過去認為母乳是無菌的，但後來發現母乳中具有乳酸菌 (lactic acid bacteria, LAB) 的存在，乳酸菌中的乳桿菌屬 (Lactobacillus) 是最常見的菌屬，且目前許多的研究發現乳汁中除了擁有乳桿菌屬外，還有雙歧桿菌屬 (Bifidobacterium)、葡萄球菌屬 (Staphylococcus)、擬桿菌屬 (Bacteroides)、梭菌屬 (Clostridium) 及腸球菌 (Enterococcus) 等等，不過母乳中菌屬會隨著不同族群以及女性個體差異會有所不同。有很多證據顯示，乳酸桿菌具有抗發炎的效果，且也有研究指出乳酸桿菌對於哺乳女性以及健康兒童有正面的影響，使得乳酸桿菌成為益生菌的新目標。本次研究想要探討乳酸桿菌的益生特性，使用葡聚糖硫酸鈉 (dextran sodium sulfate, DSS) 誘導小鼠產生潰瘍性結腸炎，使用乳酸桿菌來評估改善腸道發炎的效果。
本次實驗挑選過去實驗室利用細胞模式篩選出來的乳酸桿菌，本研究利用該乳酸桿菌使用於潰瘍性結腸炎的動物模式，將乳酸桿菌分為活菌以及熱殺菌，探討兩種母乳酸桿菌預防與改善腸道發炎的能力。實驗結果顯示，餵食熱殺菌的實驗小鼠，糞便潛血、結腸長度與糞便型態均有顯著改善，而餵食活菌的實驗小鼠，在糞便潛血與糞便型態有顯著改善，進一步組織學分析發現餵食母乳酸桿菌的腸壁完整性、細胞浸潤、潰瘍等等均有改善，腸道組織的緊密連接 (tight junction) 相關分子也有受到改善的情形。
藉由以上結果得知，該乳酸桿菌對於緩解腸道發炎症狀具有良好的預防效果，未來可作為在探討益生菌對於腸道發炎的相關研究，並且具有可應用於舒緩臨床潰瘍性結腸炎患者的潛力。

In the past, breast milk was considered sterile, but the presence of lactic acid bacteria (LAB) in breast milk was found in healthy women later, and now multiple genera have been found in breast milk in many studies. At present, there are a lot of evidence suggest that lactic acid bacteria have anti-inflammatory effects, and some studies have also pointed out that breast milk bacteria have positive impacts on breastfeeding women and healthy children, making breast milk bacteria a new target for probiotics. This study aimed to investigate the probiotic properties of human milk bacteria on ulcerative colitis in mice induced using dextran sodium sulfate (DSS). The ability of human milk bacteria in improving intestinal inflammation was evaluated.
In this experiment, the breast milk bacteria screened by the laboratory using cell models in the past was applied to the animal model of ulcerative colitis. Both live and heat sterilized bacteria were explored their ability in ameliorating intestinal inflammation. The experimental results showed that the fecal occult blood, colon length, and feces pattern were significantly improved in the ulcerative colitis mice fed with heat-killed bacteria, while the fecal occult blood and feces pattern were significantly improved with live bacteria. Further histological analysis found that the integrity of the intestinal wall, cell infiltration, and ulcers were also improved. In addition, the tight junction markers of the intestinal tissue were also upregulated.
From the above results, we suggest that the human milk bacteria has the ability to allelieve intestinal inflammation, and it can be used in research to explore the molecular effect of probiotics on intestinal inflammation in the future, and it could be potential to be used in clinical application to relieve ulcerative colitis of patients.

1. König, H. and J. Fröhlich, Lactic Acid Bacteria, in Biology of Microorganisms on Grapes, in Must and in Wine, H. König, G. Unden, and J. Fröhlich, Editors. 2017, Springer International Publishing: Cham. p. 3-41.
2. Mokoena, M.P., Lactic Acid Bacteria and Their Bacteriocins: Classification, Biosynthesis and Applications against Uropathogens: A Mini-Review. Molecules, 2017. 22(8).
3. Walter, J., Ecological role of lactobacilli in the gastrointestinal tract: implications for fundamental and biomedical research. Appl Environ Microbiol, 2008. 74(16): p. 4985-96.
