Microbial-Derived Butyrate Promotes Epithelial Barrier Function through IL-10 Receptor-Dependent Repression of Claudin-2

Leon Zheng, Caleb J Kelly, Kayla D Battista, Rachel Schaefer, Jordi M Lanis, Erica E Alexeev, Ruth X Wang, Joseph C Onyiah, Douglas J Kominsky, Sean P Colgan, Leon Zheng, Caleb J Kelly, Kayla D Battista, Rachel Schaefer, Jordi M Lanis, Erica E Alexeev, Ruth X Wang, Joseph C Onyiah, Douglas J Kominsky, Sean P Colgan

Abstract

Commensal interactions between the enteric microbiota and distal intestine play important roles in regulating human health. Short-chain fatty acids (SCFAs), such as butyrate, produced through anaerobic microbial metabolism represent a major energy source for the host colonic epithelium and enhance epithelial barrier function through unclear mechanisms. Separate studies revealed that the epithelial anti-inflammatory IL-10 receptor α subunit (IL-10RA) is also important for barrier formation. Based on these findings, we examined if SCFAs promote epithelial barrier through IL-10RA-dependent mechanisms. Using human intestinal epithelial cells (IECs), we discovered that SCFAs, particularly butyrate, enhanced IEC barrier formation, induced IL-10RA mRNA, IL-10RA protein, and transactivation through activated Stat3 and HDAC inhibition. Loss and gain of IL-10RA expression directly correlates with IEC barrier formation and butyrate represses permeability-promoting claudin-2 tight-junction protein expression through an IL-10RA-dependent mechanism. Our findings provide a novel mechanism by which microbial-derived butyrate promotes barrier through IL-10RA-dependent repression of claudin-2.

Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1. Butyrate enhances intestinal epithelial cell… — **Figure 1. Butyrate enhances intestinal epithelial cell barrier formation**
T84 cells were treated with HHBS (Hanks’ Buffer with 10mM HEPES) at time 0h ± (A) butyrate (5mM), (B) propionate (20mM), or (C) acetate (20mM). Transepithelial electrical resistance (TEER) was measured and analyzed over 72h. Data are representative of at least two independent experiments. Error bars represent mean ± SEM. * p

**Figure 2. Butyrate upregulates interleukin-10 receptor α…**

**Figure 2. Butyrate upregulates interleukin-10 receptor α (IL-10RA)**

(A) Caco-2 and (B) T84 cells were…

**Figure 2. Butyrate upregulates interleukin-10 receptor α (IL-10RA)**
(A) Caco-2 and (B) T84 cells were treated with HHBS ± acetate (20mM), propionate (20mM), or butyrate (5mM) for up to 24h. RNA was isolated, cDNA was synthesized and IL-10RA mRNA was quantitated by qPCR (data normalized to β-actin). (C, D) In a separate experiment, cells were treated with HHBS ± butyrate (0–10mM) for 18h and IL10RA mRNA was analyzed by qPCR (data normalized to β-actin). (E) Caco-2 and (F) T84 cells were treated for 24h with HHBS ± butyrate (0–20mM). Whole-cell lysates were collected and probed for IL-10RA by immunoblot (β-actin was used as loading control). (G) Representative photographs of immunofluorescence staining of IL-10RA (red) in T84 cells following HHBS ± butyrate (10mM) for 24h. Nuclei stained with DAPI (blue). (H) Caco-2 cells were transfected with empty vector control (EV) and an IL10RA promoter reporter (IL10RA-luc). After 24h, cells were treated with HHBS ± butyrate (0–10mM) for another 24h and luciferase activity was quantified. (I) T84 cells were treated with HHBS ± butyrate (10mM) for 24h and stimulated with PBS ± IL-10 (20ng/ml) for 2h. SOCS3 mRNA measured by qPCR (data normalized to β-actin). Data are representative of two or three independent experiments. Error bars represent mean ± SEM.

