發炎性腸道疾病 (inflammatory bowel disease, IBD)是一種慢性、反覆性的腸道發炎性疾病。先前研究發現，自山苦瓜 (學名: Momordica charantia Linn. var. abbreviata
Ser.)葉片乙醇萃取物中，分離得到的富含三萜類區分萃取物 (triterpenoid-enriched extract, TEE)，可藉由調控輔助型T細胞 (helper T cells)和調節型T細胞 (regulatory T cells)，預防性緩解葡聚糖硫酸鈉 (dextran sulfate sodium, DSS)誘導小鼠急性腸炎的發炎反應，因此本研究欲進一步探討TEE是否具有治療或預防慢性腸炎的功用。本研究共進行兩次動物實驗，分述於下：
實驗一為模擬治療模式，先連續7天給予C57BL/6J小鼠含有3% DSS飲水誘導腸炎後，於飼料中添加TEE (攝取劑量為100 mg/kg BW)或苦瓜葉粉末 (bitter melon leaf powder, BMLP；攝取劑量為1g/kg)持續餵食14天後犧牲，實驗期間每日紀錄體重變化，並於實驗結束後記錄器官重量，以及分析脾臟中免疫細胞與腸炎相關基因表現。實驗結果發現給予TEE或BMLP組與單獨給予DSS誘導組比較，給予TEE或BMLP並未顯著影響小鼠體重與器官重量變化、脾臟T細胞分化、腸炎相關基因和組織發炎評分，因此推斷TEE和BMLP在此劑量與實驗模式下，並無治療慢性腸炎的功效。
實驗二為模擬預防模式先投與TEE，觀察TEE對於DSS誘導腸炎的急性後期與慢性期的影響。將C57BL/6J小鼠分為一般控制組 (NC組)、DSS誘導組 (DC組)、DSS+低劑量TEE (攝取劑量為100 mg/kg BW；DL組)與DSS+高劑量TEE (攝取劑量為150 mg/kg BW；DH組)。在DSS誘導腸炎前，先給予一周TEE，並分別於3% DSS誘導腸炎後第14天(急性後期)與第21天(慢性期)犧牲動物，從大腸組織切片觀察發現，與DC組比較，TEE組的組織發炎評分較低、腸道上皮結構較完整、以及嗜中性白血球的浸潤程度較低，且分杯狀細胞數量與分泌的黏液較多。由qPCR分析結果發現於誘導腸炎急性後期，給予TEE能提高大腸組織的MUC (mucin)2、ZO-1 (zonula occludens-1)、Occludin與Claudin-2 mRNA表現量，而大腸組織的MUC1、MUC4、TNF-α (tumor necrosis factor-α)、IL (interleukin)-1β與CXCL1 (chemokine (CXC motif) ligand) mRNA表現量也被TEE所抑制。於誘導腸炎慢性期時，TEE能降低大腸組織的TFF (trefoil factors)3、MUC4、TNF-α、IL-1β與CXCL1 mRNA表現量，並增加杯狀細胞數量與MUC2 mRNA的表現量。以上證據顯示TEE在大腸組織微環境具有預防性保護腸炎的效果。由流式細胞儀分析，結果發現TEE對於血液與脾臟之單核球、嗜中性球與T細胞分布並沒有顯著影響。綜合上述結果，推論TEE於大腸微環境中透過減少嗜中性白血球浸潤、減少促發炎因子、增加黏液與維持腸道屏障完整，而具有預防性保護慢性腸炎的作用。

Inflammatory bowel disease (IBD) is a chronically recurrent inflammatory disturbance in gastrointestinal tract, clinically characterized as Crohn’s disease and ulcerative colitis. Our previous study demonstrated that the protective effects of triterpenoid enriched-extract (TEE) of wild bitter melon (WBM; Momordica charantia L.var.abbreviata Seringe) leaf in mitigating dextran sulfate sodium (DSS)-induced acute colitis by regulating Th/Treg-mediated immunity and inflammatory responses. In this study, we investigated the preventive and therapeutic effects of TEE on chronic colitis in DSS-treated mice. This study consisted of two independent experiments as follows.
In Experiment I, C57BL/6 mice were randomly divided into four groups: one normal control (NC) group and four DSS-treated groups, including DSS group (colitis model), DT group (DSS+ 82.4 mg/kg BW of TEE), and DP group (DSS + 804.7 mg/kg BW of bitter melon leaf powder (BMLP)). The DSS-treated groups drank distilled water containing 3.5% DSS for 7 d to induce colitis before TEE or BMLP administrations, while NC group drank distilled water. DT and DP groups was respectively administrated with AIN-93 diet containing TEE (100 mg/kg diet) and BMLP (1g/kg diet) for 14 days. Our results showed that either post-treatments of TEE or BMLP did not significantly affect body weight, colon shortening, organ weight, spleen T cell population, and inflammation-related factors. These data suggested that post-treatments of TEE or BMLP did not possess the beneficial effects on alleviating chronic colitis.
In Experiment II, C57BL/6 mice were randomly divided into four groups: one normal control (NC) group and four DSS-treated groups, including DSS group (colitis model), DL group (DSS+ 100 mg/kg BW of TEE), and DH group (DSS+150 mg/kg BW of TEE). The DSS-treated groups drank distilled water containing 3% DSS for 7 days to induce colitis, while NC group drank distilled water. DL and DH groups was administrated TEE supplemented to an AIN-93 diet for 7 days before DSS-induced colitis and subsequently received TEE supplemented to an AIN-93 diet after DSS-induced colitis for 14 days (late-acute phase) and 21 days (chronic phase). Results from H&E staining of colonic tissue disclosed the distinct pathological changes upon DSS treatment, including serious epithelial disruption, inflammatory cells infiltration, and obvious decreased goblet cell number, whereas TEE led to improvements of these pathological changes. These results suggested that TEE could protect the colonic tissue from the DSS-induced damage. Next, we evaluated the mRNA levels of colonic pro-inflammatory cytokines by qPCR analysis. We found that TEE administration up-regulated MUC (mucin)2, ZO-1 (zonula occludens-1), occludin and claudin-2 mRNA levels and down-regulated colonic MUC1, MUC4, TNF-α (tumor necrosis factor-α), IL (interleukin)-1β and CXCL (chemokine (CXC motif) ligand)1 mRNA levels on Day-14. In addition, TEE administration inhibited DSS-induced TFF3 (trefoil factors), MUC4, TNF-α, IL-1β, and CXCL1 mRNA levels of colon tissue and elevated colonic goblet cells and MUC2 mRNA level on Day-21. The evidence suggested the pre-treatment of TEE exerted the protective role in attenuating chronic colitis. However, the results of flow cytometry assay showed that TEE had no influence on the proportions of monocytes, neutrophils, and Tregs in blood or spleen.
