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

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.

Adjunctive Probiotic Lactobacillus rhamnosus Probio-M9 Administration Enhances the Effect of Anti-PD-1 Antitumor Therapy via Restoring Antibiotic-Disrupted Gut Microbiota

“…This study evaluated the effect of the probiotic, L. rhamnosus Probio-M9, on anti-PD-1-based ICB treatment using a heterotopic in vivo model of colorectal cancer constructed in mice with antibiotic-disrupted gut microbiota. It is interesting to note that taking probiotics after administration of antibiotics enhanced the tumor growth inhibitory effect in subsequent ICB treatment; such tumor inhibitory effect was significantly stronger than that in non-probiotic-treated mice ( P < 0.05), which was consistent with the observations of a previous study ( 24 ), showing that Probio-M9 could promote the therapeutic efficacy in both orthotopic and ectopic colon cancer.…”

“…At day 24, the mean tumor volume of CT group (both anti-PD-1 antibody and probiotics; mean tumor size ± SEM = 1,681.02 ± 77.86 mm 3 ) was the smallest, followed by MC group (received anti-PD-1 antibody but not probiotics; mean tumor size ± SEM = 2,511.05 ± 83.64 mm 3 ), PA group (received probiotics but not anti-PD-1 antibody; mean tumor size ± SEM = 2,867.67 ± 144.60 mm 3 ), and NC group (did not receive probiotics nor anti-PD-1 antibody; mean tumor size ± SEM = 3,695.74 ± 134.39 mm 3 ) (Figure 1B). Notably, the anti-PD-1 treatment significantly reduced the tumor volume compared with other groups (P < 0.05 at day 24), suggesting that the anti-PD-1 treatment was effective in tumor suppression with or without probiotic supplementation. No significant difference was seen in the tumor volume between PA and NC groups at any monitored time point, suggesting that administration of Probio-M9 alone had no significant effect on tumor suppression.…”

“…Our previous work isolated a probiotic strain from human colostrum, L. rhamnosus Probio-M9, which exhibited inhibitory effects on colitis-associated carcinogenesis possibly via restoring the gut microbiota ( 23 , 24 ). We hypothesized that the efficacy of anti-PD-1-based antitumor therapy required an intact host gut microbiota, and it was established that probiotics could modulate and enhance the recovery of gut microbiota disruption by external stimuli.…”

Lactulose Modulates the Structure of Gut Microbiota and Alleviates Colitis-Associated Tumorigenesis

“…The score for the percentage area involvement (P) is as follows: 1 = 1–25%; 2 = 26–50%; 3 = 51–75%; and 4 = 76–100%. The total histological score was calculated as I + E + R + C + P [ 27 ].…”

Study on the Mechanism of Lactobacillus Rhamnosus Probio-M9 on Staphylococcus Aureus Mastitis in Rat

“…2019). Studies have shown that it can improve the immune response function of the body and reduce the degree of in ammation by Oral Probio-M9 (Xu et al 2021). Moreover it has a prevention and treatment effect on breast in ammation (Yang et al 2021), and has a good therapeutic effect on in ammatory bowel disease and breast cancer of rats (data not published).…”