4. Khalid, K., An overview of lactic acid bacteria. International Journal of Biosciences, 2011. 1: p. 1-13.
5. Liu, S.-n., Y. Han, and Z.-j. Zhou, Lactic acid bacteria in traditional fermented Chinese foods. Food Research International, 2011. 44(3): p. 643-651.
6. Djadouni, F. and M. Kihal, Antimicrobial activity of lactic acid bacteria and the spectrum of their biopeptides against spoiling germs in foods. Brazilian Archives of Biology and Technology, 2012. 55.
7. Balthazar, C.F., et al., The future of functional food: Emerging technologies application on prebiotics, probiotics and postbiotics. Comprehensive Reviews in Food Science and Food Safety, 2022. 21(3): p. 2560-2586.
8. Hill, C., et al., The International Scientific Association for Probiotics and Prebiotics consensus statement on the scope and appropriate use of the term probiotic. Nature Reviews Gastroenterology & Hepatology, 2014. 11(8): p. 506-514.
9. Zhang, K., et al., Prodrug Integrated Envelope on Probiotics to Enhance Target Therapy for Ulcerative Colitis. Advanced Science, 2023. 10(4): p. 2205422.
10. Limketkai, B.N., et al., Probiotics for induction of remission in Crohn's disease. Cochrane Database of Systematic Reviews, 2020(7).
11. Ibrahim, S.A., et al., Fermented foods and probiotics: An approach to lactose intolerance. Journal of Dairy Research, 2021. 88(3): p. 357-365.
12. Preidis, G.A., et al., Probiotics, Enteric and Diarrheal Diseases, and Global Health. Gastroenterology, 2011. 140(1): p. 8-14.e9.
13. Drago, L., Probiotics and Colon Cancer. Microorganisms, 2019. 7(3).
14. Yadav, M.K., et al., Probiotics, prebiotics and synbiotics: Safe options for next-generation therapeutics. Applied Microbiology and Biotechnology, 2022. 106(2): p. 505-521.
15. Merenstein, D., et al., Emerging issues in probiotic safety: 2023 perspectives. Gut Microbes, 2023. 15(1): p. 2185034.
16. Crits-Christoph, A., et al., Good microbes, bad genes? The dissemination of antimicrobial resistance in the human microbiome. Gut Microbes, 2022. 14(1): p. 2055944.
17. D'Agostin, M., et al., Invasive Infections Associated with the Use of Probiotics in Children: A Systematic Review. Children (Basel), 2021. 8(10).
18. Wilson, I.D. and J.K. Nicholson, Gut microbiome interactions with drug metabolism, efficacy, and toxicity. Transl Res, 2017. 179: p. 204-222.
19. Sanders, M.E., et al., Safety assessment of probiotics for human use. Gut Microbes, 2010. 1(3): p. 164-185.
20. Dorato, M.A. and L.A. Buckley, Toxicology testing in drug discovery and development. Current protocols in toxicology, 2007. 31(1): p. 19.1. 1-19.1. 35.
21. Jackson, S.A., et al., Improving End-User Trust in the Quality of Commercial Probiotic Products. Front Microbiol, 2019. 10: p. 739.
22. Smith, S.M., et al., Adverse event assessment, analysis, and reporting in recent published analgesic clinical trials: ACTTION systematic review and recommendations. Pain, 2013. 154(7): p. 997-1008.
23. Piqué, N., M. Berlanga, and D. Miñana-Galbis, Health Benefits of Heat-Killed (Tyndallized) Probiotics: An Overview. Int J Mol Sci, 2019. 20(10).
24. Goldenberg, J.Z., et al., Probiotics for the prevention of Clostridium difficile-associated diarrhea in adults and children. Cochrane Database Syst Rev, 2017. 12(12): p. Cd006095.
25. Boyle, R.J., R.M. Robins-Browne, and M.L. Tang, Probiotic use in clinical practice: what are the risks? Am J Clin Nutr, 2006. 83(6): p. 1256-64; quiz 1446-7.
26. Zorzela, L., et al., Is there a role for modified probiotics as beneficial microbes: a systematic review of the literature. Benef Microbes, 2017. 8(5): p. 739-754.
27. Adams, C.A., The probiotic paradox: live and dead cells are biological response modifiers. Nutr Res Rev, 2010. 23(1): p. 37-46.