IBD has been associated with mucus producing deficiency and decreased goblet cell number. These results revealed that TEE supplement may contribute to the management of colonic inflammation via regulation of neutrophils, decreasing pro-inflammatory cytokine, upregulating mucin, and improving epithelial barrier defectsin in colonic microenvironment. In conclusion, our results suggested that the preventive treatment of TEE plays a protective role of the mucosal layer in maintaining intestinal health.

全中和，(2008)。山苦瓜種源蒐集與利用。農業生技產業應用研討會專輯。21- 28。
全中和，(2008)。苦瓜新品種花蓮3號之育成。花蓮區農業改良場研究彙報。53-62。
陳巧紋，(2019)。山苦瓜葉萃取物對葡聚醣硫酸鈉誘導小鼠腸炎的保護效應與免疫調節之影響。國立臺灣師範大學人類發展與家庭學系碩士論文。未出版。
Abraham, B., & Quigley, E. M. M. (2020). Antibiotics and probiotics in inflammatory bowel disease: when to use them? Frontline gastroenterology, 11(1), 62-69.
Ahmad, R., Chaturvedi, R., Olivares-Villagómez, D., Habib, T., Asim, M., Shivesh, P., . . . Singh, A. B. (2014). Targeted colonic claudin-2 expression renders resistance to epithelial injury, induces immune suppression, and protects from colitis. Mucosal immunology, 7(6), 1340-1353.
Anderson, J. M., & Van Itallie, C. M. (2009). Physiology and function of the tight junction. Cold Spring Harbor perspectives in biology, 1(2), a002584-a002584.
Atuma, C., Strugala, V., Allen, A., & Holm, L. (2001). The adherent gastrointestinal mucus gel layer: thickness and physical state in vivo. Am J Physiol Gastrointest Liver Physiol, 280(5), G922-929.
Bain, C. C., Bravo-Blas, A., Scott, C. L., Perdiguero, E. G., Geissmann, F., Henri, S., . . . Mowat, A. M. (2014). Constant replenishment from circulating monocytes maintains the macrophage pool in the intestine of adult mice. Nat Immunol, 15(10), 929-937.
Bankole, E., Read, E., Curtis, M. A., Neves, J. F., & Garnett, J. A. (2021). The Relationship between Mucins and Ulcerative Colitis: A Systematic Review. J Clin Med, 10(9).
Baral, S., Raja, R., Sen, P., & Dixit, N. M. (2019). Towards multiscale modeling of the CD8(+) T cell response to viral infections. Wiley interdisciplinary reviews. Systems biology and medicine, 11(4), e1446-e1446.
Bengtson, May-Bente, Geir Aamodt, Morten H. Vatn, Jennifer R. Harris, Concordance for IBD among twins compared to ordinary siblings — A Norwegian population-based study, Journal of Crohn's and Colitis, Volume 4, Issue 3, September 2010, 312–318.
Bennike, T. B., Carlsen, T. G., Ellingsen, T., Bonderup, O. K., Glerup, H., Bøgsted, M., . . . Andersen, V. (2015). Neutrophil Extracellular Traps in Ulcerative Colitis: A Proteome Analysis of Intestinal Biopsies. Inflammatory bowel diseases, 21(9), 2052-2067.
Bernardo, D., Marin, A. C., Fernández-Tomé, S., Montalban-Arques, A., Carrasco, A., Tristán, E., . . . Gisbert, J. P. (2018). Human intestinal pro-inflammatory CD11c(high)CCR2(+)CX3CR1(+) macrophages, but not their tolerogenic CD11c(-)CCR2(-)CX3CR1(-) counterparts, are expanded in inflammatory bowel disease. Mucosal immunology, 11(4), 1114-1126.
Billmeier, U., Dieterich, W., Neurath, M. F., & Atreya, R. (2016). Molecular mechanism of action of anti-tumor necrosis factor antibodies in inflammatory bowel diseases. World journal of gastroenterology, 22(42), 9300-9313.
Binder, M. T., Becker, E., Wiendl, M., Schleier, L., Fuchs, F., Leppkes, M., . . . Zundler, S. (2018). Similar Inhibition of Dynamic Adhesion of Lymphocytes From IBD Patients to MAdCAM-1 by Vedolizumab and Etrolizumab-s. Inflammatory bowel diseases, 24(6), 1237-1250.
Boeltz, S., Amini, P., Anders, H.-J., Andrade, F., Bilyy, R., Chatfield, S., . . . Herrmann, M. (2019). To NET or not to NET:current opinions and state of the science regarding the formation of neutrophil extracellular traps. Cell death and differentiation, 26(3), 395-408.
Boschetti, G., Nancey, S., Moussata, D., Cotte, E., Francois, Y., Flourié, B., & Kaiserlian, D. (2016). Enrichment of Circulating and Mucosal Cytotoxic CD8+ T Cells Is Associated with Postoperative Endoscopic Recurrence in Patients with Crohn's Disease. Journal of Crohn's & colitis, 10(3), 338-345.
Britto, S. L., Krishna, M., & Kellermayer, R. (2019). Weight loss is a sufficient and economical single outcome measure of murine dextran sulfate sodium colitis. FASEB bioAdvances, 1(8), 493-497.
