Hannah McQueen

Background: Chronic systemic inflammation is a recognized contributor to various pathological states, including obesity and cancer. The gut microbiome serves as a crucial interface between environmental exposures and host immunity, influencing inflammatory responses across multiple systems. Dysbiosis – an imbalance in gut microbial communities – can trigger systemic inflammation, contributing to metabolic dysregulation and increasing risk for obesity-related malignancies, including breast cancer.¹ New evidence suggest links between microbial composition – particularly reductions in beneficial strains like Lactobacillus and Bifidobacterium – and elevated levels of inflammatory cytokines such as TNF-a, which has a known role in cell regulation.²

Objective: This literature review explores the role of TNF-a in elevating the risk of diabetes and cancer progression, and its modulation by Lactobacillus and Bifidobacterium probiotic supplementation.

Search Methods: An online PubMed database search was conducted using the keywords “dysbiosis”, “cancer”, “chronic inflammation”, “microbiome”, “breast cancer”, and “diabetes” for the timeframe 2017-2025.

Results: The TNF-a signaling pathway is a well-established mediator of inflammation which both decreases rates of apoptosis and increases insulin resistance.³  One upstream pathway through which proinflammatory cytokines and TNF-α are increased, is the nuclear retention of NF-κB. Such proinflammatory cytokines include IL-1B, L-6, and IL-18.⁴  One downstream actor in the TNF-α pathway of cancer progression is the induction of the family of TNFAIP8 proteins. Tumor necrosis factor α-inducible protein 8 (TNFAIP8), as the name suggests, is induced by tumor necrosis factor α and is an anti-apoptotic.⁵  Tumor necrosis factor-α-induced protein 8-like 3 (TIPE3) is a newly discovered member of the TNFAIP8 family. Given the evidence for this protein family’s anti-apoptotic properties, this serves as another potential cancer-preventative therapeutic target.⁶  These proteins act as inhibitors of apoptosis and are implicated in tumor development and immune evasion, making them attractive candidates for pharmacological intervention. Additionally, the Lactobacillus and Bifidobacterium bacteria strains present prophylactic potential for modulating the TNF-a pathway as they have been shown to downregulate inflammatory markers and enhance mucosal immunity. Thus, these probiotics offer a non-invasive strategy for reducing systemic inflammation. However, while animal and in-vitro studies have demonstrated promising results, in-vivo human studies remain limited. This underscores the need for more, and stain-specific, clinical trials to validate the therapeutic efficacy and safety of such probiotic-centered interventions^.2

Conclusion: The TNF-a pathway presents a critical target linking inflammation, metabolism, and carcinogenesis. Evidence suggests that targeting this pathway – whether through direct pharmacological antagonism or via microbiome modulation with probiotics – could offer novel routes for prevention and treatment of inflammation-related cancers, particularly breast cancer. Future research should aim to deepen our understanding of the TNF-a signaling mechanisms and clarify the role of microbial-host interactions. Such studies should aim to establish evidence-based protocols for probiotic therapy in clinical practice with strain specific investigations and extrapolation to oncogenic subtypes.

Works Cited:

1. Lian K, Ma C, Hao C, et al. TIPE3 protein promotes breast cancer metastasis through activating AKT and NF-κB signaling pathways. Oncotarget. 2017;8(30):48889-48904. doi:10.18632/oncotarget.16522
2. Tonucci LB, Olbrich Dos Santos KM, Licursi de Oliveira L, Rocha Ribeiro SM, Duarte Martino HS. Clinical application of probiotics in type 2 diabetes mellitus: A randomized, double-blind, placebo-controlled study. Clin Nutr. 2017;36(1):85-92. doi:10.1016/j.clnu.2015.11.011
3. Amin MN, Hussain MS, Sarwar MS, et al. How the association between obesity and inflammation may lead to insulin resistance and cancer. Diabetes & Metabolic Syndrome: Clinical Research & Reviews. 2019;13(2):1213–1224. doi:10.1016/j.dsx.2019.01.041
4. Lv X, Ding P, Li L, et al. Increased α-HB links colorectal cancer and diabetes by potentiating NF-κB signaling. Mol Metab. 2023;75:101766. doi:10.1016/j.molmet.2023.101766
5. Niture S, Ramalinga M, Kedir H, et al. TNFAIP8 promotes prostate cancer cell survival by inducing autophagy. Oncotarget. 2018;9(42):26884-26899. Published 2018 Jun 1. doi:10.18632/oncotarget.25529
6. Gao HY, Huo FC, Wang HY, Pei DS. MicroRNA-9 inhibits the gastric cancer cell proliferation by targeting TNFAIP8. Cell Prolif. 2017;50(2):e12331. doi:10.1111/cpr.12331