28. Taverniti, V. and S. Guglielmetti, The immunomodulatory properties of probiotic microorganisms beyond their viability (ghost probiotics: proposal of paraprobiotic concept). Genes Nutr, 2011. 6(3): p. 261-74.
29. Sarkar, A. and S. Mandal, Bifidobacteria-Insight into clinical outcomes and mechanisms of its probiotic action. Microbiol Res, 2016. 192: p. 159-171.
30. Castro-Bravo, N., et al., Interactions of Surface Exopolysaccharides From Bifidobacterium and Lactobacillus Within the Intestinal Environment. Front Microbiol, 2018. 9: p. 2426.
31. Vandenplas, Y., et al., Efficacy and safety of APT198K for the treatment of infantile colic: a pilot study. J Comp Eff Res, 2017. 6(2): p. 137-144.
32. Burta, O., et al., Efficacy and safety of APT036 versus simethicone in the treatment of functional bloating: a multicentre, randomised, double-blind, parallel group, clinical study. Transl Gastroenterol Hepatol, 2018. 3: p. 72.
33. Deshpande, G., G. Athalye-Jape, and S. Patole Para-probiotics for Preterm Neonates—The Next Frontier. Nutrients, 2018. 10, DOI: 10.3390/nu10070871.
34. Kataria, J., et al., Probiotic microbes: do they need to be alive to be beneficial? Nutr Rev, 2009. 67(9): p. 546-50.
35. Fernández, L., et al., The Microbiota of the Human Mammary Ecosystem. Frontiers in Cellular and Infection Microbiology, 2020. 10.
36. Notarbartolo, V., et al., Composition of Human Breast Milk Microbiota and Its Role in Children's Health. Pediatr Gastroenterol Hepatol Nutr, 2022. 25(3): p. 194-210.
37. Okumura, R. and K. Takeda, Maintenance of intestinal homeostasis by mucosal barriers. Inflamm Regen, 2018. 38: p. 5.
38. Salzman, N.H., M.A. Underwood, and C.L. Bevins, Paneth cells, defensins, and the commensal microbiota: a hypothesis on intimate interplay at the intestinal mucosa. Semin Immunol, 2007. 19(2): p. 70-83.
39. Rodríguez-Piñeiro, A.M., et al., Studies of mucus in mouse stomach, small intestine, and colon. II. Gastrointestinal mucus proteome reveals Muc2 and Muc5ac accompanied by a set of core proteins. Am J Physiol Gastrointest Liver Physiol, 2013. 305(5): p. G348-56.
40. Johansson, M.E., et al., The inner of the two Muc2 mucin-dependent mucus layers in colon is devoid of bacteria. Proc Natl Acad Sci U S A, 2008. 105(39): p. 15064-9.
41. Desai, M.S., et al., A Dietary Fiber-Deprived Gut Microbiota Degrades the Colonic Mucus Barrier and Enhances Pathogen Susceptibility. Cell, 2016. 167(5): p. 1339-1353.e21.
42. Kobayashi, K.S., et al., Nod2-dependent regulation of innate and adaptive immunity in the intestinal tract. Science, 2005. 307(5710): p. 731-4.
43. Ivanov, II, et al., Induction of intestinal Th17 cells by segmented filamentous bacteria. Cell, 2009. 139(3): p. 485-98.
44. Atarashi, K., et al., Th17 Cell Induction by Adhesion of Microbes to Intestinal Epithelial Cells. Cell, 2015. 163(2): p. 367-80.
45. Goto, Y., et al., Innate lymphoid cells regulate intestinal epithelial cell glycosylation. Science, 2014. 345(6202): p. 1254009.
46. Liang, S.C., et al., Interleukin (IL)-22 and IL-17 are coexpressed by Th17 cells and cooperatively enhance expression of antimicrobial peptides. J Exp Med, 2006. 203(10): p. 2271-9.
47. Pull, S.L., et al., Activated macrophages are an adaptive element of the colonic epithelial progenitor niche necessary for regenerative responses to injury. Proc Natl Acad Sci U S A, 2005. 102(1): p. 99-104.
48. Capaldo, C.T., et al., IFN-γ and TNF-α-induced GBP-1 inhibits epithelial cell proliferation through suppression of β-catenin/TCF signaling. Mucosal Immunol, 2012. 5(6): p. 681-90.