Chang, M.-L., Lin, Y.-T., Kung, H.-N., Hou, Y.-C., Liu, J.-J., Pan, M.-H., . . . Tsai, P.-J. (2021). A triterpenoid-enriched extract of bitter melon leaves alleviates hepatic fibrosis by inhibiting inflammatory responses in carbon tetrachloride-treated mice. Food & Function.
Chassaing, B., Aitken, J. D., Malleshappa, M., & Vijay-Kumar, M. (2014). Dextran sulfate sodium (DSS)-induced colitis in mice. Current protocols in immunology, 104, 15.25.11-15.25.14.
Chen, X., Li, M., Li, D., Luo, T., Xie, Y., Gao, L., . . . Lai, X. (2020). Ethanol extract of Pycnoporus sanguineus relieves the dextran sulfate sodium-induced experimental colitis by suppressing helper T cell-mediated inflammation via apoptosis induction. Biomedicine & Pharmacotherapy, 127, 110212.
Chi, H., Wang, D., Chen, M., Lin, J., Zhang, S., Yu, F., . . . Zou, Y. (2021). Shaoyao Decoction Inhibits Inflammation and Improves Intestinal Barrier Function in Mice With Dextran Sulfate Sodium-Induced Colitis. Frontiers in pharmacology, 12, 524287-524287.
Cortez-Navarrete, M., Martínez-Abundis, E., Pérez-Rubio, K. G., González-Ortiz, M., & Méndez-Del Villar, M. (2018). Momordica charantia Administration Improves Insulin Secretion in Type 2 Diabetes Mellitus. J Med Food, 21(7), 672-677.
Da Silva, A. P., Pollett, A., Rittling, S. R., Denhardt, D. T., Sodek, J., & Zohar, R. (2006). Exacerbated tissue destruction in DSS-induced acute colitis of OPN-null mice is associated with downregulation of TNF-alpha expression and non-programmed cell death. J Cell Physiol, 208(3), 629-639.
Daniluk, J., Daniluk, U., Reszec, J., Rusak, M., Dabrowska, M., & Dabrowski, A. (2017). Protective effect of cigarette smoke on the course of dextran sulfate sodium-induced colitis is accompanied by lymphocyte subpopulation changes in the blood and colon. International journal of colorectal disease, 32(11), 1551-1559.
Das, S., Rachagani, S., Sheinin, Y., Smith, L. M., Gurumurthy, C. B., Roy, H. K., & Batra, S. K. (2016). Mice deficient in Muc4 are resistant to experimental colitis and colitis-associated colorectal cancer. Oncogene, 35(20), 2645-2654.
Deng, Q., Chen, H., Liu, Y., Xiao, F., Guo, L., Liu, D., . . . Shi, M. (2016). Psychological stress promotes neutrophil infiltration in colon tissue through adrenergic signaling in DSS-induced colitis model. Brain, Behavior, and Immunity, 57, 243-254.
Eden, K. (2019). Adoptive Transfer Colitis. Methods Mol Biol, 1960, 207-214.
Eichele, D. D., & Kharbanda, K. K. (2017). Dextran sodium sulfate colitis murine model: An indispensable tool for advancing our understanding of inflammatory bowel diseases pathogenesis. World journal of gastroenterology, 23(33), 6016-6029.
Esensten, J. H., Muller, Y. D., Bluestone, J. A., & Tang, Q. (2018). Regulatory T-cell therapy for autoimmune and autoinflammatory diseases: The next frontier. Journal of Allergy and Clinical Immunology, 142(6), 1710-1718.
Fan, M., Kim, E.-K., Choi, Y.-J., Tang, Y., & Moon, S.-H. (2019). The Role of Momordica charantia in Resisting Obesity. International journal of environmental research and public health, 16(18), 3251.
Meier, T. M., Jørgensen, P. B., Niss, K., Rubin, S. J. S., Mörbe, U. M., Riis, L. B., . . . Agace, W. W. (2020). Immune Profiling of Human Gut-Associated Lymphoid Tissue Identifies a Role for Isolated Lymphoid Follicles in Priming of Region-Specific Immunity. Immunity, 52(3), 557-570.e556.
Feuerstein, J. D., Isaacs, K. L., Schneider, Y., Siddique, S. M., Falck-Ytter, Y., Singh, S., & Committee, A. G. A. I. C. G. (2020). AGA Clinical Practice Guidelines on the Management of Moderate to Severe Ulcerative Colitis. Gastroenterology, 158(5), 1450-1461.
Fritz, T., Niederreiter, L., Adolph, T., Blumberg, R. S., & Kaser, A. (2011). Crohn's disease: NOD2, autophagy and ER stress converge. Gut, 60(11), 1580-1588.
Fujimoto, K., Karuppuchamy, T., Takemura, N., Shimohigoshi, M., Machida, T., Haseda, Y., . . . Uematsu, S. (2011). A new subset of CD103+CD8alpha+ dendritic cells in the small intestine expresses TLR3, TLR7, and TLR9 and induces Th1 response and CTL activity. The Journal of Immunology, 186(11), 6287.
Gaglani, T., Davis, C. H., Bailey, H. R., & Cusick, M. V. (2019). Trends and Outcomes for Minimally Invasive Surgery for Inflammatory Bowel Disease. Journal of Surgical Research, 235, 303-307.
Gajendran, M., Loganathan, P., Catinella, A. P., & Hashash, J. G. (2018). A comprehensive review and update on Crohn's disease. Disease-a-Month, 64(2), 20-57.
Gajendran, M., Loganathan, P., Jimenez, G., Catinella, A. P., Ng, N., Umapathy, C., . . . Hashash, J. G. (2019). A comprehensive review and update on ulcerative colitis. Disease-a-Month, 65(12), 100851.
Gersemann, M., Becker, S., Kübler, I., Koslowski, M., Wang, G., Herrlinger, K. R., . . . Stange, E. F. (2009). Differences in goblet cell differentiation between Crohn's disease and ulcerative colitis. Differentiation, 77(1), 84-94.
