Short-chain fatty acids manifest stimulative and protective effects on intestinal barrier function through the inhibition of NLRP3 inflammasome and autophagy
Open accessAbstract
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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Treatment with SCFA such as acetate, propionate, and butyrate induced expression of tight junction proteins of intestinal epithelial cells.
“Furthermore, Feng et al83 reported that treatment with SCFA such as acetate, propionate, and butyrate induced expression of TJ proteins of IECs.83”
From Regulation of Intestinal Barrier Function by Microbial Metabolites (2021) · cites this paper as [83]
Probiotic strains such as L. plantarum elevate the levels of host defense peptides such as pBD2, PG1-5 and pBD2 and improve gut barrier function.
“Furthermore, probiotic strains such as L. plantarum also elevate the levels of host defense peptides such as pBD2, PG1-5 and pBD2 and improve gut barrier function.83”
From Regulation of Intestinal Barrier Function by Microbial Metabolites (2021) · cites this paper as [83]
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- Authors
- Feng, Y., Wang, Y., Wang, P., Huang, Y., & Wang, F.
- Affiliations
- Army Medical University (CN)
- Venue
- Cellular Physiology and Biochemistry
- Publisher
- S. Karger AG
- Published
- 2018
- Volume
- 49
- Issue
- 1
- Pages
- 190-205
- ISSN
- 1015-8987 (ISSN-L)
- 1421-9778
- OpenAlex
- W2888059941
- Cited by
- 471
- References
- 44
- Citations by year
- 2026: 63 · 2025: 73 · 2024: 71 · 2023: 63 · 2022: 73 · 2021: 66 · 2020: 32 · 2019: 27 · 2018: 2
- FWCI
- 11.29
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Cellular Physiology and Biochemistry (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Natural Science Foundation of China
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
- Health Sciences › Medicine › Gastroenterology › Gastrointestinal motility and disorders
- Health Sciences › Nursing › Nutrition and Dietetics › Microbial Metabolites in Food Biotechnology
- Keywords
- short-chain fatty acids, intestinal barrier function, NLRP3 inflammasome, autophagy, tight junctions, ZO-1, occludin, lipopolysaccharide, butyrate, propionate, acetate, histone deacetylase inhibition, intestinal epithelial permeability, Caco-2 cells, intestinal inflammation, energy metabolism, rapamycin, trichostatin A, etomoxir, dextran
- MeSH terms
- Beclin-1, NLR Family, Pyrin Domain-Containing 3 Protein, Autophagy, Energy Metabolism, Epoxy Compounds, Fatty Acids, Volatile, Humans, Hydroxamic Acids, Intestinal Mucosa, Lipopolysaccharides, Microtubule-Associated Proteins, Permeability, Cytokines, Reactive Oxygen Species, Caco-2 Cells, Tight Junctions, Sirolimus, Inflammasomes, Occludin, Zonula Occludens-1 Protein
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