Procyanidin C1 Modulates the Microbiome to Increase FOXO1 Signaling and Valeric Acid Levels to Protect the Mucosal Barrier in Inflammatory Bowel Disease

Xifan Wang, Pengjie Wang, Yixuan Li, Huiyuan Guo, Ran Wang, Siyuan Liu, Ju Qiu, Xiaoyu Wang, Yanling Hao, Yunyi Zhao, Haiping Liao, Zhongju Zou, Josephine Thinwa, Rong Liu

Engineering ›› 2024, Vol. 42 ›› Issue (11) : 108-120.

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Engineering ›› 2024, Vol. 42 ›› Issue (11) : 108-120. DOI: 10.1016/j.eng.2023.10.016
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Procyanidin C1 Modulates the Microbiome to Increase FOXO1 Signaling and Valeric Acid Levels to Protect the Mucosal Barrier in Inflammatory Bowel Disease

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Abstract

Inflammatory bowel disease (IBD) refers to a pair of prevalent conditions (Crohn’s disease and ulcerative colitis) distinguished by persistent inflammation of the large intestine. Procyanidin C1 (PCC1) is a naturally occurring substance derived from grape seeds that has demonstrated notable anti-inflammatory properties. This study examines the potential utility of PCC1 as a treatment for IBD and subsequently examines the host-cell- and microbiome-related mechanisms underlying the detected therapeutic benefits. Working with a classic dextran sodium sulfate (DSS)-induced mouse IBD model, we show that PCC1 protects the mucosal barrier and thereby confers strong protective effects against IBD. PCC1 pretreatment resulted in anti-inflammatory effects and protection against multiple pathological phenotypes in the IBD model mice, including reduced weight loss, lower disease activity index (DAI) totals, and enhanced colon size, as well as obviously beneficial effects on the mucosal barrier (e.g., barrier thickness and activity of mucus-degrading enzymes). We also analyzed the autophagy marker microtubule- associated protein1 light chain 3 (LC3) and found that the level of LC3 was significantly elevated in the intestinal epithelial cell samples of the PCC1-pretreatment group as compared with the non-model mice samples. PCC1 altered the fecal microbiome composition, which included elevating the abundance of Akkermansia muciniphila and Christensenella minuta. Fecal microbiome transplant (FMT) experiments showed that delivering a microbiome from PCC1-treated animals into PCC1-naïve animals conferred protection. Metabolic profiling revealed that both the PCC1-pretreatment and PCC1 FMT groups had elevated levels of the microbiota-derived metabolite valeric acid, and supplementation with this short-chain fatty acid (SCFA) also conferred strong protection against IBD. Finally, inhibitor experiments confirmed that the beneficial effects of valeric acid on the mucus layer are mediated by FOXO1 signaling in the goblet cells of the intestinal epithelium. Beyond showing that PCC1 confers anti-inflammatory effects and protection against IBD by altering the microbiome, our study demonstrates proof of principle for multiple straightforward interventions (PCC1, FMT, and valeric acid supplementation) for ameliorating mucosal barrier damage to treat IBD.

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Inflammatory bowel disease / Mucosal Barrier / Autophagy

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Xifan Wang, Pengjie Wang, Yixuan Li, Huiyuan Guo, Ran Wang, Siyuan Liu, Ju Qiu, Xiaoyu Wang, Yanling Hao, Yunyi Zhao, Haiping Liao, Zhongju Zou, Josephine Thinwa, Rong Liu. Procyanidin C1 Modulates the Microbiome to Increase FOXO1 Signaling and Valeric Acid Levels to Protect the Mucosal Barrier in Inflammatory Bowel Disease. Engineering, 2024, 42(11): 108‒120 https://doi.org/10.1016/j.eng.2023.10.016

