Nononcogenic restoration of the intestinal barrier by E. coli–delivered human EGF
Mira Yu, Juil Kim, Jung Hoon Ahn, Yuseok Moon
Mira Yu, Juil Kim, Jung Hoon Ahn, Yuseok Moon
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Research Article Microbiology

Nononcogenic restoration of the intestinal barrier by E. coli–delivered human EGF

Abstract

Although mucoactive proteins, such as epidermal growth factor (EGF), could improve clinical outcomes of intestinal ulcerative diseases, their gastrointestinal application is limited because of their proteolytic digestion or concerns about tumor promotion. In the present study, ATP-binding cassette (ABC) transporter–linked secretion of human EGF from probiotic Escherichia coli (EGF-EcN) was created to promote beneficial actions of the EGF receptor, which is notably attenuated in patients with intestinal ulcerative injuries. Preventive and postinjury treatment with EGF-EcN alleviated intestinal ulcers and other readouts of disease severity in murine intestinal ulcer models. EGF-EcN administration promoted the restitutive recovery of damaged epithelial layers, particularly via upward expansion of highly proliferating progenitor cells from the lower crypts. Along with the epithelial barrier benefit, EGF-EcN improved goblet cell–associated mucosal integrity, which controls the access of luminal microbiota to the underlying host tissues. Despite concern about the oncogenic action of EGF, EGF-EcN did not aggravate colitis-associated colon cancer; instead, it alleviated protumorigenic activities and improved barrier integrity in the lesions. All findings indicate that probiotic bacteria–based precision delivery of human EGF is a promising mucosal intervention against gastrointestinal ulcers and malignant distress through crypt-derived barrier restoration.

Authors

Mira Yu, Juil Kim, Jung Hoon Ahn, Yuseok Moon

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Figure 2

Actions of EGF-EcN in DSS-induced acute colitis.

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Actions of EGF-EcN in DSS-induced acute colitis. Schematic overview of t...
Schematic overview of the DSS-induced colitis model with EGF-EcN treatment. (A) Six-week-old female mice were pretreated twice with vehicle, EcN, or EGF-EcN over 7 days (n = 12–15). The mice were then exposed to 3% DSS for 5 days to induce colitis. (B) Mouse body weight was monitored for indicated times after DSS exposure. The asterisks in the graph represent significant differences from mass changes of the DSS treatment group at each time point (*P < 0.05; **P < 0.01; ***P < 0.001 using 2-tailed, unpaired Student’s t test). (C) Changes in colon length were measured on the 10th day after DSS treatment (the left box) and quantitatively analyzed (the right graph). The asterisks in the box-and-whisker plot (min to max) represent significant differences between 2 groups (*P < 0.05; **P < 0.01 using 2-tailed, unpaired Student’s t test). (D and G) Representative hematoxylin and eosin staining in intestinal lesions demonstrated using microscopy. Original magnification, ×100 (D), 400 (G). Scale bars: 100 μm. (E–G) Histopathological scores (E), levels of ulcer area (F), and neutrophil infiltration (G, red arrows) were compared between the DSS and EcN or EGF-EcN treatments. Results are shown as mean ± SEM (E) or box-and-whisker plots (min to max) (F and G). Different letters represent a significant difference between groups in each parameter (P < 0.05 using 1-way ANOVA with the Newman-Keuls post hoc test). The box plots depict the minimum and maximum values (whiskers), the upper and lower quartiles, and the median. The length of the box represents the interquartile range.