Expression of the cathelicidin LL-37 is modulated by short chain fatty acids in colonocytes: relevance of signalling pathways
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BACKGROUND AND AIMS: Short chain fatty acids (SCFA) exert profound effects on the colonic mucosa. In particular, SCFA modulate mucosal immune functions. The antimicrobial cathelicidin LL-37 is expressed by colon epithelial cells. In the present study the effect of SCFA on LL-37 expression was investigated. METHODS: LL-37 expression in vivo was assessed by immunohistochemistry. Real time quantitative reverse transcription-polymerase chain reaction was employed to determine LL-37 expression in colonocytes in vitro after treatment with various cytokines, SCFA, or flavone. LL-37 levels were correlated to cell differentiation which was determined by alkaline phosphatase (AP) activity. In addition, intracellular signalling pathways such as MEK-ERK (mitogen/extracellular signal protein kinase (MEK)/extracellular signal regulated protein kinase (ERK)) and p38/mitogen activated protein (MAP) kinase were explored. RESULTS: In vivo, LL-37 expression in healthy mucosa was restricted to differentiated epithelial cells in human colon and ileum. In colonocytes, increased LL-37 expression associated with cell differentiation was detected in vitro following treatment with butyrate, isobutyrate, propionate, and trichostatin A. Flavone induced LL-37 transcription but did not affect AP activity while cytokines had no effect. To dissect pathways mediating differentiation and LL-37 expression, specific inhibitors were applied. Inhibition of the protein kinase MEK enhanced butyrate induced AP activity while LL-37 expression in colon epithelial cells was blocked. In contrast, inhibition of p38/MAP kinase blocked cell differentiation without inhibiting LL-37 expression. CONCLUSIONS: Expression of the cathelicidin LL-37 in colonocytes and cellular differentiation are separately modulated by SCFA via distinct signalling pathways. These data may provide a rationale for dietary modulation of mucosal defence mechanisms.
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Microbial metabolites are integral for promoting immune responses in the gut against pathogens, including inducing secretion of IL-18 and defensins.
“microbial metabolites are integral for promoting immune responses in the gut against pathogens, including inducing secretion of IL-18 (36) and defensins (37, 38)”
From Respiratory viral infection-induced microbiome alterations and secondary bacterial pneumonia. (2018) · cites this paper as [37]
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- Authors
- Schauber, J.
- Affiliations
- University of Würzburg (DE)
- Corresponding author
- Schauber, J
- Venue
- Gut
- Publisher
- BMJ
- Published
- 2003-05-01
- Volume
- 52
- Issue
- 5
- Pages
- 735-741
- ISSN
- 0017-5749 (ISSN-L)
- PMC
- PMC1773650
- OpenAlex
- W2130246343
- Cited by
- 383
- References
- 41
- Citations by year
- 2026: 10 · 2025: 11 · 2024: 15 · 2023: 21 · 2022: 27 · 2021: 15 · 2020: 24 · 2019: 25 · 2018: 23 · 2017: 17 · 2016: 21 · 2015: 12 · 2014: 20 · 2013: 17 · 2012: 19
- FWCI
- 8.91
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Gut (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- HighWire Press Open Archive (submittedVersion)
- Funders
- Boehringer Ingelheim Fonds
- Deutsche Forschungsgemeinschaft
- Stiftelsen för Strategisk Forskning
- Karolinska Institutet
- Julius-Maximilians-Universität Würzburg
- Medical Research Council
- Topics
- Life Sciences › Immunology and Microbiology › Microbiology › Antimicrobial Peptides and Activities
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
- Life Sciences › Agricultural and Biological Sciences › Food Science › Probiotics and Fermented Foods
- Keywords
- cathelicidin LL-37, short-chain fatty acids, colonic epithelial cells, butyrate, MEK/ERK signaling, p38 MAPK, flavones, alkaline phosphatase activity, mucosal immunity
- MeSH terms
- Adult, Alkaline Phosphatase, Biopsy, Butyrates, Cell Differentiation, Cell Line, Colon, Epithelial Cells, Fatty Acids, Volatile, Flavonoids, Humans, Hydroxamic Acids, Immunohistochemistry, Intestinal Mucosa, Protein Kinases, Protein Synthesis Inhibitors, Signal Transduction, Apoptosis, Reverse Transcriptase Polymerase Chain Reaction, Antimicrobial Cationic Peptides, Flavones, Cathelicidins
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