The gut microbiota as a booster for radiotherapy: novel insights into radio-protection and radiation injury

Abstract

Approximately 60-80% of cancer patients treated with abdominopelvic radiotherapy suffer post-radiotherapy toxicities including radiation enteropathy and myelosuppression. Effective preventive and therapeutic strategies are lacking for such radiation injury. The gut microbiota holds high investigational value for deepening our understanding of the pathogenesis of radiation injury, especially radiation enteropathy which resembles inflammatory bowel disease pathophysiology and for facilitating personalized medicine by providing safer therapies tailored for cancer patients. Preclinical and clinical data consistently support that gut microbiota components including lactate-producers, SCFA-producers, indole compound-producers and Akkermansia impose intestinal and hematopoietic radio-protection. These features serve as potential predictive biomarkers for radiation injury, together with the microbial diversity which robustly predicts milder post-radiotherapy toxicities in multiple types of cancer. The accordingly developed manipulation strategies including selective microbiota transplantation, probiotics, purified functional metabolites and ligands to microbe-host interactive pathways are promising radio-protectors and radio-mitigators that merit extensive validation in clinical trials. With massive mechanistic investigations and pilot clinical trials reinforcing its translational value the gut microbiota may boost the prediction, prevention and mitigation of radiation injury. In this review, we summarize the state-of-the-art landmark researches related with radio-protection to provide illuminating insights for oncologists, gastroenterologists and laboratory scientists interested in this overlooked complexed disorder.

Keywords: Akkermansia; Gut microbiota; Lactobacillus; Microbiota transplantation; Probiotic; Radio-protection; Short chain fatty acid; Toll-like receptor.

Fig. 1

Microbiota features associated with radiation injury concordantly revealed in clinical and experimental studies. Left panel: Eubiosis associated with radio-protection phenotype in hosts, as featured by increased bacterial diversity and overrepresentation of beneficial microbes like SCFA-producers including Lachnospiraceae as well as Lactobacillus and Akkermansia which promote intestinal stem cell repairment by activating EGF and Wnt pathways. Dynamically, microbial diversity and Lachnospiraceae abundance is consistently reported to decline whereas Akkermansia abundance rises throughout radiotherapy. Right panel: Dysbiosis related with radiation injury vulnerability in hosts, as featured by enrichment of potentially harmful microbes including pro-diarrhea Escherichia, IgA-degrader Sutterella as well as pro-inflammatory Fusobacterium, whose abundances all correspondingly increase after radiotherapy. SDI Shannon diversity index. Created with Biorender.com

Fig. 2

A Microbe-host interactions in radiation injury attenuation and augmentation. Microbes impact radiation injury development by regulating cytotoxicity and repairment in crypt-villous units: 1 Undefined microbes suppress the secretion of Fiaf from epithelium, thereby aggravating enteritis by increasing apoptosis of lymphocytes and endothelial cells in villus mesenchyme. 2 Probiotics-derived lactate interacts with Gpr81 on Paneth cells and stromal cells to stimulate secretion of Wnt3 and Wnt2b, which prompt epithelial replenishment by activating β-catenin pathway in intestinal stem cells. 3 Lactobacillus-derived lipoteichoic acid activates TLR-2/MYD88 on macrophages to induce secretion of chemotactic CXCL12 which binds CXCR4 to mediate the migration of mesenchymal stem cells to where intestinal stem cells locate, so as to boost enterocyte regeneration through the PGE2-EP2-EGF-Akt-Bax pathway. 4 Akkermansia-derived acetate and propionate bind Gpr41/43 to up-regulate the Wnt3/β-catenin-RAS-ERK pathway in intestinal stem cells, so as to promote their renewal and differentiation into secretory cells demonstrated as the thickened mucus layer. B SCFAs and indole compounds produced by representative microorganisms impose radio-protection through regulating inflammation and immune reseponse: 5 SCFAs promote anti-inflammation response and decrease barrier permeability by decreasing DNA damage and cell loss as well as by increasing expression of proteins related with gut integrity maintainment. 6 IPA reactivates the post-radiation declined PXR/ACBP pathway to control inflammation and improve gut integrity. C Microbiota-regulated oxidative stress augments radiation injury: Psedumonas aeruginosa-derived 15-lipoxygenase increases lipid peroxidation, induces ferroptosis and exacerbates inflammation by promoting immunocyte recruitment and elevating proinflammatory cytokines, chemokines and lipid mediators. Pro-inflammatory molecules: LCN2, TNF-α, IL-6, IL-1, IL-2, LTB4, HxA3; anti-inflammatory markers: IL-10, IL-4, TGF-β. Fiaf fasting-induced adipose factor, Gpr G-protein-coupled receptor; TLR-2 Toll-like-receptor-2, PGE2 prostaglandin E2, EP2 E prostaglandin recepter-2, EGF epidermal growth factor, SCFA short chain fatty acid, IPA indole-3-propionic acid, I3A indole-3-carboxaldehyde, ROS = reactive oxygen species, LCN2 lipocalin, KRT1 Keratin, type II cytoskeletal 1, PXR pregnane X receptor, ACBP acyl-CoA binding protein, LTB4 leukotriene B4, HxA3 hepoxilin A3. Created with Biorender.com