Gordon, S., & Martinez, F. O. (2010). Alternative Activation of Macrophages: Mechanism and Functions. Immunity, 32(5), 593-604.
Guaní-Guerra, E., Santos-Mendoza, T., Lugo-Reyes, S. O., & Terán, L. M. (2010). Antimicrobial peptides: General overview and clinical implications in human health and disease. Clinical Immunology, 135(1), 1-11.
Hall, L. J., Faivre, E., Quinlan, A., Shanahan, F., Nally, K., & Melgar, S. (2011). Induction and Activation of Adaptive Immune Populations During Acute and Chronic Phases of a Murine Model of Experimental Colitis. Digestive Diseases and Sciences, 56(1), 79-89.
Hamamoto, N., Maemura, K., Hirata, I., Murano, M., Sasaki, S., & Katsu, K. (1999). Inhibition of dextran sulphate sodium (DSS)-induced colitis in mice by intracolonically administered antibodies against adhesion molecules (endothelial leucocyte adhesion molecule-1 (ELAM-1) or intercellular adhesion molecule-1 (ICAM-1)). Clinical and experimental immunology, 117(3), 462-468.
Hart, A. L., Al-Hassi, H. O., Rigby, R. J., Bell, S. J., Emmanuel, A. V., Knight, S. C., . . . Stagg, A. J. (2005). Characteristics of intestinal dendritic cells in inflammatory bowel diseases. Gastroenterology, 129(1), 50-65.
Hernández-Chirlaque, C., Aranda, C. J., Ocón, B., Capitán-Cañadas, F., Ortega-González, M., Carrero, J. J., . . . Martínez-Augustin, O. (2016). Germ-free and Antibiotic-treated Mice are Highly Susceptible to Epithelial Injury in DSS Colitis. J Crohns Colitis, 10(11), 1324-1335.
Hill, A. A., & Diehl, G. E. (2018). Identifying the Patterns of Pattern Recognition Receptors. Immunity, 49(3), 389-391.
Hovhannisyan, Z., Treatman, J., Littman, D. R., & Mayer, L. (2011). Characterization of interleukin-17-producing regulatory T cells in inflamed intestinal mucosa from patients with inflammatory bowel diseases. Gastroenterology, 140(3), 957-965.
Hsiung, Y.-C., Liu, J.-J., Hou, Y.-C., Yeh, C.-L., & Yeh, S.-L. (2014). Effects of dietary glutamine on the homeostasis of CD4+ T cells in mice with dextran sulfate sodium-induced acute colitis. PloS one, 9(1), e84410-e84410.
Huang, H.-M., Pai, M.-H., Yeh, S.-L., & Hou, Y.-C. (2020). Dietary exposure to chlorpyrifos inhibits the polarization of regulatory T cells in C57BL/6 mice with dextran sulfate sodium-induced colitis. Archives of Toxicology, 94(1), 141-150.
Huang, W. C., Tsai, T. H., Huang, C. J., Li, Y. Y., Chyuan, J. H., Chuang, L. T., & Tsai, P. J. (2015). Inhibitory effects of wild bitter melon leaf extract on Propionibacterium acnes-induced skin inflammation in mice and cytokine production in vitro. Food Funct, 6(8), 2550-2560.
Imdad, A., Nicholson, M. R., Tanner-Smith, E. E., Zackular, J. P., Gomez-Duarte, O. G., Beaulieu, D. B., & Acra, S. (2018). Fecal transplantation for treatment of inflammatory bowel disease. The Cochrane database of systematic reviews, 11(11), CD012774-CD012774.
Italiani, P., & Boraschi, D. (2014). From Monocytes to M1/M2 Macrophages: Phenotypical vs. Functional Differentiation. Frontiers in immunology, 5, 514-514.
Jiang, Z., Mu, W., Yang, Y., Sun, M., Liu, Y., Gao, Z., . . . Wang, H. (2020). Cadmium exacerbates dextran sulfate sodium-induced chronic colitis and impairs intestinal barrier. Science of The Total Environment, 744, 140844.
Johansson, M. E. V., & Hansson, G. C. (2016). Immunological aspects of intestinal mucus and mucins. Nature reviews. Immunology, 16(10), 639-649.
Jones, D. P., Richardson, T. G., Davey Smith, G., Gunnell, D., Munafò, M. R., & Wootton, R. E. (2020). Exploring the Effects of Cigarette Smoking on Inflammatory Bowel Disease Using Mendelian Randomization. Crohn's & colitis 360, 2(1), otaa018-otaa018.
Jones, G.-R., Bain, C. C., Fenton, T. M., Kelly, A., Brown, S. L., Ivens, A. C., . . . MacDonald, A. S. (2018). Dynamics of Colon Monocyte and Macrophage Activation During Colitis. Frontiers in immunology, 9, 2764.
Kadayakkara, D. K., Beatty, P. L., Turner, M. S., Janjic, J. M., Ahrens, E. T., & Finn, O. J. (2010). Inflammation driven by overexpression of the hypoglycosylated abnormal mucin 1 (MUC1) links inflammatory bowel disease and pancreatitis. Pancreas, 39(4), 510-515.
Khemiri, M., Doghri, R., Mrad, K., Friedrich, K., & Oueslati, R. (2019). Mucin-1 expression and localization in epithelial cells shows characteristic and distinct patterns in inflammatory bowel diseases and colorectal cancer. International journal of clinical and experimental pathology, 12(5), 1731-1737.
Kim, Y. S., & Ho, S. B. (2010). Intestinal goblet cells and mucins in health and disease: recent insights and progress. Current gastroenterology reports, 12(5), 319-330.
Kimura, M. Y., Hayashizaki, K., Tokoyoda, K., Takamura, S., Motohashi, S., & Nakayama, T. (2017). Crucial role for CD69 in allergic inflammatory responses: CD69-Myl9 system in the pathogenesis of airway inflammation. Immunological reviews, 278(1), 87-100.
