The Impact of Microbially Modified Metabolites Associated with Obesity and Bariatric Surgery on Anti-tumor Immunity

Introduction: Obesity, an independent risk factor for breast cancer growth and metastatic progression, is also closely intertwined with gut dysbiosis; and both obese state and dysbiosis promote each other. Enteric abundance of Bacteroides fragilis is strongly linked with obesity, and we recently discovered the presence of B. fragilis in malignant breast cancer. Given that enterotoxigenic B. fragilis or ETBF, which secretes B. fragilis toxin (BFT), has been identified as a procarcinogenic microbe in breast cancer, it is necessary to examine its impact on distant metastasis and underlying systemic and localized alterations promoting metastatic progression of breast cancer.

Methods: We used syngeneic mammary intraductal (MIND) model harboring gut colonization with ETBF to query distant metastasis of breast cancer cells. Alterations in the immune network and cytokines/chemokines in the tumor microenvironment and distant metastatic sites were examined using flow cytometry, immunohistochemistry, and multiplex arrays.

Results: ETBF infection initiates a systemic inflammation aiding in the establishment of the premetastatic niche formation in vital organs via increased proinflammatory and protumorigenic cytokines like IL17A, IL17E, IL27p28, IL17A/F, IL6, and IL10 in addition to creating a prometastatic immunosuppressive environment in the liver and lungs rich in myeloid cells, macrophages, and T regulatory cells. It induces remodeling of the tumor microenvironment via immune cell and stroma infiltration, increased vasculogenesis, and an EMT-like response, thereby encouraging early metastatic dissemination ready to colonize the conducive environment in liver and lungs of the breast tumor-bearing mice.

Discussion: In this study, we show that enteric ETBF infection concomitantly induces systemic inflammation, reshapes the tumor immune microenvironment, and creates conducive metastatic niches to potentiate early dissemination and seeding of metastases to liver and lung tissues in agreement with the “seed and soil hypothesis.” Our results also support the ETBF-induced “parallel model” of metastasis that advocates for an early dissemination of tumor cells that form metastatic lesions independent of the primary tumor load.

Type 2 diabetes (T2DM) clinically exhibits a higher incidence of hepatocellular carcinoma (HCC), contributing to a lousy prognosis in patients harboring both diseases. Microflora-based therapy draws attention with low side effects. Accumulating evidence shows that Lactobacillus brevis can improve blood glucose and body weight of the T2DM mice model and reduce several cancer incidences. However, the therapeutic effect of Lactobacillus brevis in affecting the prognosis of T2DM+HCC remains unknown. In this study, we aim to explore this question via an established T2DM+HCC mice model. We observed a significant alleviation after the probiotic intervention. Lactobacillus brevis improves blood glucose and insulin resistance and ameliorates Mechanically. Combined with a multi-omics approach including 16SrDNA, GC-MS, and RNA-seq, we identified distinct intestinal microflora composition and metabolites after Lactobacillus brevis intervention. Furthermore, we found that Lactobacillus brevis delayed disease progression by regulating MMP9 and NOTCH 1 signaling pathways, potentially through gut microflora and BA interaction. This study indicates that Lactobacillus brevis may improve the prognosis of T2DM + HCC, providing novel therapeutic opportunities via targeting intestinal flora for patients with T2DM+HCC.