Antioxidant Role of Probiotics in Inflammation-Induced Colorectal Cancer

Abstract

Colorectal cancer (CRC) continues to be a significant contributor to global morbidity and mortality. Emerging evidence indicates that disturbances in gut microbial composition, the formation of reactive oxygen species (ROS), and the resulting inflammation can lead to DNA damage, driving the pathogenesis and progression of CRC. Notably, bacterial metabolites can either protect against or contribute to oxidative stress by modulating the activity of antioxidant enzymes and influencing signaling pathways that govern ROS-induced inflammation. Additionally, microbiota byproducts, when supplemented through probiotics, can affect tumor microenvironments to enhance treatment efficacy and selectively mediate the ROS-induced destruction of CRC cells. This review aims to discuss the mechanisms by which taxonomical shifts in gut microbiota and related metabolites such as short-chain fatty acids, secondary bile acids, and trimethylamine-N-oxide influence ROS concentrations to safeguard or promote the onset of inflammation-mediated CRC. Additionally, we focus on the role of probiotic species in modulating ROS-mediated signaling pathways that influence both oxidative status and inflammation, such as Nrf2-Keap1, NF-κB, and NLRP3 to mitigate carcinogenesis. Overall, a deeper understanding of the role of gut microbiota on oxidative stress may aid in delaying or preventing the onset of CRC and offer new avenues for adjunct, CRC-specific therapeutic interventions such as cancer immunotherapy.

Keywords: antioxidants; bile acids; gut microbiota; oxidative stress; reactive oxygen species.

Figure 1

Visualization of the Nrf2-Keap1 pathway and antioxidant enzyme transcription. Under oxidative stress, Nrf2 is phosphorylated and dissociates from Keap1. Phosphorylated Nrf2 then translocates to the nucleus where it binds to small musculoaponeurotic fibrosarcoma (sMAF), activating the antioxidant response element (ARE). This initiates antioxidant enzyme gene transcription including superoxide dismutase, catalase, glutathione peroxidase, glutathione-S-transferase, and heme-oxygenase 1. Conversely, under physiological conditions, Keap1 targets Nrf2 for proteasomal degradation, and antioxidant enzymatic transcription is not upregulated. Abbreviations: Nrf2, nuclear factor erythroid 2; Keap1, Kelch-like ECH-associated protein 1; ROS, reactive oxygen species; p-Nrf2; phosphorylated Nrf2; ARE, antioxidant response element; sMAF, small musculoaponeurotic fibrosarcoma.

Figure 2

Short chain fatty acids (SCFAs) and antioxidant roles against CRC development. SCFA improves CRC through a reduction in oxidative stress, which enhances antioxidase release and attenuates inflammation. SCFA binding to its receptor, GPR43, and activates the Nrf2-Keap1 pathway. Keap1 dissociates from Nrf2, allowing Nrf2 to enter the nucleus and upregulate the transcription of antioxidant enzymes. This, in turn, reduces ROS concentrations to attenuate the onset of inflammation-induced CRC. On the right, butyrate is shown to enhance HDAC inhibitor activity, which reduces ROS production. Decreased ROS production leads to less activation of the NF-KB signaling pathway and NLRP3 inflammasome, again lessening the development of inflammation-induced CRC. Abbreviations: GPR43, G-coupled Receptor 43; Nrf2, nuclear erythroid factor 2; Keap1, Kelch-like ECH associated protein 1; GST, glutathione-S-transferase; SOD, superoxide dismutase; GPx, glutathione peroxidase; CAT, catalase; ROS, reactive oxygen species; CRC, colorectal cancer; HDACi, histone deacetylase inhibitors; NF-κB, nuclear factor kappa beta; NLRP3, NLR family pyrin domain containing 3.

Figure 3

Secondary bile acids and their oxidative role in development or protection against CRC. Lithocholic acid and deoxycholic acid increase oxidative stress through the activation of membrane-bound NADPH oxidases. In turn, this increases NF-κB inflammatory signaling, thereby worsening intestinal tract inflammation. At the same time, ROS production induced from these secondary bile acids can damage DNA, induce cytochrome C release, and initiate apoptosis. These mechanisms influence CRC development. Conversely, ursodeoxycholic acid is a more favorable secondary bile acid that improves microbial composition and decreases ROS production. The stimulation of ERK1/2 in colon cancer cell lines via UDCA-induced ROS reduction influences cell cycle arrest by preventing cell cycle progression in colon cancer cell lines. This anti-proliferative effect through modulation of oxidative status is beneficial in preventing against progression into CRC. Abbreviations: LCA, lithocholic acid; DCA, deoxycholic acid; UDCA, ursodeoxycholic acid; NOX, NADPH oxidase; ROS, reactive oxygen species; NF-κB, nuclear factor kappa beta; Cyt C, cytochrome C; CRC, colorectal cancer; ERK1/2, extracellular signal-regulated kinase.

Figure 4

Pro-oxidative role of gut etabolite, Trimethylamine-N-Oxide (TMAO) on CRC development. TMAO increases ROS production to initiate inflammatory signaling, mediating the activation of the NLRP3 inflammasome. NLRP3 activity increases pro-inflammatory cytokines, leading to inflammatory gut pathology leading to the onset of inflammation-induced CRC. The administration of N-acetylcysteine, an ROS inhibitor, attenuates TMAO-induced oxidative stress and related inflammation. Abbreviations: ROS, reactive oxygen species; NLRP3, NLRP3, NLR family pyrin domain containing 3; IL-1, interleukin-1; TNF, tumor necrosis factor; IL-6, Interleukin 6; CRC, colorectal cancer.