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Effects of valerate on intestinal barrier function in cultured Caco-2 epithelial cell monolayers

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Abstract

Background

Short-chain fatty acids (SCFAs) are a group of microbial metabolites of undigested dietary fiber, protein and unabsorbed amino acids in the colon, well-known for their gut health promoting benefits. A relatively high intestinal level of valerate was found in the healthy human subjects. However, the intestinal protection effects and the underlying mechanism of valerate are waiting to be verified and elucidated.

Methods and Results

In the present study, valerate, a SCFAs mainly converted from proteins or amino acids, was demonstrated to promote intestinal barrier function at its physiological concentrations of 0–4 mM in the Caco-2 cell monolayer model of intestinal barrier using transepithelial electrical resistance (TEER) assay and paracellular permeability assay. Valerate achieved the maximum increase in the TEER at 2 mM and reduced the paracellular permeability. Its intestinal barrier function promoting activity is similar to that of butyrate, with a broader range of effective concentrations than the later. Through western blot analysis, this activity is linked to the valerate-induced AMPK activation and tight junctions (TJs) assembly, but not to the reinforced expression of TJs related proteins.

Conclusions

It provides direct experimental evidence supporting valerate’s function in intestinal health, implying the once under-valued function of valerate and its amino acid precursors. The valerate’s role in regulating intestine homeostasis and its possible synergetic effects with other SCFAs warranted to be further investigated.

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Data availability

The datasets generated during the current study are available from the corresponding author on reasonable request.

References

  1. Rios-Covian D, González S, Nogacka AM et al (2020) An overview on fecal branched short-chain fatty acids along human life and as related with body mass index: associated dietary and anthropometric factors. Front Microbiol 11:1–9

    Article  Google Scholar 

  2. Parada Venegas D, la Fuente MK, Landskron G et al (2019) Short chain fatty acids (SCFAs)-mediated gut epithelial and immune regulation and its relevance for inflammatory bowel diseases. Front Immunol 10:277

    Article  Google Scholar 

  3. Bilotta AJ, Cong Y (2019) Gut microbiota metabolite regulation of host defenses at mucosal surfaces: implication in precision medicine. Precis Clin Med 2:110–119

    Article  Google Scholar 

  4. Chambers ES, Preston T, Frost G, Morrison DJ (2018) Role of gut microbiota-generated short-chain fatty acids in metabolic and cardiovascular health. Curr Nutr Rep 7:198–206

    Article  CAS  Google Scholar 

  5. Gomes SD, Oliveira CS, Azevedo-Silva J et al (2020) The role of diet related short-chain fatty acids in colorectal cancer metabolism and survival: prevention and therapeutic implications. Curr Med Chem 27:4087–4108

    Article  CAS  Google Scholar 

  6. Ahmadmehrabi S, Tang WHW (2017) Gut microbiome and its role in cardiovascular diseases. Curr Opin Cardiol 32:761–766

    Article  Google Scholar 

  7. Yuille S, Reichardt N, Panda S et al (2018) Human gut bacteria as potent class I histone deacetylase inhibitors in vitro through production of butyric acid and valeric acid. PLoS ONE 13:e0201073–e0201073

    Article  Google Scholar 

  8. Skrzypecki J, Niewęgłowska K, Samborowska E (2020) Valeric acid, a gut microbiota product, penetrates to the eye and lowers intraocular pressure in rats. Nutrients 12:387–395

    Article  CAS  Google Scholar 

  9. Luu M, Pautz S, Kohl V et al (2019) The short-chain fatty acid pentanoate suppresses autoimmunity by modulating the metabolic-epigenetic crosstalk in lymphocytes. Nat Commun 10:760

    Article  CAS  Google Scholar 

  10. McDonald JAK, Mullish BH, Pechlivanis A et al (2018) Inhibiting growth of clostridioides difficile by restoring valerate, produced by the intestinal microbiota. Gastroenterology 155:1495–1507

    Article  CAS  Google Scholar 

  11. Naseribafrouei A, Hestad K, Avershina E et al (2014) Correlation between the human fecal microbiota and depression. Neurogastroenterol Motil 26:1155–1162

