Assessment of the Effect of Probiotic Supplementation on Proinflammatory Mechanisms Induced by Systemic Treatment in Women With Breast Cancer

Overview

The gut microbiota and its role in cancer treatment are currently the subject of intensive research. It has long been known that interactions between the microbiome and the host are responsible for the proper functioning of many physiological processes and for maintaining systemic homeostasis. Although the precise mechanisms underlying these interactions remain unclear, they appear to have a significant impact on the development and treatment of various diseases, including cancer. One of the crucial functions regulated by the gut microbiota is the body's immune response. The appropriate quantitative and qualitative composition of the gut microbiota supports the maintenance of a critical balance between pro- and anti-inflammatory processes. Even a slight disruption of this balance can lead to systemic metabolic and biochemical changes, affecting the overall condition of the body and its systems. Chemotherapy and immunotherapy are standard treatment protocols for cancer patients, including those with breast cancer. Despite their proven role in prolonging remission and improving patient survival, their effectiveness remains limited. Regardless of the regimen, the use of cytotoxic drugs does not fully prevent metastasis. In women with breast cancer, the risk of local recurrence or distant metastasis-primarily to the bones, lungs, and liver-is approximately 30% and increases over time following the initial diagnosis. Although the risk of cancer recurrence in this group is largely influenced by the baseline characteristics of the tumor, increasing attention is being paid to the immune response to treatment. The effectiveness of anticancer therapies depends not only on the response of cancer cells but also on the condition of the entire organism, particularly the host's immune system. Recent studies indicate that chemotherapy induces a systemic inflammatory state that may persist long after treatment completion. Prolonged inflammation, along with increased levels of chemoattractants, cytokines, and metalloproteinases, creates an environment conducive to cancer progression and metastasis. Therefore, it is increasingly suggested that chemotherapy-induced chronic inflammation may be a significant factor limiting therapeutic effectiveness. Although the precise mechanisms underlying inflammation during chemotherapy are not fully understood, a growing body of evidence points to a key role of the gut microbiota in this process. Cytotoxic drugs used during chemotherapy disrupt both the quantitative and qualitative composition of the gut microbiota, leading to dysbiosis. Dysbiosis is associated with the overgrowth of pathogenic species and alterations in the profile of microbial metabolites, often favoring those that negatively affect the intestinal barrier. Consequently, inflammation of the intestinal mucosa and increased intestinal permeability are observed during chemotherapy. Bacterial components, collectively known as pathogen-associated molecular patterns (PAMPs), can enter the bloodstream through the compromised intestinal barrier, triggering immune cell activation and systemic inflammation. An important link between the gut microbiota and progressive inflammation involves Toll-like receptors (TLRs), particularly TLR4, which is expressed on the surface of monocytes and recognizes, among other ligands, lipopolysaccharide (LPS) produced by Gram-negative bacteria. This interaction activates transcription factors such as Nuclear factor-κB (NF-κB), leading to the expression of genes involved in the immune response, including pro-inflammatory cytokines such as Tumor Necrosis Factor-α (TNF-α), Interleukin-6 (IL-6), and Cyclooxygenase-2 (COX-2). These cytokines promote tumor progression and metastasis both directly, by acting on cancer cells, and indirectly, by enhancing cell proliferation and angiogenesis. Several studies have reported increased expression and activity of TLR4 in various types of cancer, including breast cancer. Animal model studies have shown that blocking TLR4 reduces tumor metastasis and significantly decreases invasiveness. Therefore, inhibition of TLR4 signaling appears to be a promising therapeutic strategy for counteracting metastasis and chemoresistance. Probiotic therapy may contribute to this effect, as it has been shown to downregulate TLR4 expression and reduce levels of pro-tumor inflammatory mediators. The aim of this study is to evaluate the impact of probiotic therapy on immunological, biochemical, morphological, and anthropometric parameters in a group of women with breast cancer undergoing chemotherapy or immunotherapy. The study will include two visits: one before treatment initiation and another eight weeks later. The main hypothesis is that probiotic supplementation will reduce inflammation associated with systemic breast cancer treatment.