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 8

Effects of EGF-EcN on NSAID-induced ulcerative injuries in the small intestine.

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Effects of EGF-EcN on NSAID-induced ulcerative injuries in the small int...
Ten-week-old male mice were pretreated twice with vehicle, EcN, and EGF-EcN over 7 days (n = 12). The mice were then treated with 30 mg/kg of indomethacin via gavage. (A) At 24 hours after indomethacin treatment, tissues were observed in “Swiss rolls” of small intestines and analyzed using a stereoscopic microscope. The white arrows indicate hemorrhages along the line of intestines. Inset magnification, x18. (B–D) At 24 hours after indomethacin treatment, tissues were assessed for H&E staining patterns (B, upper), pathological severity score (B, lower), neutrophil infiltration (C, the representative images and the quantitation in the right graph), and ulcer area (D). Results in B are shown as mean ± SEM with asterisks representing significant differences between 2 groups (*P < 0.05; **P < 0.01; ***P < 0.001 using 2-tailed, unpaired Student’s t test). Scale bars: 100 μm. Different letters (C) represent significant differences between groups (P < 0.05 using 1-way ANOVA with the Newman-Keuls post hoc test). The asterisks in the box-and-whisker plot (min to max, D) represent significant differences between 2 groups (*P < 0.05; **P < 0.01; ***P < 0.001 using 2-tailed, unpaired Student’s t 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.