Inhibitory Effects of Breast Milk-Derived Lactobacillus rhamnosus Probio-M9 on Colitis-Associated Carcinogenesis by Restoration of the Gut Microbiota in a Mouse Model.

Haiyan Xu,Yoko Matsuda,Yuko Nakano-Narusawa,Xiaodong Li,Yaopeng Hu,Katsuya Hirano,Heping Zhang,Lin-Hai Kurahara,Keizo Hiraishi

doi:10.3390/nu13041143

Abstract

Chronic inflammation is a risk factor for colorectal cancer, and inflammatory cytokines secreted from inflammatory cells and active oxygen facilitate tumorigenesis. Intestinal bacteria are thought to regulate tumorigenesis. The longer the breastfeeding period, the lower is the risk of inflammatory bowel disease. Here, we investigated preventive effects of the probiotic Lactobacillus rhamnosus M9 (Probio-M9) on colitis-associated tumorigenesis. An inflammatory colorectal tumor model was established using a 6-week-old male C57BL/6NCrSlc mouse, which was intraperitoneally administered with azoxymethane (AOM: 12 mg/kg body weight). On weeks 2 and 4, 2% dextran sulfate sodium (DSS) was administered to mice for 7 days through drinking water. On weeks 8 and 10, Probio-M9 (2 × 109/day) was orally administered for 7 days. Animals were sacrificed at 20 weeks after AOM administration and immunohistochemical staining and Western blotting was performed. The α-diversity of microflora (Shannon index), principal coordinate analysis, and distribution of intestinal bacterium genera and metabolic pathways were compared. The AOM/DSS group showed weight loss, diarrhea, intestinal shortening, increased number of colon tumors, proliferating tumorigenesis, increased inflammation score, fibrosis, increased CD68+, or CD163+ macrophage cells in the subserosal layer of non-tumor areas. Inflammation and tumorigenesis ameliorated after Probio-M9 treatment. Fecal microbial functions were altered by AOM/DSS treatment. Probio-M9 significantly upregulated the fecal microbial diversity and reversed fecal microbial functions. Thus, Probio-M9 could suppress tumor formation in the large intestine by regulating the intestinal environment and ameliorating inflammation, suggesting its therapeutic potential for treatment of inflammation and colitis-associated tumorigenesis.

Highlights

Colorectal cancer can be divided into two types, namely, colitis-associated cancer (CAC) and sporadic colorectal cancer [1]
The AOM/dextran sulfate sodium (DSS) group showed a significant decrease in the BW as compared with the vehicle group, while the AOM/DSS+M9 group showed a tendency of improvement in BW loss but without any significant difference (Figure 1A, p < 0.01 vs. vehicle, after 15 and 20 weeks of AOM administration)
We examined the proliferation activity of proliferating cell nuclear antigen (PCNA)+ cells, which is associated with tumorigenesis, and found it to be significantly higher in the tumor areas of AOM/DSS mice

Summary

Introduction

Colorectal cancer can be divided into two types, namely, colitis-associated cancer (CAC) and sporadic colorectal cancer [1]. We examined the effects of probiotics on carcinogenic progression by intervening in the long process from IBD to CAC [3]. Many studies have shown that oral administration of a commercial probiotic cocktail containing probiotic VSL#3 (four strains of lactobacilli, three strains of Bifidobacterium, and one strain of Streptococcus) could reduce chronic inflammation and delay the onset of carcinoma in a mouse model of CAC [7]. Administration of probiotics to restore the balance between the microbiome community is thought to be effective in patients with IBD and CAC [8,9]. These studies support the view that probiotics prevent inflammation and carcinogenesis. The mechanisms underlying the therapeutic effects of probiotic treatment in CAC are not clearly elucidated

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