    Article  CAS  Google Scholar 

  12. Liu S, Li E, Sun Z et al (2019) Altered gut microbiota and short chain fatty acids in Chinese children with autism spectrum disorder. Sci Rep 9:287

    Article  Google Scholar 

  13. Scheppach W, Christl SU, Bartram HP et al (1997) Effects of short-chain fatty acids on the inflamed colonic mucosa. Scand J Gastroenterol Suppl 222:53–57

    Article  CAS  Google Scholar 

  14. Hoverstad T, Fausa O, Bjoneklett A, Bohmer T (1984) Short-chain fatty acids in the normal human feces. Scand J Gastroenterol 19:375–381

    Article  CAS  Google Scholar 

  15. Peng L, He Z, Chen W et al (2007) Effects of butyrate on intestinal barrier function in a caco-2 cell monolayer model of intestinal barrier. Pediatr Res 61:37–41

    Article  CAS  Google Scholar 

  16. Lee B, Moon KM, Kim CY (2018) Tight junction in the intestinal epithelium: Its association with diseases and regulation by phytochemicals. J Immunol Res 2018:2645465

  17. Peng L, Li Z-R, Green RS et al (2009) Butyrate enhances the intestinal barrier by facilitating tight junction assembly via activation of AMP-activated protein kinase in Caco-2 cell monolayers. J Nutr 139:1619

    Article  CAS  Google Scholar 

  18. Olivier S, Leclerc J, Grenier A et al (2019) Ampk activation promotes tight junction assembly in intestinal epithelial caco-2 cells. Int J Mol Sci 20:5171–5186

    Article  CAS  Google Scholar 

  19. Zhang L, Li J, Young LH, Caplan MJ (2006) AMP-activated protein kinase regulates the assembly of epithelial tight junctions. Proc Natl Acad Sci U S A 103:17272–17277

    Article  CAS  Google Scholar 

  20. Chen L, Wang J, You Q, et al (2018) Activating AMPK to restore tight junction assembly in intestinal epithelium and to attenuate experimental colitis by metformin. Front Pharmacol 9:761–772

    Article  Google Scholar 

  21. Ríos-Covián D, Ruas-Madiedo P, Margolles A et al (2016) Intestinal short chain fatty acids and their link with diet and human health. Front Microbiol 7:185–193

    Article  Google Scholar 

  22. Yap YA, Mariño E (2018) An insight into the intestinal web of mucosal immunity, microbiota, and diet in inflammation. Front Immunol 9:2617

    Article  Google Scholar 

  23. Wang HB, Wang PY, Wang X et al (2012) Butyrate enhances intestinal epithelial barrier function via up-regulation of tight junction protein claudin-1 transcription. Dig Dis Sci 57:3126–3135

    Article  CAS  Google Scholar 

  24. Mariadason JM, Barkla DH, Gibson PR (1997) Effect of short-chain fatty acids on paracellular permeability in Caco- 2 intestinal epithelium model. Am J Physiol Liver Physiol 272:705–712

    Google Scholar 

  25. Jha R, Berrocoso JFD (2016) Dietary fiber and protein fermentation in the intestine of swine and their interactive effects on gut health and on the environment: A review. Anim Feed Sci Technol 212:18–26

    Article  CAS  Google Scholar 

  26. Mortensen PB, Holtug K, Bonnén H, Clausen MR (1990) The degradation of amino acids, proteins, and blood to short-chain fatty acids in colon is prevented by lactulose. Gastroenterology 98:353–360

    Article  CAS  Google Scholar 

  27. Kim H, Jeon BS, Sang BI (2019) An efficient new process for the selective production of odd-chain carboxylic acids by simple carbon elongation using megasphaera hexanoica. Sci Rep 9:1–10

    Google Scholar 

  28. Iino T, Mori K, Tanaka K et al (2007) Oscillibacter valericigenes gen. nov., sp. nov., a valerate-producing anaerobic bacterium isolated from the alimentary canal of a Japanese corbicula clam. Int J Syst Evol Microbiol 57:1840–1845

    Article  Google Scholar 

  29. Hugenholtz F, Davids M, Schwarz J et al (2018) Metatranscriptome analysis of the microbial fermentation of dietary milk proteins in the murine gut. PLoS ONE 13:e0194066

