Suppression of local type I interferon by gut microbiota-derived butyrate impairs antitumor effects of ionizing radiation.
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ABSTRACT:
SUBMITTER: Yang K
PROVIDER: S-EPMC7844434 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundThe human gut microbiota is defined as the microorganisms that collectively inhabit the intestinal tract. Its composition is relatively stable; however, an imbalance can be precipitated by various factors and is known to be associated with various diseases. Humans are daily exposed to ionizing radiation from ambient and medical procedures, and gastrointestinal side effects are not rare.MethodsA systematic search of PubMed, EMBASE, and Cochrane Library databases was conducted. Primary outcomes were changes in composition, richness, and diversity of the gut microbiota after ionizing radiation exposure. Standard methodological procedures expected by Cochrane were used.ResultsA total of 2929 nonduplicated records were identified, and based on the inclusion criteria, 11 studies were considered. Studies were heterogeneous, with differences in population and outcomes. Overall, we found evidence for an association between ionizing radiation exposure and dysbiosis: reduction in microbiota diversity and richness, increase in pathogenic bacteria abundance (Proteobacteria and Fusobacteria), and decrease in beneficial bacteria (Faecalibacterium and Bifidobacterium).ConclusionsThis review highlights the importance of considering the influence of ionizing radiation exposure on gut microbiota, especially when considering the side effects of abdominal and pelvic radiotherapy. Better knowledge of these effects, with larger population studies, is needed.
| S-EPMC8465723 | biostudies-literature
Project description:Gut microbiota-derived metabolites are important for the replication and pathogenesis of many viruses. However, the roles of bacterial metabolites in swine enteric coronavirus (SECoV) infection remain poorly understood. Recent studies show that SECoVs infection in vivo significantly alters the composition of short-chain fatty acids (SCFAs)-producing gut microbiota. This prompted us to investigate whether and how SCFAs impact SECoV infection. Employing alphacoronavirus transmissible gastroenteritis virus (TGEV), a major cause of diarrhea in piglets, as a model, we found that SCFAs, particularly butyrate, enhanced TGEV infection both in porcine intestinal epithelial cells and swine testicular (ST) cells at the late stage of viral infection. This effect depended on the inhibited productions of virus-induced type I interferon (IFN) and downstream antiviral IFN-stimulated genes (ISGs) by butyrate. Mechanistically, butyrate suppressed the expression of retinoic acid-inducible gene I (RIG-I), a key viral RNA sensor, and downstream mitochondrial antiviral-signaling (MAVS) aggregation, thereby impairing type I IFN responses and increasing TGEV replication. Using pharmacological and genetic approaches, we showed that butyrate inhibited RIG-I-induced type I IFN signaling by suppressing class I histone deacetylase (HDAC). In summary, we identified a novel mechanism where butyrate enhances TGEV infection by suppressing RIG-I-mediated type I IFN responses. Our findings highlight that gut microbiota-derived metabolites like butyrate can be exploited by SECoV to dampen innate antiviral immunity and establish infection in the intestine.IMPORTANCESwine enteric coronaviruses (SECoVs) infection in vivo alters the composition of short-chain fatty acids (SCFAs)-producing gut microbiota, but whether microbiota-derived SCFAs impact coronavirus gastrointestinal infection is largely unknown. Here, we demonstrated that SCFAs, particularly butyrate, substantially increased alphacoronavirus TGEV infection at the late stage of infection, without affecting viral attachment or internalization. Furthermore, enhancement of TGEV by butyrate depended on impeding virus-induced type I interferon (IFN) responses. Mechanistically, butyrate suppressed the cytoplasmic viral RNA sensor RIG-I expression and downstream type I IFN signaling activation by inhibiting class I HDAC, thereby promoting TGEV infection. Our work reveals novel functions of gut microbiota-derived SCFAs in enhancing enteric coronavirus infection by impairing RIG-I-dependent type I IFN responses. This implies that bacterial metabolites could be therapeutic targets against SECoV infection by modulating antiviral immunity in the intestine.
| S-EPMC10878070 | biostudies-literature
Project description:Overexpression of manganese superoxide dismutase (MnSOD), when combined with certain chemicals that inhibit peroxide removal, increases cancer cell cytotoxicity. Elevating MnSOD levels in cells enhances the conversion of superoxide (O(2)(*-)) to hydrogen peroxide (H(2)O(2)), combined with inhibiting the removal of H(2)O(2), further increases H(2)O(2) levels, leading to increased cytotoxicity. We hypothesized that increasing endogenous O(2)(*-) production in cells that were pretreated with adenoviral MnSOD (AdMnSOD) plus 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) would lead to an increased level of intracellular H(2)O(2) accumulation and increased cell killing. The cytotoxic effects of Adriamycin or radiation, agents known to produce O(2)(*-), were determined in MDA-MB-231 breast cancer cells pretreated with AdMnSOD plus BCNU both in vitro and in vivo. In vitro, AdMnSOD plus BCNU sensitized cells to the cytotoxicity of Adriamycin or radiation. In vivo, AdMnSOD, BCNU, and Adriamycin or ionizing radiation inhibited tumor growth and prolonged survival. The results suggest that agents that produce O(2)(*-) in combination with AdMnSOD plus BCNU may represent a powerful new antitumor regimen against breast cancer.