**Figure 3. Butyrate regulates IL-10RA through Stat3…**

**Figure 3. Butyrate regulates IL-10RA through Stat3 activation and histone deacetylase inhibition**

(A) T84 cells…

**Figure 3. Butyrate regulates IL-10RA through Stat3 activation and histone deacetylase inhibition**
(A) T84 cells were pretreated with DMSO ± Stattic (20mM) for 30min followed by HHBS ± butyrate (10mM) for 24h. Cells were stimulated with PBS ± IL-10 (20ng/ml) for 1h prior to harvesting the whole-cell lysates and probing for pStat3 by immunoblotting (β-actin was used as loading control). (B) T84 cells were pretreated with DMSO ± Stattic (20mM) for 30min followed by HHBS ± butyrate (5mM) for 6h. IL10RA mRNA was measured by qPCR (data normalized to β-actin). (C) T84 cells were stimulated with DMSO control or TSA (100, 250, or 500ng/ml) for 18h. RNA was isolated, cDNA was synthesized, and IL10RA mRNA was quantitated by qPCR (data normalized to β-actin). (D) T84 cells were treated with HHBS ± butyrate (2.5, 5mM) for 24h, then whole-cell lysates were collected and acH3K9 was probed by immunoblot (β-actin was used as loading control). Data are representative of at least three independent experiments. Error bars represent mean ± SEM.

**Figure 4. IL-10RA plays a pivotal role…**

**Figure 4. IL-10RA plays a pivotal role in formation and integrity of the intestinal epithelial…**

**Figure 4. IL-10RA plays a pivotal role in formation and integrity of the intestinal epithelial cell barrier**
(A) Relative IL10RA mRNA in T84 cells transduced with lentivirus shRNA targeting IL10RA (shIL10RA) v. shControl by qPCR. (B) IL10RA gene expression, by qPCR, in T84 cells transduced with IL10RA ORF lentivirus (LentiORF; oeIL10-RA) v. shControl cells (data normalized to β-actin). (C) T84 shControl (shCtrl) and shIL10RA were treated with HHBS ± butyrate (5mM) at 0h. TEER was measured and analyzed over 75h. (D) T84 shCtrl and oeIL10RA were treated with HHBS ± butyrate (5mM) at 0h. TEER was recorded over 75h. Data are representative of three independent experiments. (A, B) Error bars represent mean ± SEM. (C, D) Error bars represent mean ± SD.

**Figure 5. Butyrate represses Claudin-2 through IL-10RA…**

**Figure 5. Butyrate represses Claudin-2 through IL-10RA and pStat3**

(A) Caco-2 and (B) T84 cells…

**Figure 5. Butyrate represses Claudin-2 through IL-10RA and pStat3**
(A) Caco-2 and (B) T84 cells were stimulated with HHBS ± butyrate (5mM) for 18h. cDNA generated from RNA isolation was analyzed by qPCR and data was normalized to β-actin. (C) Claudin-2 (Cldn2) was probed by immunoblot in T84 cells treated with HHBS ± butyrate (2.5 or 5mM) for 24h and also T84 shCtrl, shIL10RA, and oeIL10RA cell lines (β-actin was loading control). (D) T84 cells were pretreated with DMSO ± Stattic (20mM) for 30min followed by HHBS ± butyrate (5mM) for 6h. Cldn2 mRNA was measured by qPCR (data normalized to actin). Data are representative of at least three independent experiments. Error bars represent mean ± SEM.

**Figure 6. Microbial-derived butyrate enhances Il10ra in…**

**Figure 6. Microbial-derived butyrate enhances Il10ra in an *in vivo* system**

C57BL/6 mice were gavaged…

**Figure 6. Microbial-derived butyrate enhances Il10ra in an *in vivo* system**
C57BL/6 mice were gavaged with broad-spectrum antibiotics for 3d and euthanized. (A) Colon and (B) ileal tissue collected from the control and antibiotic treated mice were lysed, RNA was isolated, cDNA was synthesized, and Il10ra mRNA was analyzed by qPCR. (C and D) Data collected from Geo Profiles of both Rank % and transformed counts of germ free mice colonic Il10ra during conventionalization were graphed. Data are representative of three independent experiments (A, B). Error bars represent mean ± SEM.

