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

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.

Sex

Female

Minimum age

18 Years

Maximum age

75 Years

Inclusion Criteria:

* first-time chemotherapy
* written consent to participate in the research
* no antibiotic and probiotic therapy in the last 3 months

Exclusion Criteria:

* serious comorbidities (chronic renal failure, diabetes, autoimmune diseasese, unstable coronary artery disease or other cancers)
* previous history of cancer
* smoking cigarettes or using other stimulants
* another probiotic supplementation
* qualification for another type of treatment - surgery or hormone therapy

• BACKGROUNDYang X, Fu Y, Liu J, Ren HY. Impact of probiotics on toll-like receptor 4 expression in an experimental model of ulcerative colitis. J Huazhong Univ Sci Technolog Med Sci. 2013 Oct;33(5):661-665. doi: 10.1007/s11596-013-1177-9. Epub 2013 Oct 20. PMID 24142717
• BACKGROUNDKhademalhosseini M, Arababadi MK. Toll-like receptor 4 and breast cancer: an updated systematic review. Breast Cancer. 2019 May;26(3):265-271. doi: 10.1007/s12282-018-00935-2. Epub 2018 Dec 12. PMID 30543015
• BACKGROUNDAhmed A, Redmond HP, Wang JH. Links between Toll-like receptor 4 and breast cancer. Oncoimmunology. 2013 Feb 1;2(2):e22945. doi: 10.4161/onci.22945. PMID 23526132
• BACKGROUNDYiu JH, Dorweiler B, Woo CW. Interaction between gut microbiota and toll-like receptor: from immunity to metabolism. J Mol Med (Berl). 2017 Jan;95(1):13-20. doi: 10.1007/s00109-016-1474-4. Epub 2016 Sep 17. PMID 27639584
• BACKGROUNDVelloso LA, Folli F, Saad MJ. TLR4 at the Crossroads of Nutrients, Gut Microbiota, and Metabolic Inflammation. Endocr Rev. 2015 Jun;36(3):245-71. doi: 10.1210/er.2014-1100. Epub 2015 Mar 26. PMID 25811237
• BACKGROUNDGe Y, Wang X, Guo Y, Yan J, Abuduwaili A, Aximujiang K, Yan J, Wu M. Gut microbiota influence tumor development and Alter interactions with the human immune system. J Exp Clin Cancer Res. 2021 Jan 25;40(1):42. doi: 10.1186/s13046-021-01845-6. PMID 33494784
• BACKGROUNDSecombe KR, Coller JK, Gibson RJ, Wardill HR, Bowen JM. The bidirectional interaction of the gut microbiome and the innate immune system: Implications for chemotherapy-induced gastrointestinal toxicity. Int J Cancer. 2019 May 15;144(10):2365-2376. doi: 10.1002/ijc.31836. Epub 2018 Oct 1. PMID 30155890