| S-EPMC2688464 | biostudies-other
Project description:Ionizing radiation has a variety of acute and long-lasting adverse effects on the immune system. Whereas measureable effects of radiation on immune cell cytotoxicity and population change have been well studied in human and animal models, little is known about the functional alterations of the surviving immune cells after ionizing radiation. The objective of this study was to delineate the effects of radiation on T cell function by studying the alterations of T cell receptor activation and metabolic changes in activated T cells isolated from previously irradiated animals. Using a global metabolomics profiling approach, for the first time we demonstrate that ionizing radiation impairs metabolic reprogramming of T cell activation, which leads to substantial decreases in the efficiency of key metabolic processes required for activation, such as glucose uptake, glycolysis, and energy metabolism. In-depth understanding of how radiation impacts T cell function highlighting modulation of metabolism during activation is not only a novel approach to investigate the pivotal processes in the shift of T cell homeostasis after radiation, it also may lead to new targets for therapeutic manipulation in the combination of radiotherapy and immune therapy. Given that appreciable effects were observed with as low as 10 cGy, our results also have implications for low dose environmental exposures.
| S-EPMC4466454 | biostudies-literature
Project description:Ad.Egr-TNF is a radioinducible adenovector currently in phase 3 trials for inoperable pancreatic cancer. The combination of Ad.Egr-TNF and ionizing radiation (IR) contributes to local tumor control through the production of tumor necrosis factor-alpha (TNFalpha) in the tumor microenvironment. Moreover, clinical and preclinical studies with Ad.Egr-TNF/IR have suggested that this local approach suppresses the growth of distant metastatic disease; however, the mechanisms responsible for this effect remain unclear. These studies have been performed in wild-type (WT) and TNFR1,2(-/-) mice to assess the role of TNFalpha-induced signaling in the suppression of draining lymph node (DLN) metastases. The results demonstrate that production of TNFalpha in the tumor microenvironment induces expression of interferon (IFNbeta). In turn, IFNbeta stimulates the production of chemokines that recruit CD8(+) T cells to the tumor. The results further demonstrate that activation of tumor antigen-specific CD8(+) CTLs contributes to local antitumor activity and suppression of DLN metastases. These findings support a model in which treatment of tumors with Ad.Egr-TNF and IR is mediated by local and distant immune-mediated antitumor effects that suppress the development of metastases.
| S-EPMC2890103 | biostudies-literature
Project description:Ionizing radiation (IR)-induced intestinal damage is the major and common injury of patients receiving radiotherapy. Urolithin A (UroA) is a metabolite of the intestinal flora of ellagitannin, a compound found in fruits and nuts such as pomegranates, strawberries and walnuts. UroA shows the immunomodulatory and anti-inflammatory capacity in various metabolic diseases. To evaluate the radioprotective effects, UroA(0.4, 2 and 10 mg/kg) were intraperitoneally injected to C57BL/6 male mice 48, 24, 1 h prior to and 24 h after 9.0Gy TBI. The results showed that UroA markedly upregulated the survival of irradiated mice, especially at concentration of 2 mg/kg. UroA improved the intestine morphology architecture and the regeneration ability of enterocytes in irradiated mice. Then, UroA significantly decreased the apoptosis of enterocytes induced by radiation. Additionally, 16S rRNA sequencing analysis showed the effect of UroA is associated with the recovery of the IR-induced intestinal microbacteria profile changes in mice. Therefore, our results determinated UroA could be developed as a potential candidate for radiomitigators in radiotherapy and accidental nuclear exposure. And the beneficial functions of UroA might be associated with the inhibition of p53-mediated apoptosis and remodelling of the gut microbes.
| S-EPMC8572803 | biostudies-literature
Project description:Gut microbiota has a strong influence on the onset and development of systemic lupus erythematosus (SLE), and several studies have demonstrated the effectiveness of microbiota-derived butyrate to ameliorate SLE. However, the roles of butyrate on gut microbiota in SLE are not understood. Using MRL/lpr lupus-prone mice, we examined gut microbiota profiles after butyrate treatment by 16S rRNA sequencing. Alterations in intestinal microbiome in mice with lupus-like disease were mainly characterized by a reduction in microbial diversity, with an increased abundance of Bacteroidetes and a decrease of Firmicutes. Treatment of lupus-prone mice with butyrate resulted in increased abundance of Firmicutes (P = 0.003), Clostridia (P = 0.005), Clostridiales (P = 0.005), Lachnospiraceae (P = 0.009), Ruminococcaceae (P = 0.021), Peptostreptococcaceae (P = 0.021), Ruminiclostridium (P = 0.016), Oscillibacter (P = 0.048), Romboutsia (P = 0.025), Lachnoclostridium (P = 0.012), Coprococcus (P = 0.015), Ruminococcus (P = 0.011), Clostridium leptum (P < 0.05), and Dorea_spp. (P = 0.019), and a reduced proportion of Bacteroidetes (P = 0.004), Bacteroidia (P = 0.004), and Bacteroidales (P = 0.004). Further, butyrate supplementation could ameliorate kidney damage. Overall, this study suggests that gut microbiota alterations occur in MRL/lpr lupus-prone mice following treatment with butyrate. Butyrate supplementation ameliorated gut microbiota dysbiosis. These findings support the use of butyrate and butyrate-producing bacteria as potential treatments for SLE.
