Synergistic antiproliferative and pro-apoptotic effects of postbiotics and chemotherapy in human lymphoma cells: mechanistic insights from proteomics and oxidative stress pathways

Abstract

The gut microbiota has emerged as a central regulator of human health and disease, exerting its influence through complex interactions with host immunity, metabolism, and inflammation. Disruptions in gut microbial composition and activity, known as dysbiosis, have been linked to carcinogenesis, including the development of lymphoma. Beyond structural shifts in microbial communities, bioactive metabolites produced by gut microbiota, collectively referred to as postbiotics, exert systemic effects that can modulate tumour initiation, progression, and therapeutic responsiveness. The overarching aim of this thesis was to investigate the anticancer potential of selected gut microbial metabolites, alone and in combination with the chemotherapeutic agent vincristine, against human lymphoma cell lines and to elucidate the molecular mechanisms underlying their synergistic anti-lymphoma effects. Specifically, this thesis aimed to (i) screen multiple gut microbial metabolites for antiproliferative activity against lymphoma cells, (ii) evaluate synergistic interactions between the most promising metabolites, (iii) assess their combined efficacy with vincristine, and (iv) characterise the underlying cellular and proteomic mechanisms of action. Collectively, the results presented in this thesis emphasised the substantial therapeutic potential of integrating food and gut microbiome-derived metabolites into lymphoma treatment regimens. By providing comprehensive mechanistic evidence and synergistic combinations with the standard chemotherapeutic drug Vinc, this proof-of-concept research makes significant contributions to nutritional oncology, microbiome science, and lymphoma. However, the findings are limited by their in vitro nature, reliance on immortalised cell lines, and use of relatively high metabolite concentrations compared to likely physiological levels. In addition, the absence of in vivo animal or organoid models restricts direct translational relevance, and pharmacokinetic and bioavailability aspects of N and UB remain to be addressed. Future studies, including preclinical (animal and organoid) models and clinical trials, are warranted to confirm these promising outcomes and to evaluate practical delivery strategies for the potential implementation of safer, more effective dietary and microbiome-based interventions in lymphoma therapy.

Date of Thesis submission	2025
Original language	English
Awarding Institution	Western Sydney University
Supervisor	Deep Bhuyan (Supervisor)