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. 2022 Jun 7;21(1):113.
doi: 10.1186/s12934-022-01840-2.

A recombinant Bifidobacterium bifidum BGN4 strain expressing the streptococcal superoxide dismutase gene ameliorates inflammatory bowel disease

Sini Kang  1   2 , Zhaoyan Lin  2 , Yang Xu  1 , Minju Park  2 , Geun Eog Ji  2   3 , Tony V Johnston  4 , Seockmo Ku  5 , Myeong Soo Park  6
Affiliations

A recombinant Bifidobacterium bifidum BGN4 strain expressing the streptococcal superoxide dismutase gene ameliorates inflammatory bowel disease

Sini Kang et al. Microb Cell Fact. .

Abstract

Background: Inflammatory bowel disease (IBD) is a gastrointestinal disease characterized by diarrhea, rectal bleeding, abdominal pain, and weight loss. Recombinant probiotics producing specific proteins with IBD therapeutic potential are currently considered novel drug substitutes. In this study, a Bifidobacterium bifidum BGN4-SK strain was designed to produce the antioxidant enzymes streptococcal superoxide dismutase (SOD) and lactobacillus catalase (CAT), and a B. bifidum BGN4-pBESIL10 strain was proposed to generate an anti-inflammatory cytokine, human interleukin (IL)-10. In vitro and in vivo efficacy of these genetically modified Bifidobacterium strains were evaluated for colitis amelioration.

Results: In a lipopolysaccharide (LPS)-stimulated HT-29 cell model, tumor necrosis factor (TNF)-α and IL-8 production was significantly suppressed in the B. bifidum BGN4-SK treatment, followed by B. bifidum BGN4-pBESIL10 treatment, when compared to the LPS-treated control. Synergistic effects on TNF-α suppression were also observed. In a dextran sodium sulphate (DSS)-induced colitis mouse model, B. bifidum BGN4-SK treatment significantly enhanced levels of antioxidant enzymes SOD, glutathione peroxidase (GSH-Px) and CAT, compared to the DSS-only group. B. bifidum BGN4-SK significantly ameliorated the symptoms of DSS-induced colitis, increased the expression of tight junction genes (claudin and ZO-1), and decreased pro-inflammatory cytokines IL-6, IL-1β and TNF-α.

Conclusions: These findings suggest that B. bifidum BGN4-SK ameliorated DSS-induced colitis by generating antioxidant enzymes, maintaining the epithelial barrier, and decreasing the production of pro-inflammatory cytokines. Although B. bifidum BGN4-pBESIL10 exerted anti-inflammatory effects in vitro, the enhancement of IL-10 production and alleviation of colitis were very limited.

Keywords: Bifidobacterium bifidum; Catalase; Human interleukin-10; Inflammatory bowel disease; Superoxide peroxidase.

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Conflict of interest statement

Myeong Soo Park is directly employed by BIFIDO Co., Ltd. and he also hold BIFIDO Co., Ltd stocks as a CTO. Other authors declare no conflicts of interest.

Figures

Fig. 1
Fig. 1
Schematic overview of the murine model of DSS-induced colitis
Fig. 2
Fig. 2
Production of TNF-α (A) and IL-8 (B) in lipopolysaccharide (LPS)-stimulated HT-29 cells when treated with cell-free supernatants (CFSs) of B. bifidum BGN4-SK, B. bifidum BGN4-pBESIL10 or their combination. Treatments with different letters are significantly different at P < 0.05. BGN4, B. bifidum BGN4; SK, B. bifidum BGN4-SK; IL-10, B. bifidum BGN4-pBESIL10
Fig. 3
Fig. 3
Effects of B. bifidum BGN4-SK, B. bifidum BGN4-pBESIL10 or their combination on clinical symptoms in DSS-induced colitis model. A Body weight change (%), B colon length (n = 8), C histopathologic score and D histological images of colonic tissues stained with H&E (n = 3). Data are expressed as mean ± SD. *Significant versus control. #Significant versus DSS. *P < 0.05. The scale bars represent 500 μm (whole colon) and 50 μm (colonic segments). BGN4, Bifidobacterium bifidum BGN4; SK, B. bifidum BGN4-SK; IL-10, B. bifidum BGN4-pBESIL10
Fig. 4
Fig. 4
Superoxide dismutase (SOD) activity (A), glutathione peroxidase (GSH-Px) activity (B), and catalase (CAT) activity (C) in the blood serum of mice at the final day. Data are expressed as mean ± SD. *Significant versus control. #Significant versus DSS. (n = 8). P < 0.05. BGN4, Bifidobacterium bifidum BGN4; SK, B. bifidum BGN4-SK; IL-10, B. bifidum BGN4-pBESIL10
Fig. 5
Fig. 5
Relative mRNA expression of tight junction genes involving claudin (A) and ZO-1 (B). Data are expressed as mean ± SD. *Significant versus control. #Significant versus DSS. P < 0.05. (n = 5). BGN4, Bifidobacterium bifidum BGN4; SK, B. bifidum BGN4-SK; IL-10, B. bifidum BGN4-pBESIL10
Fig. 6
Fig. 6
Myeloperoxidase (MPO) activities (A) and relative mRNA expression of pro-inflammatory cytokines (B–F). Data are expressed as mean ± SD. *Significant versus control. #Significant versus DSS. (n = 5). P < 0.05. BGN4, Bifidobacterium bifidum BGN4; SK, B. bifidum BGN4-SK; IL-10, B. bifidum BGN4-pBESIL10
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