References

Publishing order | Descend order by publishing year | Descend order by cited within
[1]
D.C. Rubin, A. Shaker, M.S. Levin. Chronic intestinal inflammation: inflammatory bowel disease and colitis-associated colon cancer. Front Immunol, 3 (2012), p. 107
[2]
Y. Kang, H. Park, B.H. Choe, B. Kang. The role and function of mucins and its relationship to inflammatory bowel disease. Front Med, 9 (2022), p. 848344
[3]
H.A. McCauley, G. Guasch. Three cheers for the goblet cell: maintaining homeostasis in mucosal epithelia. Trends Mol Med, 21 (8) (2015), pp. 492-503
[4]
R. Bansil, B.S. Turner. The biology of mucus: composition, synthesis and organization. Adv Drug Deliv Rev, 124 (2018), pp. 3-15
[5]
M. Zarepour, K. Bhullar, M. Montero, C. Ma, T. Huang, A. Velcich, et al. The mucin MUC 2 limits pathogen burdens and epithelial barrier dysfunction during Salmonella enterica serovar typhimurium colitis. Infect Immun, 81 (10) (2013), pp. 3672-3683
[6]
S.K. Linden, P. Sutton, N.G. Karlsson, V. Korolik, M.A. McGuckin. Mucins in the mucosal barrier to infection. Mucosal Immunol, 1 (3) (2008), pp. 183-197
[7]
P. Paone, P.D. Cani. Mucus barrier, mucins and gut microbiota: the expected slimy partners?. Gut, 69 (12) (2020), pp. 2232-2243
[8]
K. Hou, Z.X. Wu, X.Y. Chen, J.Q. Wang, D. Zhang, C. Xiao, et al. Microbiota in health and diseases. Signal Transduct Target Ther, 7 (1) (2022), p. 135
[9]
J.K. Triantafillidis, E. Merikas, F. Georgopoulos. Current and emerging drugs for the treatment of inflammatory bowel disease. Drug Des Devel Ther, 5 (2011), pp. 185-210
[10]
J. Lopez, A. Grinspan. Fecal microbiota transplantation for inflammatory bowel disease. Gastroenterol Hepatol, 12 (6) (2016), pp. 374-379
[11]
C. González-Quilen, E. Rodríguez-Gallego, R. Beltrán-Debón, M. Pinent, A. Ardévol, M.T. Blay, et al. Health-promoting properties of proanthocyanidins for intestinal dysfunction. Nutrients, 12 (1) (2020), p. 130
[12]
J. Zhao, J. Wang, Y. Chen, R. Agarwal.Anti-tumor-promoting activity of a polyphenolic fraction isolated from grape seeds in the mouse skin two-stage initiation-promotion protocol and identification of procyanidinB5-3 ′-gallate as the most effective antioxidant constituent. Carcinogenesis, 20 (9) (1999), pp. 1737-1745
[13]
L. Wang, Y. Yamashita, S. Komeda, A. Saito, H. Ashida. Absorption, metabolism, distribution and faecal excretion of B-type procyanidin oligomers in mice after a single oral administration of black soybean seed coat extract. Food Funct, 9 (10) (2018), pp. 5362-5370
[14]
K. Kawabata, Y. Yoshioka, J. Terao. Role of intestinal microbiota in the bioavailability and physiological functions of dietary polyphenols. Molecules, 24 (2) (2019), p. 370
[15]
Y. Shi, H. Zhang, S. Li, D. Xin, S. Li, B. Yan, et al. Procyanidin improves experimental colitis by regulating macrophage polarization. Biomed Pharmacother, 165 (2023), p. 115076
[16]
H. Zhang, W. Lang, X. Liu, J. Bai, Q. Jia, Q. Shi. Procyanidin A1 alleviates DSS-induced ulcerative colitis via regulating AMPK/mTOR/p70S6K-mediated autophagy. J Physiol Biochem, 78 (1) (2022), pp. 213-227
[17]