Koboziev, I., Karlsson, F., & Grisham, M. B. (2010). Gut-associated lymphoid tissue, T cell trafficking, and chronic intestinal inflammation. Annals of the New York Academy of Sciences, 1207 Suppl 1(Suppl 1), E86-E93.
Leal, R. F., Planell, N., Kajekar, R., Lozano, J. J., Ordás, I., Dotti, I., . . . Salas, A. (2015). Identification of inflammatory mediators in patients with Crohn's disease unresponsive to anti-TNFα therapy. Gut, 64(2), 233.
Lee, S. H. (2015). Intestinal permeability regulation by tight junction: implication on inflammatory bowel diseases. Intestinal research, 13(1), 11-18.
Leung, S., Liu, X., Fang, L., Chen, X., Guo, T., & Zhang, J. (2010). The cytokine milieu in the interplay of pathogenic Th1/Th17 cells and regulatory T cells in autoimmune disease. Cell Mol Immunol, 7(3), 182-189.
Li, J., Ueno, A., Fort Gasia, M., Luider, J., Wang, T., Hirota, C., . . . Ghosh, S. (2016). Profiles of Lamina Propria T Helper Cell Subsets Discriminate Between Ulcerative Colitis and Crohn's Disease. Inflammatory bowel diseases, 22(8), 1779-1792.
Li, X., Tan, J., Zhang, F., Xue, Q., Wang, N., Cong, X., & Wang, J. (2019). H.pylori Infection Alleviates Acute and Chronic Colitis with the Expansion of Regulatory B Cells in Mice. Inflammation, 42(5), 1611-1621.
Lindén, S. K., Florin, T. H. J., & McGuckin, M. A. (2008). Mucin dynamics in intestinal bacterial infection. PloS one, 3(12), e3952-e3952.
Lissner, D., Schumann, M., Batra, A., Kredel, L. I., Kühl, A. A., Erben, U., . . . Siegmund, B. (2015). Monocyte and M1 Macrophage-induced Barrier Defect Contributes to Chronic Intestinal Inflammation in IBD. Inflammatory bowel diseases, 21(6), 1297-1305.
Liu, Q., Yu, Z., Tian, F., Zhao, J., Zhang, H., Zhai, Q., & Chen, W. (2020). Surface components and metabolites of probiotics for regulation of intestinal epithelial barrier. Microbial cell factories, 19(1), 23-23.
Luheshi, N., Davies, G., Poon, E., Wiggins, K., McCourt, M., & Legg, J. (2014). Th1 cytokines are more effective than Th2 cytokines at licensing anti-tumour functions in CD40-activated human macrophages in vitro. European journal of immunology, 44(1), 162-172.
Lycke, N. Y., & Bemark, M. (2017). The regulation of gut mucosal IgA B-cell responses: recent developments. Mucosal immunology, 10(6), 1361-1374.
Mahamat, O., Flora, H., Tume, C., & Kamanyi, A. (2020). Immunomodulatory Activity of Momordica charantia L. (Cucurbitaceae) Leaf Diethyl Ether and Methanol Extracts on Salmonella typhi-Infected Mice and LPS-Induced Phagocytic Activities of Macrophages and Neutrophils. Evid Based Complement Alternat Med, 2020, 5248346.
Mak, W. Y., Zhao, M., Ng, S. C., & Burisch, J. (2020). The epidemiology of inflammatory bowel disease: East meets west. J Gastroenterol Hepatol, 35(3), 380-389.
Marotto, D., Atzeni, F., Ardizzone, S., Monteleone, G., Giorgi, V., & Sarzi-Puttini, P. (2020). Extra-intestinal manifestations of inflammatory bowel diseases. Pharmacological Research, 161, 105206.
Martín, P., Gómez, M., Lamana, A., Cruz-Adalia, A., Ramírez-Huesca, M., Ursa, M. A., . . . Sánchez-Madrid, F. (2010). CD69 association with Jak3/Stat5 proteins regulates Th17 cell differentiation. Molecular and cellular biology, 30(20), 4877-4889.
McLeod, J. J. A., Baker, B., & Ryan, J. J. (2015). Mast cell production and response to IL-4 and IL-13. Cytokine, 75(1), 57-61.
Meier, D., Docena, G. H., Ramisch, D., Toscanini, U., Berardi, G., Gondolesi, G. E., & Rumbo, M. (2014). Immunological status of isolated lymphoid follicles after intestinal transplantation. Am J Transplant, 14(9), 2148-2158.
Melgar, S., Karlsson, A., & Michaëlsson, E. (2005). Acute colitis induced by dextran sulfate sodium progresses to chronicity in C57BL/6 but not in BALB/c mice: correlation between symptoms and inflammation. American Journal of Physiology-Gastrointestinal and Liver Physiology, 288(6), G1328-G1338.
Miossec, P., & Kolls, J. K. (2012). Targeting IL-17 and TH17 cells in chronic inflammation. Nat Rev Drug Discov, 11(10), 763-776.
Mitchell, A. J., Roediger, B., & Weninger, W. (2014). Monocyte homeostasis and the plasticity of inflammatory monocytes. Cellular Immunology, 291(1), 22-31.
Mizoguchi, A., & Mizoguchi, E. (2010). Animal models of IBD: linkage to human disease. Current opinion in pharmacology, 10(5), 578-587.
Moreira Lopes, T. C., Mosser, D. M., & Gonçalves, R. (2020). Macrophage polarization in intestinal inflammation and gut homeostasis. Inflamm Res, 69(12), 1163-1172.
Morgan, M. E., Zheng, B., Koelink, P. J., van de Kant, H. J. G., Haazen, L. C. J. M., van Roest, M., . . . Kraneveld, A. D. (2013). New perspective on dextran sodium sulfate colitis: antigen-specific T cell development during intestinal inflammation. PloS one, 8(7), e69936-e69936.
Muronga, M., Quispe, C., Tshikhudo, P. P., Msagati, T. A. M., Mudau, F. N., Martorell, M., . . . Sharifi-Rad, J. (2021). Three Selected Edible Crops of the Genus Momordica as Potential Sources of Phytochemicals: Biochemical, Nutritional, and Medicinal Values. Frontiers in pharmacology, 12, 625546-625546.