49. Graham, D.B. and R.J. Xavier, Pathway paradigms revealed from the genetics of inflammatory bowel disease. Nature, 2020. 578(7796): p. 527-539.
50. Chang, J.T., Pathophysiology of Inflammatory Bowel Diseases. New England Journal of Medicine, 2020. 383(27): p. 2652-2664.
51. Pithadia, A.B. and S. Jain, Treatment of inflammatory bowel disease (IBD). Pharmacological Reports, 2011. 63(3): p. 629-642.
52. Vavassori, P., et al., The Bile Acid Receptor FXR Is a Modulator of Intestinal Innate Immunity1. The Journal of Immunology, 2009. 183(10): p. 6251-6261.
53. Forman, B.M., et al., Identification of a nuclear receptor that is activated by farnesol metabolites. Cell, 1995. 81(5): p. 687-93.
54. Stojancevic, M., K. Stankov, and M. Mikov, The impact of farnesoid X receptor activation on intestinal permeability in inflammatory bowel disease. Can J Gastroenterol, 2012. 26(9): p. 631-7.
55. Mikov, M., et al., Pharmacology of bile acids and their derivatives: absorption promoters and therapeutic agents. Eur J Drug Metab Pharmacokinet, 2006. 31(3): p. 237-51.
56. Fu, T., et al., FXR mediates ILC-intrinsic responses to intestinal inflammation. Proceedings of the National Academy of Sciences, 2022. 119(51): p. e2213041119.
57. Zhou, M., et al., Farnesoid-X receptor as a therapeutic target for inflammatory bowel disease and colorectal cancer. Frontiers in Pharmacology, 2022. 13.
58. Wilson, A., et al., Attenuation of bile acid-mediated FXR and PXR activation in patients with Crohn’s disease. Scientific Reports, 2020. 10(1): p. 1866.
59. Marônek, M., et al., Metalloproteinases in Inflammatory Bowel Diseases. J Inflamm Res, 2021. 14: p. 1029-1041.
60. Derkacz, A., et al., The Role of Extracellular Matrix Components in Inflammatory Bowel Diseases. Journal of Clinical Medicine, 2021. 10(5): p. 1122.
61. Opdenakker, G., S. Vermeire, and A. Abu El-Asrar, How to place the duality of specific MMP-9 inhibition for treatment of inflammatory bowel diseases into clinical opportunities? Frontiers in Immunology, 2022. 13.
62. O'Shea, N.R. and A.M. Smith, Matrix Metalloproteases Role in Bowel Inflammation and Inflammatory Bowel Disease: An Up to Date Review. Inflammatory Bowel Diseases, 2014. 20(12): p. 2379-2393.
63. Heljasvaara, R., et al., Generation of biologically active endostatin fragments from human collagen XVIII by distinct matrix metalloproteases. Exp Cell Res, 2005. 307(2): p. 292-304.
64. Visse, R. and H. Nagase, Matrix metalloproteinases and tissue inhibitors of metalloproteinases: structure, function, and biochemistry. Circ Res, 2003. 92(8): p. 827-39.
65. Michalak, A., B. Kasztelan-Szczerbińska, and H. Cichoż-Lach, Impact of Obesity on the Course of Management of Inflammatory Bowel Disease-A Review. Nutrients, 2022. 14(19).
66. Zhao, X., et al., Th17 Cell-Derived Amphiregulin Promotes Colitis-Associated Intestinal Fibrosis Through Activation of mTOR and MEK in Intestinal Myofibroblasts. Gastroenterology, 2023. 164(1): p. 89-102.
67. Tossetta, G., et al., Role of CD93 in Health and Disease. Cells, 2023. 12(13).
68. Polosukhina, D., et al., CCL11 exacerbates colitis and inflammation-associated colon tumorigenesis. Oncogene, 2021. 40(47): p. 6540-6546.
69. Mizoguchi, E., Chitinase 3-like-1 exacerbates intestinal inflammation by enhancing bacterial adhesion and invasion in colonic epithelial cells. Gastroenterology, 2006. 130(2): p. 398-411.
70. Kuboi, Y., et al., Blockade of the fractalkine-CX3CR1 axis ameliorates experimental colitis by dislodging venous crawling monocytes. Int Immunol, 2019. 31(5): p. 287-302.