X. Zhu, X. Tian, M. Yang, Y. Yu, Y. Zhou, Y. Gao, et al. Procyanidin B 2 promotes intestinal injury repair and attenuates colitis-associated tumorigenesis via suppression of oxidative stress in mice. Antioxid Redox Signal, 35 (2) (2021), pp. 75-92
[18]
H. Zhong, Y. Xue, X. Lu, Q. Shao, Y. Cao, Z. Wu, et al. The effects of different degrees of procyanidin polymerization on the nutrient absorption and digestive enzyme activity in mice. Molecules, 23 (11) (2018), p. 2916
[19]
N.Y. Sung, M.S. Yang, D.S. Song, E.B. Byun, J.K. Kim, J.H. Park, et al. The procyanidin trimer C1 induces macrophage activation via NF-κB and MAPK pathways, leading to Th1 polarization in murine splenocytes. Eur J Pharmacol, 714 (1-3) (2013), pp. 218-228
[20]
W. Xiao, J. Su, X. Gao, H. Yang, R. Weng, W. Ni, et al. The microbiota-gut-brain axis participates in chronic cerebral hypoperfusion by disrupting the metabolism of short-chain fatty acids. Microbiome, 10 (1) (2022), pp. 1-27
[21]
B. Chassaing, B. Chassaing, J.D. Aitken, M. Malleshappa, M. Vijay-Kumar. Dextran sulfate sodium DSS-induced colitis in mice. J.E. Coligan, A.M. Kruisbeek, D.H. Margulies, E.M. Shevach, W. Strober (Eds.), Current protocols in immunology, 104, Greene Publishing Associates and Wiley InterScience, New York City (2014), pp. 15-25
[22]
Y.H. Park, N. Kim, Y.K. Shim, Y.J. Choi, R.H. Nam, Y.J. Choi, et al. Adequate dextran sodium sulfate-induced colitis model in mice and effective outcome measurement method. J Cancer Prev, 20 (4) (2015), pp. 260-267
[23]
K.A. Papadakis, S.R. Targan. Role of cytokines in the pathogenesis of inflammatory bowel disease. Annu Rev Med, 51 (1) (2000), pp. 289-298
[24]
J.R. Turner. Intestinal mucosal barrier function in health and disease. Nat Rev Immunol, 9 (11) (2009), pp. 799-809
[25]
M.E. Johansson, M. Phillipson, J. Petersson, A. Velcich, L. Holm, G.C. Hansson. The inner of the two MUC2 mucin-dependent mucus layers in colon is devoid of bacteria. Proc Natl Acad Sci, 105 (39) (2008), pp. 15064-15069
[26]
P. Kiesler, I.J. Fuss, W. Strober. Experimental models of inflammatory bowel diseases. Cell Mol Gastroenterol Hepatol, 1 (2) (2015), pp. 154-170
[27]
L. Antoni, S. Nuding, J. Wehkamp, E. Stange. Intestinal barrier in inflammatory bowel disease. World J Gastroenterol, 20 (5) (2014), pp. 1165-1179
[28]
M. Van der Sluis, B.A.E. De Koning, A.C.J.M. De Bruijn, A. Velcich, J.P.P. Meijerink, J.B. Van Goudoever, et al. MUC2-deficient mice spontaneously develop colitis, indicating that MUC 2 is critical for colonic protection. Gastroenterology, 131 (1) (2006), pp. 117-129
[29]
K.O. Danquah, E. Adjei, S. Quayson, E. Adankwah, D. Gyamfi, P.P. Sampene, et al. Mucin expression patterns in histological grades of colonic cancers in Ghanaian population. Pan Afr Med J, 27 (2017), p. 267
[30]
L.E. Tailford, E.H. Crost, D. Kavanaugh, N. Juge. Mucin glycan foraging in the human gut microbiome. Front Genet, 6 (2015), p. 81
[31]
Z. Chen, J. Luo, J. Li, G. Kim, E.S. Chen, S. Xiao, et al.. FOXO 1 controls gut homeostasis and commensalism by regulating mucus secretion. J Exp Med, 218 (9) (2021), p. e20210324
[32]
M.J. Cires, M.J. Cires, X. Wong, C. Carrasco-Pozo, M. Gotteland. The gastrointestinal tract as a key target organ for the health-promoting effects of dietary proanthocyanidins. Front Nutr, 3 (2016), p. 57
