ORIGINAL RESEARCH article
Front. Immunol.
Sec. Inflammation
Volume 16 - 2025 | doi: 10.3389/fimmu.2025.1585007
Lactobacillus delbrueckii subsp. bulgaricus 2038 and Streptococcus thermophilus 1131 ameliorate barrier dysfunction in human induced pluripotent stem cell-derived crypt-villus structural small intestine
Provisionally accepted
Kyousuke Kobayashi1
Yuri Imai2
Yuka Shimizu2Isamu Ogawa2*Takaaki Nakai2Yuri Mizuno2Yoshika Kaneda2Yumiko Watanabe-Yasuoka1Fuka Yamazaki1Junko Mochizuki3
Toshihiro Sashihara1Tamihide Matsunaga2Takahiro Iwao2- 1Meiji Holdings Co., Ltd., Hachioji, Japan
- 2Nagoya City University, Nagoya, Aichi, Japan
- 3Meiji Co., Ltd., Tokyo, Japan
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Background: Lactic acid bacteria (LABs) have been widely used as probiotics which contribute to our health. We previously reported that Lactobacillus delbrueckii subsp. bulgaricus 2038 and Streptococcus thermophilus 1131, two yogurt starter strains, ameliorate the intestinal barrier dysfunction caused by tumor necrosis factor (TNF)-α and interferon (IFN)-γ in Caco-2 cells. However, Caco-2 cells differ from living organisms in various ways. We have developed a human induced pluripotent stem cell-derived crypt-villus structural small intestine (hiPSC-SI) was established with a villus-like structure containing constituent cells of the small intestine. Methods: A hiPSC-SI and LABs co-culture model was established to assess the impact of LAB on barrier function and elucidate the underlying mechanisms. Results: The medium on the luminal side for coculturing cells and bacteria was examined and determined to use Hanks' balanced salt solution without glucose in terms of bacterial survival rate. LAB were found to ameliorate permeability and decrease the gene expression of tight junction associated proteins induced by TNF-α and IFN-γ. Regarding cell differentiation, LAB suppressed the downregulation of LGR5, VIL1, LYZ and MUC2 by cytokines. Moreover, they ameliorated reduced mucin 2 protein production and decreased the number of mucin 2-positive cells. Finally, transcriptome analysis suggested that they ameliorated the aberration in cytokine-induced cell differentiation via an anti-inflammatory effect on intestinal stem cells. Conclusions: The results indicate that LAB ameliorate the cytokine-induced dysfunction of intestinal barrier integrity and homeostasis disrupted by cytokines in a co-culture model of hiPSC-SI and LAB.
Keywords: induced pluripotent stem cell-derived crypt-villus structural small intestine, Barrier function, differentiation, anti-inflammation, Lactic acid bacteria, tight junction, mucin 2
Received: 28 Feb 2025; Accepted: 21 May 2025.
Copyright: © 2025 Kobayashi, Imai, Shimizu, Ogawa, Nakai, Mizuno, Kaneda, Watanabe-Yasuoka, Yamazaki, Mochizuki, Sashihara, Matsunaga and Iwao. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Isamu Ogawa, Nagoya City University, Nagoya, 467-8601, Aichi, Japan
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