Chemotherapeutic Drugs Induce Different Gut Microbiota Disorder Pattern and NOD/RIP2/NF-κB Signaling Pathway Activation That Lead to Different Degrees of Intestinal Injury
ABSTRACT 5-Fluorouracil (5-FU), irinotecan (CPT-11), oxaliplatin (L-OHP), and calcium folinate (CF) are widely used chemotherapeutic drugs to treat colorectal cancer. However, chemotherapeutic use is often accompanied by intestinal inflammation and gut microbiota disorder. Changes in gut microbiota...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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American Society for Microbiology
2022-12-01
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| Series: | Microbiology Spectrum |
| Subjects: | |
| Online Access: | https://journals.asm.org/doi/10.1128/spectrum.01677-22 |
| _version_ | 1798003850580328448 |
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| author | Bin Huang Mengxuan Gui Zhuona Ni Yanbin He Jinyan Zhao Jun Peng Jiumao Lin |
| author_facet | Bin Huang Mengxuan Gui Zhuona Ni Yanbin He Jinyan Zhao Jun Peng Jiumao Lin |
| author_sort | Bin Huang |
| collection | DOAJ |
| description | ABSTRACT 5-Fluorouracil (5-FU), irinotecan (CPT-11), oxaliplatin (L-OHP), and calcium folinate (CF) are widely used chemotherapeutic drugs to treat colorectal cancer. However, chemotherapeutic use is often accompanied by intestinal inflammation and gut microbiota disorder. Changes in gut microbiota may destroy the intestinal barrier, which contributes to the severity of intestinal injury. However, intestinal injury and gut microbiota disorder have yet to be compared among 5-FU, CPT-11, L-OHP, and CF in detail, thereby limiting the development of targeted detoxification therapy after chemotherapy. In this study, a model of chemotherapy-induced intestinal injury in tumor-bearing mice was established by intraperitoneally injecting chemotherapeutic drugs at a clinically equivalent dose. 16S rRNA gene sequencing was used to detect gut microbiota. We found that 5-FU, CPT-11, and l-OHP caused intestinal injury, inflammatory cytokine (gamma interferon [IFN-γ], tumor necrosis factor alpha [TNF-α], interleukin-1β [IL-1β], and IL-6) secretion, and gut microbiota disorder. We established a complex but clear network between the pattern of changes in gut microbiota and degree of intestinal damage induced by different chemotherapeutic drugs. L-OHP caused the most severe damage in the intestine and disorder of the gut microbiota and showed a considerable overlap of the pattern of changes in microbiota with 5-FU and CPT-11. Analysis by Phylogenetic Investigation of Communities by Reconstruction of Unobserved States (PICRUSt v.1.0) showed that the microbiota disorder pattern induced by 5-FU, CPT-11, and L-OHP was related to the NOD-like signaling pathway. Therefore, we detected the protein expression of the NOD/RIP2/NF-κB signaling pathway and found that L-OHP most activated this pathway. Redundancy analysis/canonical correlation analysis (RDA/CCA) revealed that Bifidobacterium, Akkermansia, Allobaculum, Catenibacterium, Mucispirillum, Turicibacter, Helicobacter, Proteus, Escherichia Shigella, Alloprevotealla, Vagococcus, Streptococcus, and “Candidatus Saccharimonas” were highly correlated with the NOD/RIP2/NF-κB signaling pathway and influenced by chemotherapeutic drugs. IMPORTANCE Chemotherapy-induced intestinal injury limits the clinical use of drugs. Intestinal injury involves multiple signaling pathways and gut microbiota disruption. Our results suggested that the degree of intestinal injury caused by different drugs of the first-line colorectal chemotherapy regimen is related to the pattern of changes in microbiota. The activation of the NOD/RIP2/NF-κB signaling pathway was also related to the pattern of changes in microbiota. l-OHP caused the most severe damage to the intestine and showed a considerable overlap of the pattern of changes in microbiota with 5-FU and CPT-11. Thirteen bacterial genera were related to different levels of intestinal injury and correlated with the NOD/RIP2/NF-κB pathway. Here, we established a network of different chemotherapeutic drugs, gut microbiota, and the NOD/RIP2/NF-κB signaling pathway. This study likely provided a new basis for further elucidating the mechanism and clinical treatment of intestinal injury caused by chemotherapy. |
| first_indexed | 2024-04-11T12:14:11Z |
| format | Article |
| id | doaj.art-bc82edd8744645549c3de94eb2b0b62d |
| institution | Directory Open Access Journal |
| issn | 2165-0497 |
| language | English |
| last_indexed | 2024-04-11T12:14:11Z |
| publishDate | 2022-12-01 |
| publisher | American Society for Microbiology |
| record_format | Article |
| series | Microbiology Spectrum |