See this image and copyright information in PMC

Figure 2. Butyrate upregulates interleukin-10 receptor α… — **Figure 2. Butyrate upregulates interleukin-10 receptor α (IL-10RA)**
(A) Caco-2 and (B) T84 cells were treated with HHBS ± acetate (20mM), propionate (20mM), or butyrate (5mM) for up to 24h. RNA was isolated, cDNA was synthesized and IL-10RA mRNA was quantitated by qPCR (data normalized to β-actin). (C, D) In a separate experiment, cells were treated with HHBS ± butyrate (0–10mM) for 18h and IL10RA mRNA was analyzed by qPCR (data normalized to β-actin). (E) Caco-2 and (F) T84 cells were treated for 24h with HHBS ± butyrate (0–20mM). Whole-cell lysates were collected and probed for IL-10RA by immunoblot (β-actin was used as loading control). (G) Representative photographs of immunofluorescence staining of IL-10RA (red) in T84 cells following HHBS ± butyrate (10mM) for 24h. Nuclei stained with DAPI (blue). (H) Caco-2 cells were transfected with empty vector control (EV) and an IL10RA promoter reporter (IL10RA-luc). After 24h, cells were treated with HHBS ± butyrate (0–10mM) for another 24h and luciferase activity was quantified. (I) T84 cells were treated with HHBS ± butyrate (10mM) for 24h and stimulated with PBS ± IL-10 (20ng/ml) for 2h. SOCS3 mRNA measured by qPCR (data normalized to β-actin). Data are representative of two or three independent experiments. Error bars represent mean ± SEM.

Figure 3. Butyrate regulates IL-10RA through Stat3… — **Figure 3. Butyrate regulates IL-10RA through Stat3 activation and histone deacetylase inhibition**
(A) T84 cells were pretreated with DMSO ± Stattic (20mM) for 30min followed by HHBS ± butyrate (10mM) for 24h. Cells were stimulated with PBS ± IL-10 (20ng/ml) for 1h prior to harvesting the whole-cell lysates and probing for pStat3 by immunoblotting (β-actin was used as loading control). (B) T84 cells were pretreated with DMSO ± Stattic (20mM) for 30min followed by HHBS ± butyrate (5mM) for 6h. IL10RA mRNA was measured by qPCR (data normalized to β-actin). (C) T84 cells were stimulated with DMSO control or TSA (100, 250, or 500ng/ml) for 18h. RNA was isolated, cDNA was synthesized, and IL10RA mRNA was quantitated by qPCR (data normalized to β-actin). (D) T84 cells were treated with HHBS ± butyrate (2.5, 5mM) for 24h, then whole-cell lysates were collected and acH3K9 was probed by immunoblot (β-actin was used as loading control). Data are representative of at least three independent experiments. Error bars represent mean ± SEM.

Figure 4. IL-10RA plays a pivotal role… — **Figure 4. IL-10RA plays a pivotal role in formation and integrity of the intestinal epithelial cell barrier**
(A) Relative IL10RA mRNA in T84 cells transduced with lentivirus shRNA targeting IL10RA (shIL10RA) v. shControl by qPCR. (B) IL10RA gene expression, by qPCR, in T84 cells transduced with IL10RA ORF lentivirus (LentiORF; oeIL10-RA) v. shControl cells (data normalized to β-actin). (C) T84 shControl (shCtrl) and shIL10RA were treated with HHBS ± butyrate (5mM) at 0h. TEER was measured and analyzed over 75h. (D) T84 shCtrl and oeIL10RA were treated with HHBS ± butyrate (5mM) at 0h. TEER was recorded over 75h. Data are representative of three independent experiments. (A, B) Error bars represent mean ± SEM. (C, D) Error bars represent mean ± SD.

Figure 5. Butyrate represses Claudin-2 through IL-10RA… — **Figure 5. Butyrate represses Claudin-2 through IL-10RA and pStat3**
(A) Caco-2 and (B) T84 cells were stimulated with HHBS ± butyrate (5mM) for 18h. cDNA generated from RNA isolation was analyzed by qPCR and data was normalized to β-actin. (C) Claudin-2 (Cldn2) was probed by immunoblot in T84 cells treated with HHBS ± butyrate (2.5 or 5mM) for 24h and also T84 shCtrl, shIL10RA, and oeIL10RA cell lines (β-actin was loading control). (D) T84 cells were pretreated with DMSO ± Stattic (20mM) for 30min followed by HHBS ± butyrate (5mM) for 6h. Cldn2 mRNA was measured by qPCR (data normalized to actin). Data are representative of at least three independent experiments. Error bars represent mean ± SEM.

