines regulate innate immune pathways and cellular pathways within the gut mucosa. Disruption of these processes, or alterations in the cytokine milieu, can result in an improper response to the commensal gut microbial community leading to inappropriate inflammation characteristic of conditions such as inflammatory bowel disease.

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Role of Autophagy in the Maintenance of Intestinal Homeostasis

Cited by 84 publications

References 89 publications

LRRK2 but not ATG16L1 is associated with Paneth cell defect in Japanese Crohn’s disease patients

LRRK2 but not ATG16L1 is associated with Paneth cell defect in Japanese Crohn’s disease patients

Short-Chain Fatty Acids Manifest Stimulative and Protective Effects on Intestinal Barrier Function Through the Inhibition of NLRP3 Inflammasome and Autophagy

The role of barrier function, autophagy, and cytokines in maintaining intestinal homeostasis

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