| S-EPMC7688247 | biostudies-literature
Project description:The Sonic Hedgehog (Shh) pathway plays important roles in embryogenesis, stem cell maintenance, tissue repair, and tumorigenesis. Haploinsufficiency of Patched-1, a gene that encodes a repressor of the Shh pathway, dysregulates the Shh pathway and increases genomic instability and the development of spontaneous and ionizing radiation (IR)-induced tumors by an unknown mechanism. Here we show that Ptc1(+/-) mice have a defect in the IR-induced activation of the ATR-Chk1 checkpoint signaling pathway. Likewise, transient expression of Gli1, a downstream target of Shh signaling, disrupts Chk1 activation in human cells by preventing the interaction of Chk1 with Claspin, a Chk1 adaptor protein that is required for Chk1 activation. These results suggest that inappropriate Shh pathway activation promotes tumorigenesis by disabling a key signaling pathway that helps maintain genomic stability and inhibits tumorigenesis.
| S-EPMC2575780 | biostudies-literature
Project description:UnlabelledThe aim of this study was to investigate the effect of iron (Fe) availability on butyrate production in the complex bacterial ecosystem of the human gut. Hence, different Fe availabilities were mimicked in an in vitro colonic fermentation model (the polyfermenter intestinal model called PolyFermS) inoculated with immobilized gut microbiota from a child and in batch cultures of the butyrate producer Roseburia intestinalis. Shifts in the microbial community (16S rRNA sequencing and quantitative PCR), metabolic activity (high-performance liquid chromatography), and expression of genes involved in butyrate production were assessed. In the PolyFermS, moderate Fe deficiency resulted in a 1.4-fold increase in butyrate production and a 5-fold increase in butyryl-coenzyme A (CoA):acetate CoA-transferase gene expression, while very strong Fe deficiency significantly decreased butyrate concentrations and butyrate-producing bacteria compared with the results under normal Fe conditions. Batch cultures of R. intestinalis grown in a low-Fe environment preferentially produced lactate and had reduced butyrate and hydrogen production, in parallel with upregulation of the lactate dehydrogenase gene and downregulation of the pyruvate:ferredoxin-oxidoreductase gene. In contrast, under high-Fe conditions, R. intestinalis cultures showed enhanced butyrate and hydrogen production, along with increased expression of the corresponding genes, compared with the results under normal-Fe conditions. Our data reveal the strong regulatory effect of Fe on gut microbiota butyrate producers and on the concentrations of butyrate, which contributes to the maintenance of host gut health.ImportanceFe deficiency is one of the most common nutritional deficiencies worldwide and can be corrected by Fe supplementation. In this in vitro study, we show that environmental Fe concentrations in a continuous gut fermentation model closely mimicking a child's gut microbiota strongly affect the composition of the gut microbiome and its metabolic activity, particularly butyrate production. The differential expression of genes involved in the butyrate production pathway under different Fe conditions and the enzyme cofactor role of Fe explain the observed modulation of butyrate production. Our data reveal that the level of dietary Fe reaching the colon affects the microbiome, and its essential function of providing the host with beneficial butyrate.
| S-EPMC4659462 | biostudies-literature
Project description:Ferroptosis, a form of regulated cell death caused by lipid peroxidation, was recently identified as a natural tumor suppression mechanism. Here, we show that ionizing radiation (IR) induces ferroptosis in cancer cells. Mechanistically, IR induces not only reactive oxygen species (ROS) but also the expression of ACSL4, a lipid metabolism enzyme required for ferroptosis, resulting in elevated lipid peroxidation and ferroptosis. ACSL4 ablation largely abolishes IR-induced ferroptosis and promotes radioresistance. IR also induces the expression of ferroptosis inhibitors, including SLC7A11 and GPX4, as an adaptive response. IR- or KEAP1 deficiency-induced SLC7A11 expression promotes radioresistance through inhibiting ferroptosis. Inactivating SLC7A11 or GPX4 with ferroptosis inducers (FINs) sensitizes radioresistant cancer cells and xenograft tumors to IR. Furthermore, radiotherapy induces ferroptosis in cancer patients, and increased ferroptosis correlates with better response and longer survival to radiotherapy in cancer patients. Our study reveals a previously unrecognized link between IR and ferroptosis and indicates that further exploration of the combination of radiotherapy and FINs in cancer treatment is warranted.
| S-EPMC7015061 | biostudies-literature