Nadeem, M. S., Kumar, V., Al-Abbasi, F. A., Kamal, M. A., & Anwar, F. (2020). Risk of colorectal cancer in inflammatory bowel diseases. Semin Cancer Biol, 64, 51-60.
Nancey, S., Holvöet, S., Graber, I., Joubert, G., Philippe, D., Martin, S., . . . Kaiserlian, D. (2006). CD8+ Cytotoxic T Cells Induce Relapsing Colitis in Normal Mice. Gastroenterology, 131(2), 485-496.
Nishida, A., Inoue, R., Inatomi, O., Bamba, S., Naito, Y., & Andoh, A. (2018). Gut microbiota in the pathogenesis of inflammatory bowel disease. Clinical Journal of Gastroenterology, 11(1), 1-10.
Nunes, N. S., Kim, S., Sundby, M., Chandran, P., Burks, S. R., Paz, A. H., & Frank, J. A. (2018). Temporal clinical, proteomic, histological and cellular immune responses of dextran sulfate sodium-induced acute colitis. World journal of gastroenterology, 24(38), 4341-4355.
Ofuegbe, S. O., Oyagbemi, A. A., Omobowale, T. O., Adedapo, A. D., Ayodele, A. E., Yakubu, M. A., . . . Adedapo, A. A. (2020). Methanol leaf extract of Momordica charantia protects alloxan-induced hepatopathy through modulation of caspase-9 and interleukin-1β signaling pathways in rats. Veterinary World, 13(8), 1528-1535.
Oh, S. Y., Cho, K. A., Kang, J. L., Kim, K. H., & Woo, S. Y. (2014). Comparison of experimental mouse models of inflammatory bowel disease. Int J Mol Med, 33(2), 333-340.
Okeke, E. B., & Uzonna, J. E. (2019). The Pivotal Role of Regulatory T Cells in the Regulation of Innate Immune Cells. Frontiers in immunology, 10, 680.
Pabón-Carrasco, M., Ramirez-Baena, L., Vilar-Palomo, S., Castro-Méndez, A., Martos-García, R., & Rodríguez-Gallego, I. (2020). Probiotics as a Coadjuvant Factor in Active or Quiescent Inflammatory Bowel Disease of Adults-A Meta-Analytical Study. Nutrients, 12(9), 2628.
Pandiyan, P., Zheng, L., Ishihara, S., Reed, J., & Lenardo, M. J. (2007). CD4+CD25+Foxp3+ regulatory T cells induce cytokine deprivation–mediated apoptosis of effector CD4+ T cells. Nature Immunology, 8(12), 1353-1362.
Patin, E. C., Thompson, A., & Orr, S. J. (2019). Pattern recognition receptors in fungal immunity. Seminars in cell & developmental biology, 89, 24-33.
Pelaseyed, T., Bergström, J. H., Gustafsson, J. K., Ermund, A., Birchenough, G. M. H., Schütte, A., . . . Hansson, G. C. (2014). The mucus and mucins of the goblet cells and enterocytes provide the first defense line of the gastrointestinal tract and interact with the immune system. Immunological reviews, 260(1), 8-20.
Perše, M., & Cerar, A. (2012). Dextran sodium sulphate colitis mouse model: traps and tricks. Journal of biomedicine & biotechnology, 2012, 718617-718617.
Piovani, D., Danese, S., Peyrin-Biroulet, L., Nikolopoulos, G. K., Lytras, T., & Bonovas, S. (2019). Environmental Risk Factors for Inflammatory Bowel Diseases: An Umbrella Review of Meta-analyses. Gastroenterology, 157(3), 647-659.e644.
Pitchakarn, P., Ohnuma, S., Pintha, K., Pompimon, W., Ambudkar, S. V., & Limtrakul, P. (2012). Kuguacin J isolated from Momordica charantia leaves inhibits P-glycoprotein (ABCB1)-mediated multidrug resistance. The Journal of Nutritional Biochemistry, 23(1), 76-84.
Podolsky, D. K., Gerken, G., Eyking, A., & Cario, E. (2009). Colitis-associated variant of TLR2 causes impaired mucosal repair because of TFF3 deficiency. Gastroenterology, 137(1), 209-220.
Privitera, G., Pugliese, D., Lopetuso, L. R., Scaldaferri, F., Neri, M., Guidi, L., . . . Armuzzi, A. (2021). Novel trends with biologics in inflammatory bowel disease: sequential and combined approaches. Therapeutic advances in gastroenterology, 14, 17562848211006669-17562848211006669.
Pu, Z., Che, Y., Zhang, W., Sun, H., Meng, T., Xie, H., . . . Hao, H. (2019). Dual roles of IL-18 in colitis through regulation of the function and quantity of goblet cells. International journal of molecular medicine, 43(6), 2291-2302.
Raina, K., Kumar, D., & Agarwal, R. (2016). Promise of bitter melon (Momordica charantia) bioactives in cancer prevention and therapy. Semin Cancer Biol, 40-41, 116-129.
Ramos, G. P., & Papadakis, K. A. (2019). Mechanisms of Disease: Inflammatory Bowel Diseases. Mayo Clinic proceedings, 94(1), 155-165.
Reboldi, A., & Cyster, J. G. (2016). Peyer's patches: organizing B-cell responses at the intestinal frontier. Immunological reviews, 271(1), 230-245.
Reeves, P. G. (1997). Components of the AIN-93 Diets as Improvements in the AIN-76A Diet. The Journal of Nutrition, 127(5), 838S-841S.
Rivollier, A., He, J., Kole, A., Valatas, V., & Kelsall, B. L. (2012). Inflammation switches the differentiation program of Ly6Chi monocytes from antiinflammatory macrophages to inflammatory dendritic cells in the colon. The Journal of experimental medicine, 209(1), 139-155.
Rochereau, N., Verrier, B., Pin, J.-J., Genin, C., & Paul, S. (2011). Phenotypic localization of distinct DC subsets in mouse Peyer Patch. Vaccine, 29(20), 3655-3661.