Figure 6. Microbial-derived butyrate enhances Il10ra in… — **Figure 6. Microbial-derived butyrate enhances Il10ra in an *in vivo* system**
C57BL/6 mice were gavaged with broad-spectrum antibiotics for 3d and euthanized. (A) Colon and (B) ileal tissue collected from the control and antibiotic treated mice were lysed, RNA was isolated, cDNA was synthesized, and Il10ra mRNA was analyzed by qPCR. (C and D) Data collected from Geo Profiles of both Rank % and transformed counts of germ free mice colonic Il10ra during conventionalization were graphed. Data are representative of three independent experiments (A, B). Error bars represent mean ± SEM.

References

1. Lozupone CA, Stombaugh JI, Gordon JI, Jansson JK, Knight R. Diversity, stability and resilience of the human gut microbiota. Nature. 2012;489:220–230.
1. Hamer HM, Jonkers D, Venema K, Vanhoutvin S, Troost FJ, Brummer RJ. Review article: the role of butyrate on colonic function. Aliment Pharmacol Ther. 2008;27:104–119.
1. Eeckhaut V, Machiels K, Perrier C, Romero C, Maes S, Flahou B, Steppe M, Haesebrouck F, Sas B, Ducatelle R, Vermeire S, Van Immerseel F. Butyricicoccus pullicaecorum in inflammatory bowel disease. Gut. 2013;62:1745–1752.
1. Machiels K, Joossens M, Sabino J, De Preter V, Arijs I, Eeckhaut V, Ballet V, Claes K, Van Immerseel F, Verbeke K, Ferrante M, Verhaegen J, Rutgeerts P, Vermeire S. A decrease of the butyrate-producing species Roseburia hominis and Faecalibacterium prausnitzii defines dysbiosis in patients with ulcerative colitis. Gut. 2014;63:1275–1283.
1. Sokol H, Seksik P, Furet JP, Firmesse O, Nion-Larmurier I, Beaugerie L, Cosnes J, Corthier G, Marteau P, Dore J. Low counts of Faecalibacterium prausnitzii in colitis microbiota. Inflamm Bowel Dis. 2009;15:1183–1189.
1. Atreya I, Atreya R, Neurath MF. NF-kappaB in inflammatory bowel disease. J Intern Med. 2008;263:591–596.
1. Round JL, Mazmanian SK. The gut microbiota shapes intestinal immune responses during health and disease. Nat Rev Immunol. 2009;9:313–323.
1. Moore KW, de Waal Malefyt R, Coffman RL, O’Garra A. Interleukin-10 and the interleukin-10 receptor. Annu Rev Immunol. 2001;19:683–765.
1. Bourreille A, Segain JP, Raingeard de la Bletiere D, Siavoshian S, Vallette G, Galmiche JP, Blottiere HM. Lack of interleukin 10 regulation of antigen presentation-associated molecules expressed on colonic epithelial cells. Eur J Clin Invest. 1999;29:48–55.
1. Denning TL, Campbell NA, Song F, Garofalo RP, Klimpel GR, Reyes VE, Ernst PB. Expression of IL-10 receptors on epithelial cells from the murine small and large intestine. Int Immunol. 2000;12:133–139.
1. Commins S, Steinke JW, Borish L. The extended IL-10 superfamily: IL-10, IL-19, IL-20, IL-22, IL-24, IL-26, IL-28, and IL-29. J Allergy Clin Immunol. 2008;121:1108–1111.
1. Riley JK, Takeda K, Akira S, Schreiber RD. Interleukin-10 receptor signaling through the JAK-STAT pathway. Requirement for two distinct receptor-derived signals for anti-inflammatory action. J Biol Chem. 1999;274:16513–16521.
1. El Kasmi KC, Holst J, Coffre M, Mielke L, de Pauw A, Lhocine N, Smith AM, Rutschman R, Kaushal D, Shen Y, Suda T, Donnelly RP, Myers MG, Jr, Alexander W, Vignali DA, Watowich SS, Ernst M, Hilton DJ, Murray PJ. General nature of the STAT3-activated anti-inflammatory response. J Immunol. 2006;177:7880–7888.