| spelling | doaj.art-bc82edd8744645549c3de94eb2b0b62d2022-12-22T04:24:25ZengAmerican Society for MicrobiologyMicrobiology Spectrum2165-04972022-12-0110610.1128/spectrum.01677-22Chemotherapeutic Drugs Induce Different Gut Microbiota Disorder Pattern and NOD/RIP2/NF-κB Signaling Pathway Activation That Lead to Different Degrees of Intestinal InjuryBin Huang0Mengxuan Gui1Zhuona Ni2Yanbin He3Jinyan Zhao4Jun Peng5Jiumao Lin6Academy of Integrative Medicine of Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian, People’s Republic of ChinaAcademy of Integrative Medicine of Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian, People’s Republic of ChinaAcademy of Integrative Medicine of Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian, People’s Republic of ChinaAcademy of Integrative Medicine of Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian, People’s Republic of ChinaAcademy of Integrative Medicine of Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian, People’s Republic of ChinaAcademy of Integrative Medicine of Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian, People’s Republic of ChinaAcademy of Integrative Medicine of Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian, People’s Republic of ChinaABSTRACT 5-Fluorouracil (5-FU), irinotecan (CPT-11), oxaliplatin (L-OHP), and calcium folinate (CF) are widely used chemotherapeutic drugs to treat colorectal cancer. However, chemotherapeutic use is often accompanied by intestinal inflammation and gut microbiota disorder. Changes in gut microbiota may destroy the intestinal barrier, which contributes to the severity of intestinal injury. However, intestinal injury and gut microbiota disorder have yet to be compared among 5-FU, CPT-11, L-OHP, and CF in detail, thereby limiting the development of targeted detoxification therapy after chemotherapy. In this study, a model of chemotherapy-induced intestinal injury in tumor-bearing mice was established by intraperitoneally injecting chemotherapeutic drugs at a clinically equivalent dose. 16S rRNA gene sequencing was used to detect gut microbiota. We found that 5-FU, CPT-11, and l-OHP caused intestinal injury, inflammatory cytokine (gamma interferon [IFN-γ], tumor necrosis factor alpha [TNF-α], interleukin-1β [IL-1β], and IL-6) secretion, and gut microbiota disorder. We established a complex but clear network between the pattern of changes in gut microbiota and degree of intestinal damage induced by different chemotherapeutic drugs. L-OHP caused the most severe damage in the intestine and disorder of the gut microbiota and showed a considerable overlap of the pattern of changes in microbiota with 5-FU and CPT-11. Analysis by Phylogenetic Investigation of Communities by Reconstruction of Unobserved States (PICRUSt v.1.0) showed that the microbiota disorder pattern induced by 5-FU, CPT-11, and L-OHP was related to the NOD-like signaling pathway. Therefore, we detected the protein expression of the NOD/RIP2/NF-κB signaling pathway and found that L-OHP most activated this pathway. Redundancy analysis/canonical correlation analysis (RDA/CCA) revealed that Bifidobacterium, Akkermansia, Allobaculum, Catenibacterium, Mucispirillum, Turicibacter, Helicobacter, Proteus, Escherichia Shigella, Alloprevotealla, Vagococcus, Streptococcus, and “Candidatus Saccharimonas” were highly correlated with the NOD/RIP2/NF-κB signaling pathway and influenced by chemotherapeutic drugs. IMPORTANCE Chemotherapy-induced intestinal injury limits the clinical use of drugs. Intestinal injury involves multiple signaling pathways and gut microbiota disruption. Our results suggested that the degree of intestinal injury caused by different drugs of the first-line colorectal chemotherapy regimen is related to the pattern of changes in microbiota. The activation of the NOD/RIP2/NF-κB signaling pathway was also related to the pattern of changes in microbiota. l-OHP caused the most severe damage to the intestine and showed a considerable overlap of the pattern of changes in microbiota with 5-FU and CPT-11. Thirteen bacterial genera were related to different levels of intestinal injury and correlated with the NOD/RIP2/NF-κB pathway. Here, we established a network of different chemotherapeutic drugs, gut microbiota, and the NOD/RIP2/NF-κB signaling pathway. This study likely provided a new basis for further elucidating the mechanism and clinical treatment of intestinal injury caused by chemotherapy.https://journals.asm.org/doi/10.1128/spectrum.01677-22colorectal cancerchemotherapeutic drugsintestinal injury5-fluorouracilirinotecanoxaliplatin |
| spellingShingle | Bin Huang Mengxuan Gui Zhuona Ni Yanbin He Jinyan Zhao Jun Peng Jiumao Lin Chemotherapeutic Drugs Induce Different Gut Microbiota Disorder Pattern and NOD/RIP2/NF-κB Signaling Pathway Activation That Lead to Different Degrees of Intestinal Injury Microbiology Spectrum colorectal cancer chemotherapeutic drugs intestinal injury 5-fluorouracil irinotecan oxaliplatin |
| title | Chemotherapeutic Drugs Induce Different Gut Microbiota Disorder Pattern and NOD/RIP2/NF-κB Signaling Pathway Activation That Lead to Different Degrees of Intestinal Injury |
| title_full | Chemotherapeutic Drugs Induce Different Gut Microbiota Disorder Pattern and NOD/RIP2/NF-κB Signaling Pathway Activation That Lead to Different Degrees of Intestinal Injury |
| title_fullStr | Chemotherapeutic Drugs Induce Different Gut Microbiota Disorder Pattern and NOD/RIP2/NF-κB Signaling Pathway Activation That Lead to Different Degrees of Intestinal Injury |
| title_full_unstemmed | Chemotherapeutic Drugs Induce Different Gut Microbiota Disorder Pattern and NOD/RIP2/NF-κB Signaling Pathway Activation That Lead to Different Degrees of Intestinal Injury |
| title_short | Chemotherapeutic Drugs Induce Different Gut Microbiota Disorder Pattern and NOD/RIP2/NF-κB Signaling Pathway Activation That Lead to Different Degrees of Intestinal Injury |
| title_sort | chemotherapeutic drugs induce different gut microbiota disorder pattern and nod rip2 nf κb signaling pathway activation that lead to different degrees of intestinal injury |
| topic | colorectal cancer chemotherapeutic drugs intestinal injury 5-fluorouracil irinotecan oxaliplatin |
| url | https://journals.asm.org/doi/10.1128/spectrum.01677-22 |
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