Rosales, C. (2020). Neutrophils at the crossroads of innate and adaptive immunity. Journal of leukocyte biology, 108(1), 377-396.
Rose, W. A., 2nd, Sakamoto, K., & Leifer, C. A. (2012). Multifunctional role of dextran sulfate sodium for in vivo modeling of intestinal diseases. BMC immunology, 13, 41-41.
Samji, T., & Khanna, K. M. (2017). Understanding memory CD8(+) T cells. Immunol Lett, 185, 32-39.
Sanderlin, E. J., Leffler, N. R., Lertpiriyapong, K., Cai, Q., Hong, H., Bakthavatchalu, V., . . . Yang, L. V. (2017). GPR4 deficiency alleviates intestinal inflammation in a mouse model of acute experimental colitis. Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, 1863(2), 569-584.
Saniabadi, A. R., Hanai, H., Fukunaga, K., Sawada, K., Shima, C., Bjarnason, I., & Lofberg, R. (2007). Therapeutic leukocytapheresis for inflammatory bowel disease. Transfusion and Apheresis Science, 37(2), 191-200.
Saxena, A., Fayad, R., Kaur, K., Truman, S., Greer, J., Carson, J. A., & Chanda, A. (2017). Dietary selenium protects adiponectin knockout mice against chronic inflammation induced colon cancer. Cancer biology & therapy, 18(4), 257-267.
Schwerd, T., Pandey, S., Yang, H. T., Bagola, K., Jameson, E., Jung, J., . . . Uhlig, H. H. (2017). Impaired antibacterial autophagy links granulomatous intestinal inflammation in Niemann-Pick disease type C1 and XIAP deficiency with NOD2 variants in Crohn's disease. Gut, 66(6), 1060-1073.
Segal, A. W. (2019). Studies on patients establish Crohn's disease as a manifestation of impaired innate immunity. J Intern Med, 286(4), 373-388.
Senda, T., Dogra, P., Granot, T., Furuhashi, K., Snyder, M. E., Carpenter, D. J., . . . Farber, D. L. (2019). Microanatomical dissection of human intestinal T-cell immunity reveals site-specific changes in gut-associated lymphoid tissues over life. Mucosal immunology, 12(2), 378-389.
Shea-Donohue, T., Thomas, K., Cody, M. J., Aiping, Z., Detolla, L. J., Kopydlowski, K. M., . . . Vogel, S. N. (2008). Mice deficient in the CXCR2 ligand, CXCL1 (KC/GRO-alpha), exhibit increased susceptibility to dextran sodium sulfate (DSS)-induced colitis. Innate immunity, 14(2), 117-124.
Sicard, J.-F., Le Bihan, G., Vogeleer, P., Jacques, M., & Harel, J. (2017). Interactions of Intestinal Bacteria with Components of the Intestinal Mucus. Frontiers in cellular and infection microbiology, 7, 387-387.
Sigall Boneh, R., Sarbagili Shabat, C., Yanai, H., Chermesh, I., Ben Avraham, S., Boaz, M., & Levine, A. (2017). Dietary Therapy With the Crohn's Disease Exclusion Diet is a Successful Strategy for Induction of Remission in Children and Adults Failing Biological Therapy. J Crohns Colitis, 11(10), 1205-1212.
Spijkerman, R., Hesselink, L., Bertinetto, C., Bongers, C., Hietbrink, F., Vrisekoop, N., . . . Koenderman, L. (2021). Refractory neutrophils and monocytes in patients with inflammatory bowel disease after repeated bouts of prolonged exercise. Cytometry B Clin Cytom.
Srivastava, S., Kedia, S., Kumar, S., Pratap Mouli, V., Dhingra, R., Sachdev, V., . . . Ahuja, V. (2015). Serum Human Trefoil Factor 3 is a Biomarker for Mucosal Healing in Ulcerative Colitis Patients with Minimal Disease Activity. Journal of Crohn's and Colitis, 9(7), 575-579.
Sterlin, D., Fadlallah, J., Adams, O., Fieschi, C., Parizot, C., Dorgham, K., . . . Gorochov, G. (2020). Human IgA binds a diverse array of commensal bacteria. J Exp Med, 217(3).
Sun, B., Liu, M., Cui, M., & Li, T. (2020). Granzyme B-expressing treg cells are enriched in colorectal cancer and present the potential to eliminate autologous T conventional cells. Immunology Letters, 217, 7-14.
Sun, X., He, S., Lv, C., Sun, X., Wang, J., Zheng, W., & Wang, D. (2017). Analysis of murine and human Treg subsets in inflammatory bowel disease. Mol Med Rep, 16(3), 2893-2898.
Suzuki, T. (2013). Regulation of intestinal epithelial permeability by tight junctions. Cellular and Molecular Life Sciences, 70(4), 631-659.
Suzuki, T., & Hara, H. (2011). Role of flavonoids in intestinal tight junction regulation. The Journal of Nutritional Biochemistry, 22(5), 401-408.
Sznurkowska, K., Luty, J., Bryl, E., Witkowski, J. M., Hermann-Okoniewska, B., Landowski, P., . . . Szlagatys-Sidorkiewicz, A. (2020). Enhancement of Circulating and Intestinal T Regulatory Cells and Their Expression of Helios and Neuropilin-1 in Children with Inflammatory Bowel Disease. Journal of inflammation research, 13, 995-1005.
Tsai, T.-H., Huang, W.-C., Ying, H.-T., Kuo, Y.-H., Shen, C.-C., Lin, Y.-K., & Tsai, P.-J. (2016). Wild Bitter Melon Leaf Extract Inhibits Porphyromonas gingivalis-Induced Inflammation: Identification of Active Compounds through Bioassay-Guided Isolation. Molecules (Basel, Switzerland), 21(4), 454-454.
Tsai, T. H., Huang, C. J., Wu, W. H., Huang, W. C., Chyuan, J. H., & Tsai, P. J. (2014). Antioxidant, cell-protective, and anti-melanogenic activities of leaf extracts from wild bitter melon (Momordica charantia Linn. var. abbreviata Ser.) cultivars. Bot Stud, 55(1), 78.