1. Chaudhry A, Samstein RM, Treuting P, Liang Y, Pils MC, Heinrich JM, Jack RS, Wunderlich FT, Bruning JC, Muller W, Rudensky AY. Interleukin-10 signaling in regulatory T cells is required for suppression of Th17 cell-mediated inflammation. Immunity. 2011;34:566–578.
1. Kuhn R, Lohler J, Rennick D, Rajewsky K, Muller W. Interleukin-10-deficient mice develop chronic enterocolitis. Cell. 1993;75:263–274.
1. Kominsky DJ, Campbell EL, Ehrentraut SF, Wilson KE, Kelly CJ, Glover LE, Collins CB, Bayless AJ, Saeedi B, Dobrinskikh E, Bowers BE, MacManus CF, Muller W, Colgan SP, Bruder D. IFN-gamma-mediated induction of an apical IL-10 receptor on polarized intestinal epithelia. J Immunol. 2014;192:1267–1276.
1. Kelly CJ, Zheng L, Campbell EL, Saeedi B, Scholz CC, Bayless AJ, Wilson KE, Glover LE, Kominsky DJ, Magnuson A, Weir TL, Ehrentraut SF, Pickel C, Kuhn KA, Lanis JM, Nguyen V, Taylor CT, Colgan SP. Crosstalk between Microbiota-Derived Short-Chain Fatty Acids and Intestinal Epithelial HIF Augments Tissue Barrier Function. Cell Host Microbe. 2015;17:662–671.
1. Furusawa Y, Obata Y, Fukuda S, Endo TA, Nakato G, Takahashi D, Nakanishi Y, Uetake C, Kato K, Kato T, Takahashi M, Fukuda NN, Murakami S, Miyauchi E, Hino S, Atarashi K, Onawa S, Fujimura Y, Lockett T, Clarke JM, Topping DL, Tomita M, Hori S, Ohara O, Morita T, Koseki H, Kikuchi J, Honda K, Hase K, Ohno H. Commensal microbe-derived butyrate induces the differentiation of colonic regulatory T cells. Nature. 2013;504:446–450.
1. Davie JR. Inhibition of histone deacetylase activity by butyrate. J Nutr. 2003;133:2485S–2493S.
1. Luettig J, Rosenthal R, Barmeyer C, Schulzke JD. Claudin-2 as a mediator of leaky gut barrier during intestinal inflammation. Tissue Barriers. 2015;3:e977176.
1. Glover LE, Bowers BE, Saeedi B, Ehrentraut SF, Campbell EL, Bayless AJ, Dobrinskikh E, Kendrick AA, Kelly CJ, Burgess A, Miller L, Kominsky DJ, Jedlicka P, Colgan SP. Control of creatine metabolism by HIF is an endogenous mechanism of barrier regulation in colitis. Proc Natl Acad Sci U S A. 2013;110:19820–19825.
1. Suzuki A, Hanada T, Mitsuyama K, Yoshida T, Kamizono S, Hoshino T, Kubo M, Yamashita A, Okabe M, Takeda K, Akira S, Matsumoto S, Toyonaga A, Sata M, Yoshimura A. CIS3/SOCS3/SSI3 plays a negative regulatory role in STAT3 activation and intestinal inflammation. J Exp Med. 2001;193:471–481.
1. Staples KJ, Smallie T, Williams LM, Foey A, Burke B, Foxwell BM, Ziegler-Heitbrock L. IL-10 induces IL-10 in primary human monocyte-derived macrophages via the transcription factor Stat3. J Immunol. 2007;178:4779–4785.
1. Schust J, Sperl B, Hollis A, Mayer TU, Berg T. Stattic: a small-molecule inhibitor of STAT3 activation and dimerization. Chem Biol. 2006;13:1235–1242.
1. Yoshida M, Horinouchi S, Beppu T. Trichostatin A and trapoxin: novel chemical probes for the role of histone acetylation in chromatin structure and function. Bioessays. 1995;17:423–430.
1. Bartova E, Krejci J, Harnicarova A, Galiova G, Kozubek S. Histone modifications and nuclear architecture: a review. J Histochem Cytochem. 2008;56:711–721.
1. Donohoe DR, Collins LB, Wali A, Bigler R, Sun W, Bultman SJ. The Warburg effect dictates the mechanism of butyrate-mediated histone acetylation and cell proliferation. Mol Cell. 2012;48:612–626.