[33]
A. Lo Presti, F. Zorzi, F. Del Chierico, A. Altomare, S. Cocca, A. Avola, et al. Fecal and mucosal microbiota profiling in irritable bowel syndrome and inflammatory bowel disease. Front Microbiol, 10 (2019), p. 1655
[34]
M.C. Kullberg, J.F. Andersen, P.L. Gorelick, P. Caspar, S. Suerbaum, J.G. Fox, et al. Induction of colitis by a CD4+ T cell clone specific for a bacterial epitope. Proc Natl Acad Sci, 100 (26) (2003), pp. 15830-15835
[35]
S. Gupta, E. Allen-Vercoe, E.O. Petrof. Fecal microbiota transplantation: in perspective. Therap Adv Gastroenterol, 9 (2) (2016), pp. 229-239
[36]
C. Stolfi, C. Maresca, G. Monteleone, F. Laudisi. Implication of intestinal barrier dysfunction in gut dysbiosis and diseases. Biomedicines, 10 (2) (2022), p. 289
[37]
Q. Zhao, J. Yu, Y. Hao, H. Zhou, Y. Hu, C. Zhang, et al. Akkermansia muciniphila plays critical roles in host health. Crit Rev Microbiol, 49 (1) (2023), pp. 82-100
[38]
Y. Li, J. Dong, H. Xiao, S. Zhang, B. Wang, M. Cui, et al. Gut commensal derived-valeric acid protects against radiation injuries. Gut Microbes, 11 (4) (2020), pp. 789-806
[39]
X. Bian, W. Wu, L. Yang, L. Lv, Q. Wang, Y. Li, et al. Administration of Akkermansia muciniphila ameliorates dextran sulfate sodium-induced ulcerative colitis in mice. Front Microbiol, 10 (2019), p. 2259
[40]
C.S. Kang, M. Ban, E.J. Choi, H.G. Moon, J.S. Jeon, D.K. Kim, et al. Extracellular vesicles derived from gut microbiota, especially Akkermansia muciniphila, protect the progression of dextran sulfate sodium-induced colitis. PLoS One, 8 (10) (2013), p. e76520
[41]
B. Shuoker, M.J. Pichler, C. Jin, H. Sakanaka, H. Wu, A.M. Gascueña, et al. Sialidases and fucosidases of Akkermansia muciniphila are crucial for growth on mucin and nutrient sharing with mucus-associated gut bacteria. Nat Commun, 14 (1) (2023), p. 1833
[42]
M.J. Liu, J.Y. Yang, Z.H. Yan, S. Hu, J.Q. Li, Z.X. Xu, et al. Recent findings in Akkermansia muciniphila-regulated metabolism and its role in intestinal diseases. Clin Nutr, 41 (10) (2022), pp. 2333-2344
[43]
C. Bárcena, R. Valdés-Mas, P. Mayoral, C. Garabaya, S. Durand, F. Rodríguez, et al. Healthspan and lifespan extension by fecal microbiota transplantation into progeroid mice. Nat Med, 25 (8) (2019), pp. 1234-1242
[44]
J. Kalabis, I. Rosenberg, D.K. Podolsky. Vangl 1 protein acts as a downstream effector of intestinal trefoil factor (ITF)/TFF3 signaling and regulates wound healing of intestinal epithelium. J Biol Chem, 281 (10) (2006), pp. 6434-6441
[45]
W.S. Ang, J.W.F. Law, V. Letchumanan, K.W. Hong, S.H. Wong, N.S. Ab Mutalib, et al. A keystone gut bacterium Christensenella minuta—a potential biotherapeutic agent for obesity and associated metabolic diseases. Foods, 12 (13) (2023), p. 2485
[46]
C. Li, Y. Zhao, J. Cheng, J. Guo, Q. Zhang, X. Zhang, et al. A proresolving peptide nanotherapy for site-specific treatment of inflammatory bowel disease by regulating proinflammatory microenvironment and gut microbiota. Adv Sci, 6 (18) (2019), p. 1900610
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