Gut Microbiota-Derived PGF2α Fights against Radiation-Induced Lung Toxicity through the MAPK/NF-κB Pathway

Abstract

Radiation pneumonia is a common and intractable side effect associated with radiotherapy for chest cancer and involves oxidative stress damage and inflammation, prematurely halting the remedy and reducing the life quality of patients. However, the therapeutic options for the complication have yielded disappointing results in clinical application. Here, we report an effective avenue for fighting against radiation pneumonia. Faecal microbiota transplantation (FMT) reduced radiation pneumonia, scavenged oxidative stress and improved lung function in mouse models. Local chest irradiation shifted the gut bacterial taxonomic proportions, which were preserved by FMT. The level of gut microbiota-derived PGF2α decreased following irradiation but increased after FMT. Experimental mice with PGF2α replenishment, via an oral route, exhibited accumulated PGF2α in faecal pellets, peripheral blood and lung tissues, resulting in the attenuation of inflammatory status of the lung and amelioration of lung respiratory function following local chest irradiation. PGF2α activated the FP/MAPK/NF-κB axis to promote cell proliferation and inhibit apoptosis with radiation challenge; silencing MAPK attenuated the protective effect of PGF2α on radiation-challenged lung cells. Together, our findings pave the way for the clinical treatment of radiotherapy-associated complications and underpin PGF2α as a gut microbiota-produced metabolite.

Gut microbiome and metabolites: The potential key roles in pulmonary fibrosis

“…For example, 10% to 30% of patients with lung or breast cancer who receive radiation therapy will develop radiation-induced pneumonitis, and they are likely to develop radiation-induced lung fibrosis ( Fleckenstein et al, 2007 ; Chao et al, 2017 ). In mice with local chest irradiation, Chen et al (2021) found that Akkermansia, Desulfovibrio and Parasutterella increased and Rikenella decreased at the genus level and that Distasonis , Goldsteinii , and Rodentium decreased at the species level. These changes were ameliorated after FMT ( Chen et al, 2021 ).…”

“…In mice with local chest irradiation, Chen et al (2021) found that Akkermansia, Desulfovibrio and Parasutterella increased and Rikenella decreased at the genus level and that Distasonis , Goldsteinii , and Rodentium decreased at the species level. These changes were ameliorated after FMT ( Chen et al, 2021 ).…”

Global research trends between gut microbiota and lung cancer from 2011 to 2022: A bibliometric and visualization analysis

“…Therefore, regulating the gut microbiota may be an important method to upgrade the efficacy of immunotherapy in lung cancer patients. Moreover, multiple basic studies have reported that the gut microbiota affected the therapeutic effect of chemo-radiotherapy in lung cancer (37, 38), suggesting that modulating the gut microbiota was an important way to improve chemo-radiotherapy sensitivity. However, only two clinical trials of immunotherapy combined with probiotics for lung cancer were searched, with the registration number NCT04699721/ NCT05094167.…”

New Insights into the Relationship between Gut Microbiota and Radiotherapy for Cancer

“…Briefly, l-histidine and the imidazole propionate (ImP) produced by the gut microbiota have protective effects against radiation-induced lung and heart toxicity [ 169 ]. Fecal microbiota transplantation (FMT) can alleviate radiation pneumonia and improve lung function in mice [ 170 ]. Qin et al [ 99 ] showed that phycocyanin could attenuate the lung inflammation and fibrosis induced by radiation via regulating the imbalance of the lung and gut microbiota caused by radiotherapy in mice.…”