71. Elia, G. and G. Guglielmi, CXCL9 chemokine in ulcerative colitis. Clin Ter, 2018. 169(5): p. e235-e241.
72. Diegelmann, J., et al., Expression and regulation of the chemokine CXCL16 in Crohn's disease and models of intestinal inflammation. Inflamm Bowel Dis, 2010. 16(11): p. 1871-81.
73. Gren, S.T., et al., The protease inhibitor cystatin C down-regulates the release of IL-β and TNF-α in lipopolysaccharide activated monocytes. J Leukoc Biol, 2016. 100(4): p. 811-822.
74. Peter, M.R., et al., Impaired resolution of inflammation in the Endoglin heterozygous mouse model of chronic colitis. Mediators Inflamm, 2014. 2014: p. 767185.
75. Tolstanova, G., et al., Role of anti-angiogenic factor endostatin in the pathogenesis of experimental ulcerative colitis. Life Sci, 2011. 88(1-2): p. 74-81.
76. Gadaleta, R.M., et al., Fibroblast Growth Factor 19 modulates intestinal microbiota and inflammation in presence of Farnesoid X Receptor. EBioMedicine, 2020. 54: p. 102719.
77. Chekol Abebe, E., et al., The structure, biosynthesis, and biological roles of fetuin-A: A review. Frontiers in Cell and Developmental Biology, 2022. 10.
78. Arseneau, K.O. and F. Cominelli, Targeting leukocyte trafficking for the treatment of inflammatory bowel disease. Clin Pharmacol Ther, 2015. 97(1): p. 22-8.
79. Venuto, S., et al., IGFBP-6 Network in Chronic Inflammatory Airway Diseases and Lung Tumor Progression. Int J Mol Sci, 2023. 24(5).
80. Huang, K., S. Huang, and M. Xiong, Correlations between genetically predicted lipid-lowering drug targets and inflammatory bowel disease. Lipids in Health and Disease, 2024. 23(1): p. 31.
81. Toyonaga, T., et al., Lipocalin 2 prevents intestinal inflammation by enhancing phagocytic bacterial clearance in macrophages. Scientific Reports, 2016. 6(1): p. 35014.
82. Chen, J., et al., Therapeutic targets for inflammatory bowel disease: proteome-wide Mendelian randomization and colocalization analyses. EBioMedicine, 2023. 89: p. 104494.
83. Levitte, S., et al., Local Pentraxin-2 Deficit Is a Feature of Intestinal Fibrosis in Crohn's Disease. Dig Dis Sci, 2023. 68(7): p. 2975-2980.
84. Kato, S., et al., Increased expression of long pentraxin PTX3 in inflammatory bowel diseases. Dig Dis Sci, 2008. 53(7): p. 1910-6.
85. Lei, L., et al., Inhibition of proprotein convertase subtilisin/kexin type 9 attenuates 2,4,6-trinitrobenzenesulfonic acid-induced colitis via repressing toll-like receptor 4/nuclear factor-kappa B. The Kaohsiung Journal of Medical Sciences, 2020. 36(9): p. 705-711.
86. Louis Sam Titus, A.S.C., et al., Resistin, Elastase, and Lactoferrin as Potential Plasma Biomarkers of Pediatric Inflammatory Bowel Disease Based on Comprehensive Proteomic Screens. Mol Cell Proteomics, 2023. 22(2): p. 100487.
87. Binion, D.G., et al., Vascular cell adhesion molecule-1 expression in human intestinal microvascular endothelial cells is regulated by PI 3-kinase/Akt/MAPK/NF-kappaB: inhibitory role of curcumin. Am J Physiol Gastrointest Liver Physiol, 2009. 297(2): p. G259-68.
88. Zhang, Y., et al., Dubosiella newyorkensis modulates immune tolerance in colitis via the L-lysine-activated AhR-IDO1-Kyn pathway. Nat Commun, 2024. 15(1): p. 1333.
89. Zhou, C., et al., Amelioration of Colitis by a Gut Bacterial Consortium Producing Anti-Inflammatory Secondary Bile Acids. Microbiol Spectr, 2023. 11(2): p. e0333022.
90. Li, C., et al., The role of Lactobacillus in inflammatory bowel disease: from actualities to prospects. Cell Death Discovery, 2023. 9(1): p. 361.