Turpin, W., Goethel, A., Bedrani, L., & Croitoru Mdcm, K. (2018). Determinants of IBD Heritability: Genes, Bugs, and More. Inflammatory bowel diseases, 24(6), 1133-1148.
Ulluwishewa, D., Anderson, R. C., McNabb, W. C., Moughan, P. J., Wells, J. M., & Roy, N. C. (2011). Regulation of tight junction permeability by intestinal bacteria and dietary components. J Nutr, 141(5), 769-776.
Vancamelbeke, M., Vanuytsel, T., Farré, R., Verstockt, S., Ferrante, M., Van Assche, G., . . . Cleynen, I. (2017). Genetic and Transcriptomic Bases of Intestinal Epithelial Barrier Dysfunction in Inflammatory Bowel Disease. Inflammatory bowel diseases, 23(10), 1718-1729.
Vidal-Lletjós, S., Andriamihaja, M., Blais, A., Grauso, M., Lepage, P., Davila, A.-M., . . . Lan, A. (2019). Mucosal healing progression after acute colitis in mice. World journal of gastroenterology, 25(27), 3572-3589.
Vivinus-Nébot, M., Frin-Mathy, G., Bzioueche, H., Dainese, R., Bernard, G., Anty, R., . . . Piche, T. (2014). Functional bowel symptoms in quiescent inflammatory bowel diseases: role of epithelial barrier disruption and low-grade inflammation. Gut, 63(5), 744-752.
Wéra, O., Lancellotti, P., & Oury, C. (2016). The Dual Role of Neutrophils in Inflammatory Bowel Diseases. J Clin Med, 5(12).
Wang, S., Li, Z., Yang, G., Ho, C. T., & Li, S. (2017). Momordica charantia: a popular health-promoting vegetable with multifunctionality. Food Funct, 8(5), 1749-1762.
Wheat, C. L., Ko, C. W., Clark-Snustad, K., Grembowski, D., Thornton, T. A., & Devine, B. (2017). Inflammatory Bowel Disease (IBD) pharmacotherapy and the risk of serious infection: a systematic review and network meta-analysis. BMC Gastroenterol, 17(1), 52.
Wing, K., Yamaguchi, T., & Sakaguchi, S. (2011). Cell-autonomous and -non-autonomous roles of CTLA-4 in immune regulation. Trends in Immunology, 32(9), 428-433.
Wirtz, S., Popp, V., Kindermann, M., Gerlach, K., Weigmann, B., Fichtner-Feigl, S., & Neurath, M. F. (2017). Chemically induced mouse models of acute and chronic intestinal inflammation. Nature Protocols, 12(7), 1295-1309.
Worbs, T., Hammerschmidt, S. I., & Förster, R. (2017). Dendritic cell migration in health and disease. Nature Reviews Immunology, 17(1), 30-48.
Yan, J.-B., Luo, M.-M., Chen, Z.-Y., & He, B.-H. (2020). The Function and Role of the Th17/Treg Cell Balance in Inflammatory Bowel Disease. Journal of immunology research, 2020, 8813558-8813558.
Yan, Y., Kolachala, V., Dalmasso, G., Nguyen, H., Laroui, H., Sitaraman, S. V., & Merlin, D. (2009). Temporal and spatial analysis of clinical and molecular parameters in dextran sodium sulfate induced colitis. PloS one, 4(6), e6073-e6073.
Yasuda, K., Takeuchi, Y., & Hirota, K. (2019). The pathogenicity of Th17 cells in autoimmune diseases. Seminars in Immunopathology, 41(3), 283-297.
Yu, L., Zhao, D., Nian, Y., & Li, C. (2021). Casein-fed mice showed faster recovery from DSS-induced colitis than chicken-protein-fed mice. Food Funct.
Yue, B., Luo, X., Yu, Z., Mani, S., Wang, Z., & Dou, W. (2019). Inflammatory Bowel Disease: A Potential Result from the Collusion between Gut Microbiota and Mucosal Immune System. Microorganisms, 7(10), 440.
Yuseff, M.-I., Pierobon, P., Reversat, A., & Lennon-Duménil, A.-M. (2013). How B cells capture, process and present antigens: a crucial role for cell polarity. Nature Reviews Immunology, 13(7), 475-486.
Zgair, A., Wong, J. C. M., & Gershkovich, P. (2016). Targeting Immunomodulatory Agents to the Gut-Associated Lymphoid Tissue. In C. Constantinescu, R. Arsenescu, & V. Arsenescu (Eds.), Neuro-Immuno-Gastroenterology (pp. 237-261). Cham: Springer International Publishing.
Zhu, J. (2015). T helper 2 (Th2) cell differentiation, type 2 innate lymphoid cell (ILC2) development and regulation of interleukin-4 (IL-4) and IL-13 production. Cytokine, 75(1), 14-24.
Zhu, Y., Deng, J., Nan, M. L., Zhang, J., Okekunle, A., Li, J. Y., . . . Wang, P. H. (2019). The Interplay Between Pattern Recognition Receptors and Autophagy in Inflammation. Adv Exp Med Biol, 1209, 79-108.
Zigmond, E., Varol, C., Farache, J., Elmaliah, E., Satpathy, Ansuman T., Friedlander, G., . . . Jung, S. (2012). Ly6Chi Monocytes in the Inflamed Colon Give Rise to Proinflammatory Effector Cells and Migratory Antigen-Presenting Cells. Immunity, 37(6), 1076-1090.
Zundler, S., Becker, E., Weidinger, C., & Siegmund, B. (2017). Anti-Adhesion Therapies in Inflammatory Bowel Disease-Molecular and Clinical Aspects. Frontiers in immunology, 8, 891-891.
Zundler, S., & Neurath, M. F. (2015). Interleukin-12: Functional activities and implications for disease. Cytokine Growth Factor Rev, 26(5), 559-568.