    Article  Google Scholar 

  30. Deb-Choudhury S, Bermingham EN, Young W et al (2018) The effects of a wool hydrolysate on short-chain fatty acid production and fecal microbial composition in the domestic cat (Felis catus). Food Funct 9:4107–4121

    Article  CAS  Google Scholar 

  31. Li R, Chang L, Hou G et al (2019) Colonic microbiota and metabolites response to different dietary protein sources in a piglet model. Front Nutr 6:151

    Article  Google Scholar 

  32. Hang I, Heilmann RM, Grützner N et al (2013) Impact of diets with a high content of greaves-meal protein or carbohydrates on faecal characteristics, volatile fatty acids and faecal calprotectin concentrations in healthy dogs. BMC Vet Res 9:201

    Article  Google Scholar 

  33. Burgess DJ (2012) Metabolism: Warburg behind the butyrate paradox? Nat Rev Cancer 12:798–799

    Article  CAS  Google Scholar 

  34. Donohoe DR, Collins LB, Wali A et al (2012) The warburg effect dictates the mechanism of butyrate-mediated histone acetylation and cell proliferation. Mol Cell 48:612–626

    Article  CAS  Google Scholar 

  35. Zheng B, Cantley LC (2007) Regulation of epithelial tight junction assembly and disassembly by AMP-activated protein kinase. Proc Natl Acad Sci U S A 104:819–822

    Article  CAS  Google Scholar 

  36. Elamin EE, Masclee AA, Dekker J et al (2013) Short-chain fatty acids activate AMP-activated protein kinase and ameliorate ethanol-induced intestinal barrier dysfunction in Caco-2 cell monolayers. J Nutr 143:1872–1881

    Article  CAS  Google Scholar 

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Acknowledgements

This study was supported by the National Key Research and Development Plan of China (2016YFD0400202) and (2017YFD0400300).

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Authors and Affiliations

  1. Food Nutrition Science Centre, School of Food Science and Biotechnology, Zhejiang Gongshang University, Hangzhou, Zhejiang, China

    Guanzhen Gao, Jingru Zhou, Huiqin Wang, Yanan Ding, Jianwu Zhou, Pik Han Chong, Lijing Ke & Pingfan Rao

  2. State Key Laboratory of Breeding Base for Zhejiang Sustainable Pest and Disease Control, Institute of Plant Protection and Microbiology, Zhejiang Academy of Agricultural Sciences, Hangzhou, Zhejiang, China

    Liying Zhu & Xin Wang

  3. Institute of Food Science and Technology, Chinese Academy of Agricultural Sciences, Beijing, China

    Qiang Wang

  4. Fujian Provincial Maternity and Children Hospital, Affiliated hospital of Fujian Medical University, Fuzhou, China

    Longxin Zhang

Authors
  1. Guanzhen Gao
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  9. Xin Wang
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Contributions

Guanzhen Gao: Conceptualization, Methodology, Validation, Formal analysis, Investigation, Resources, Data curation, Writing – original draft, Visualization. Jingru Zhou: Data curation, Methodology, Validation, Formal analysis, Investigation, Writing – original draft. Huiqin Wang: Conceptualization, Methodology, Validation, Formal analysis, Writing – review & editing. Yanan Ding: Validation, Formal analysis, Writing – review & editing. Jianwu Zhou: Formal analysis, Writing – review & editing. Pik Han Chong: Writing – review & editing. Liying Zhu: Conceptualization, Methodology, Validation, Writing – review & editing. Lijing Ke: Writing – Conceptualization, Methodology, Validation, Formal analysis, Resources, Data curation, Writing – review & editing, Visualization, Supervision, Project administration. Xin Wang: Writing – review & editing. Pingfan Rao: Writing – review & editing. Qiang Wang: Writing – review & editing. Longxin Zhang: Writing – review & editing.

Corresponding authors

Correspondence to Liying Zhu or Lijing Ke.

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Gao, G., Zhou, J., Wang, H. et al. Effects of valerate on intestinal barrier function in cultured Caco-2 epithelial cell monolayers. Mol Biol Rep 49, 1817–1825 (2022). https://doi.org/10.1007/s11033-021-06991-w

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  • DOI: https://doi.org/10.1007/s11033-021-06991-w

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