91. Hu, Q., et al., Anti-Inflammatory, Barrier Maintenance, and Gut Microbiome Modulation Effects of Saccharomyces cerevisiae QHNLD8L1 on DSS-Induced Ulcerative Colitis in Mice. International Journal of Molecular Sciences, 2023. 24(7): p. 6721.
92. Alam, M.T., et al., Microbial imbalance in inflammatory bowel disease patients at different taxonomic levels. Gut Pathog, 2020. 12: p. 1.
93. Morgan, X.C., et al., Dysfunction of the intestinal microbiome in inflammatory bowel disease and treatment. Genome Biol, 2012. 13(9): p. R79.
94. Choi, K.J., et al., Gut commensal Kineothrix alysoides mitigates liver dysfunction by restoring lipid metabolism and gut microbial balance. Scientific Reports, 2023. 13(1): p. 14668.
95. Kellow, J.E., et al., Principles of applied neurogastroenterology: physiology/motility–sensation. Gut, 1999. 45(suppl 2): p. II17-II24.
96. Rebollar, E., et al., Effect of lipopolysaccharide on rabbit small intestine muscle contractility in vitro: role of prostaglandins. Neurogastroenterology & Motility, 2002. 14(6): p. 633-642.
97. Dimidi, E., et al., Mechanisms of Action of Probiotics and the Gastrointestinal Microbiota on Gut Motility and Constipation. Advances in Nutrition, 2017. 8(3): p. 484-494.
98. Randhawa, P.K., et al., A review on chemical-induced inflammatory bowel disease models in rodents. Korean J Physiol Pharmacol, 2014. 18(4): p. 279-88.
99. de Almeida, A.B., et al., Anti-inflammatory intestinal activity of Arctium lappa L. (Asteraceae) in TNBS colitis model. J Ethnopharmacol, 2013. 146(1): p. 300-10.
100. Lee, J., et al., TRPV1 expressing extrinsic primary sensory neurons play a protective role in mouse oxazolone-induced colitis. Auton Neurosci, 2012. 166(1-2): p. 72-6.
101. Al-Rejaie, S.S., et al., Protective effect of naringenin on acetic acid-induced ulcerative colitis in rats. World J Gastroenterol, 2013. 19(34): p. 5633-44.
102. Pawar, A.T., et al., Protective Effect of Hydroalcoholic Root Extract of Rubia cordifolia in Indomethacin-Induced Enterocolitis in Rats. Indian J Pharm Sci, 2011. 73(2): p. 250-3.
103. Pricolo, V.E., et al., Effects of lambda-carrageenan induced experimental enterocolitis on splenocyte function and nitric oxide production. J Surg Res, 1996. 66(1): p. 6-11.
104. Reingold, L., et al., Development of a peptidoglycan-polysaccharide murine model of Crohn's disease: effect of genetic background. Inflamm Bowel Dis, 2013. 19(6): p. 1238-44.
105. Melgar, S., et al., Validation of murine dextran sulfate sodium-induced colitis using four therapeutic agents for human inflammatory bowel disease. Int Immunopharmacol, 2008. 8(6): p. 836-44.
106. Chassaing, B., et al., Dextran sulfate sodium (DSS)-induced colitis in mice. Curr Protoc Immunol, 2014. 104: p. 15.25.1-15.25.14.
107. Kawashima, K., et al., Evaluation of the relationship between the spleen volume and the disease activity in ulcerative colitis and Crohn disease. Medicine (Baltimore), 2022. 101(1): p. e28515.
108. Lu, Q., et al., Immunology of Inflammatory Bowel Disease: Molecular Mechanisms and Therapeutics. J Inflamm Res, 2022. 15: p. 1825-1844.
109. Fritsch Fredin, M., et al., Dextran sulfate sodium-induced colitis generates a transient thymic involution--impact on thymocyte subsets. Scand J Immunol, 2007. 65(5): p. 421-9.
110. Landy, J., et al., Tight junctions in inflammatory bowel diseases and inflammatory bowel disease associated colorectal cancer. World J Gastroenterol, 2016. 22(11): p. 3117-26.
111. Matsubara, T., F. Li, and F.J. Gonzalez, FXR signaling in the enterohepatic system. Mol Cell Endocrinol, 2013. 368(1-2): p. 17-29.
112. Zhai, Q., et al., A next generation probiotic, Akkermansia muciniphila. Crit Rev Food Sci Nutr, 2019. 59(19): p. 3227-3236.