1. Singh N, Gurav A, Sivaprakasam S, Brady E, Padia R, Shi H, Thangaraju M, Prasad PD, Manicassamy S, Munn DH, Lee JR, Offermanns S, Ganapathy V. Activation of Gpr109a, receptor for niacin and the commensal metabolite butyrate, suppresses colonic inflammation and carcinogenesis. Immunity. 2014;40:128–139.
1. Mangmool S, Kurose H. G(i/o) protein-dependent and -independent actions of Pertussis Toxin (PTX) Toxins (Basel) 2011;3:884–899.
1. Groschwitz KR, Hogan SP. Intestinal barrier function: molecular regulation and disease pathogenesis. J Allergy Clin Immunol. 2009;124:3–20. quiz 21–22.
1. Saeedi BJ, Kao DJ, Kitzenberg DA, Dobrinskikh E, Schwisow KD, Masterson JC, Kendrick AA, Kelly CJ, Bayless AJ, Kominsky DJ, Campbell EL, Kuhn KA, Furuta GT, Colgan SP, Glover LE. HIF-dependent regulation of claudin-1 is central to intestinal epithelial tight junction integrity. Mol Biol Cell. 2015;26:2252–2262.
1. El Aidy S, van Baarlen P, Derrien M, Lindenbergh-Kortleve DJ, Hooiveld G, Levenez F, Dore J, Dekker J, Samsom JN, Nieuwenhuis EE, Kleerebezem M. Temporal and spatial interplay of microbiota and intestinal mucosa drive establishment of immune homeostasis in conventionalized mice. Mucosal Immunol. 2012;5:567–579.
1. El Aidy S, Derrien M, Merrifield CA, Levenez F, Dore J, Boekschoten MV, Dekker J, Holmes E, Zoetendal EG, van Baarlen P, Claus SP, Kleerebezem M. Gut bacteria-host metabolic interplay during conventionalisation of the mouse germfree colon. ISME J. 2013;7:743–755.
1. El Aidy S, Merrifield CA, Derrien M, van Baarlen P, Hooiveld G, Levenez F, Dore J, Dekker J, Holmes E, Claus SP, Reijngoud DJ, Kleerebezem M. The gut microbiota elicits a profound metabolic reorientation in the mouse jejunal mucosa during conventionalisation. Gut. 2013;62:1306–1314.
1. Garrett WS, Gordon JI, Glimcher LH. Homeostasis and inflammation in the intestine. Cell. 2010;140:859–870.
1. Honda K, Littman DR. The microbiome in infectious disease and inflammation. Annu Rev Immunol. 2012;30:759–795.
1. McGuckin MA, Eri R, Simms LA, Florin TH, Radford-Smith G. Intestinal barrier dysfunction in inflammatory bowel diseases. Inflamm Bowel Dis. 2009;15:100–113.
1. Ploger S, Stumpff F, Penner GB, Schulzke JD, Gabel G, Martens H, Shen Z, Gunzel D, Aschenbach JR. Microbial butyrate and its role for barrier function in the gastrointestinal tract. Ann N Y Acad Sci. 2012;1258:52–59.
1. Chang PV, Hao L, Offermanns S, Medzhitov R. The microbial metabolite butyrate regulates intestinal macrophage function via histone deacetylase inhibition. Proc Natl Acad Sci U S A. 2014;111:2247–2252.
1. Fraga MF, Herranz M, Espada J, Ballestar E, Paz MF, Ropero S, Erkek E, Bozdogan O, Peinado H, Niveleau A, Mao JH, Balmain A, Cano A, Esteller M. A mouse skin multistage carcinogenesis model reflects the aberrant DNA methylation patterns of human tumors. Cancer research. 2004;64:5527–5534.
1. Glocker EO, Kotlarz D, Boztug K, Gertz EM, Schaffer AA, Noyan F, Perro M, Diestelhorst J, Allroth A, Murugan D, Hatscher N, Pfeifer D, Sykora KW, Sauer M, Kreipe H, Lacher M, Nustede R, Woellner C, Baumann U, Salzer U, Koletzko S, Shah N, Segal AW, Sauerbrey A, Buderus S, Snapper SB, Grimbacher B, Klein C. Inflammatory bowel disease and mutations affecting the interleukin-10 receptor. The New England journal of medicine. 2009;361:2033–2045.
1. Lees CW, Barrett JC, Parkes M, Satsangi J. New IBD genetics: common pathways with other diseases. Gut. 2011;60:1739–1753.
1. Xavier RJ, Podolsky DK. Unravelling the pathogenesis of inflammatory bowel disease. Nature. 2007;448:427–434.
1. Waldecker M, Kautenburger T, Daumann H, Busch C, Schrenk D. Inhibition of histone-deacetylase activity by short-chain fatty acids and some polyphenol metabolites formed in the colon. The Journal of nutritional biochemistry. 2008;19:587–593.
1. Marshall S, Duong T, Wu T, Hering MA, Yada J, Higgins S, Orbus RJ, Yan ZH, Rumberger JM. Enhanced expression of uridine diphosphate-N-acetylglucosaminyl transferase (OGT) in a stable, tetracycline-inducible HeLa cell line using histone deacetylase inhibitors: kinetics of cytosolic OGT accumulation and nuclear translocation. Anal Biochem. 2003;319:304–313.
1. Colgan SP, Hershberg RM, Furuta GT, Blumberg RS. Ligation of intestinal epithelial CD1d induces bioactive IL-10: critical role of the cytoplasmic tail in autocrine signaling. Proc Natl Acad Sci U S A. 1999;96:13938–13943.
1. Nagalakshmi ML, Rascle A, Zurawski S, Menon S, de Waal Malefyt R. Interleukin-22 activates STAT3 and induces IL-10 by colon epithelial cells. International immunopharmacology. 2004;4:679–691.
1. Olszak T, Neves JF, Dowds CM, Baker K, Glickman J, Davidson NO, Lin CS, Jobin C, Brand S, Sotlar K, Wada K, Katayama K, Nakajima A, Mizuguchi H, Kawasaki K, Nagata K, Muller W, Snapper SB, Schreiber S, Kaser A, Zeissig S, Blumberg RS. Protective mucosal immunity mediated by epithelial CD1d and IL-10. Nature. 2014;509:497–502.
1. Demont A, Hacini-Rachinel F, Doucet-Ladeveze R, Ngom-Bru C, Mercenier A, Prioult G, Blanchard C. Live and heat-treated probiotics differently modulate IL10 mRNA stabilization and microRNA expression. J Allergy Clin Immunol. 2016;137:1264–1267.
1. Moens F, Verce M, De Vuyst L. Lactate- and acetate-based cross-feeding interactions between selected strains of lactobacilli, bifidobacteria and colon bacteria in the presence of inulin-type fructans. Int J Food Microbiol. 2017;241:225–236.
1. Huang H, Liu JQ, Yu Y, Mo LH, Ge RT, Zhang HP, Liu ZG, Zheng PY, Yang PC. Regulation of TWIK-related potassium channel-1 (Trek1) restitutes intestinal epithelial barrier function. Cell Mol Immunol. 2016;13:110–118.
1. Anderson JM, Van Itallie CM. Physiology and function of the tight junction. Cold Spring Harb Perspect Biol. 2009;1:a002584.
1. Valenzano MC, DiGuilio K, Mercado J, Teter M, To J, Ferraro B, Mixson B, Manley I, Baker V, Moore BA, Wertheimer J, Mullin JM. Remodeling of Tight Junctions and Enhancement of Barrier Integrity of the CACO-2 Intestinal Epithelial Cell Layer by Micronutrients. PLoS One. 2015;10:e0133926.
1. Capaldo CT, Nusrat A. Claudin switching: Physiological plasticity of the Tight Junction. Semin Cell Dev Biol. 2015;42:22–29.
1. Leonel AJ, Teixeira LG, Oliveira RP, Santiago AF, Batista NV, Ferreira TR, Santos RC, Cardoso VN, Cara DC, Faria AM, Alvarez-Leite J. Antioxidative and immunomodulatory effects of tributyrin supplementation on experimental colitis. Br J Nutr. 2013;109:1396–1407.

Source: PubMed

Microbial-Derived Butyrate Promotes Epithelial Barrier Function through IL-10 Receptor-Dependent Repression of Claudin-2

Abstract

Conflict of interest statement

Figures

References

Sponzoři a spolupracovníci

Zdravotní podmínky

Drogové intervence