Engineering the holobiont: Synthetic biology strategies for reversing bioenergetic collapse in radiation enteritis

Yingqi Li; Jiuping Liang; Hui Yin; Tao Liu; Yingqi Li; Jiuping Liang; Hui Yin; Tao Liu

doi:10.3934/microbiol.2026003

AIMS Microbiology

2026, Volume 12, Issue 1: 63-91. doi: 10.3934/microbiol.2026003

Previous Article Next Article

Review

Engineering the holobiont: Synthetic biology strategies for reversing bioenergetic collapse in radiation enteritis

Yingqi Li ¹,
Jiuping Liang ¹,
Hui Yin ^{2
,
,},
Tao Liu ^{2
,
,}

1.
Shenzhen Bao'an District Songgang People's Hospital, Shenzhen Bao'an Medical College of Guangdong Pharmaceutical University, Shenzhen, 518105, China
2.
Guangdong Provincial Key Laboratory of Pharmaceutical Bioactive Substances, School of Basic Medical Sciences, Guangdong Pharmaceutical University, Guangzhou 510006, China

Received: 05 January 2026 Revised: 03 February 2026 Accepted: 10 February 2026 Published: 13 February 2026

Radiation enteritis (RE) constitutes a catastrophic collapse of the intestinal holobiont, fundamentally constraining the curative potential of abdominopelvic radiotherapy. Current clinical management, limited by a reductionist focus on host DNA damage, often overlooks the maladaptive ecological feedback loops driving chronic pathology. This review advocates for a definitive transition from empirical probiotic supplementation to microbial synthetic biology for the rational reprogramming of the gut ecosystem. We delineate strategies for thermodynamic engineering, utilizing engineered commensals as living oxygen sinks to scavenge luminal oxygen and nitrate, thereby starving proteobacterial blooms and restoring the physiological hypoxia essential for mucosal recovery. Addressing the Akkermansia paradox, in which nutrient deprivation drives beneficial microbes toward mucin-degrading pathogenicity, we propose genetic domestication (e.g., sulfatase deletion) to decouple immunogenicity from barrier erosion. Furthermore, we explore the design of biological computers equipped with Boolean logic gates to resolve the immunological timing paradox by precisely modulating the cGAS-STING axis and reprogramming macrophage metabolism via the itaconate shunt. Integrating armored polydopamine delivery, genetic entanglement (STALEMATE) for biocontainment, and Gut-on-a-Chip validation, we outline a roadmap for colonic terraformation. This engineering-driven approach aims to actively reconstruct homeostasis, uniquely decoupling epithelial regeneration from tumor protection to improve long-term cancer survival.
- radiation enteritis,
- microbial synthetic biology,
- holobiont engineering,
- immunomodulation,
- bioenergetic collapse,
- living biotherapeutic products,
- Akkermansia muciniphila,
- colonic terraformation,
- logic gates,
- gut-on-a-chip
Citation: Yingqi Li, Jiuping Liang, Hui Yin, Tao Liu. Engineering the holobiont: Synthetic biology strategies for reversing bioenergetic collapse in radiation enteritis[J]. AIMS Microbiology, 2026, 12(1): 63-91. doi: 10.3934/microbiol.2026003

Related Papers:

Abstract

Radiation enteritis (RE) constitutes a catastrophic collapse of the intestinal holobiont, fundamentally constraining the curative potential of abdominopelvic radiotherapy. Current clinical management, limited by a reductionist focus on host DNA damage, often overlooks the maladaptive ecological feedback loops driving chronic pathology. This review advocates for a definitive transition from empirical probiotic supplementation to microbial synthetic biology for the rational reprogramming of the gut ecosystem. We delineate strategies for thermodynamic engineering, utilizing engineered commensals as living oxygen sinks to scavenge luminal oxygen and nitrate, thereby starving proteobacterial blooms and restoring the physiological hypoxia essential for mucosal recovery. Addressing the Akkermansia paradox, in which nutrient deprivation drives beneficial microbes toward mucin-degrading pathogenicity, we propose genetic domestication (e.g., sulfatase deletion) to decouple immunogenicity from barrier erosion. Furthermore, we explore the design of biological computers equipped with Boolean logic gates to resolve the immunological timing paradox by precisely modulating the cGAS-STING axis and reprogramming macrophage metabolism via the itaconate shunt. Integrating armored polydopamine delivery, genetic entanglement (STALEMATE) for biocontainment, and Gut-on-a-Chip validation, we outline a roadmap for colonic terraformation. This engineering-driven approach aims to actively reconstruct homeostasis, uniquely decoupling epithelial regeneration from tumor protection to improve long-term cancer survival.

Acknowledgments

This research was funded by grants from the National Natural Science Foundation of China (No. 82171700), Key Area Project of General Universities in Guangdong Province (No. 2024ZDZX2080) and Joint Cultivation Research Fund of Guangdong Pharmaceutical University - Shenzhen Bao'an District Songgang People's Hospital (SGYY2024A007).

Conflict of interest

The authors declare no conflict of interest.

Author contributions

Yingqi Li: Funding acquisition, Writing–original draft, Conceptualization, Writing–review & editing. Jiuping Liang: Writing–review & editing. Hui Yin: Writing–review & editing. Tao Liu: Funding acquisition, Writing–original draft, Conceptualization, Writing–review & editing.

References

[1]	Barnett GC, West CM, Dunning AM, et al. (2009) Normal tissue reactions to radiotherapy: Towards tailoring treatment dose by genotype. Nat Rev Cancer 9: 134-142. https://doi.org/10.1038/nrc2587
[2]	Wang K, Tepper JE (2021) Radiation therapy-associated toxicity: Etiology, management, and prevention. CA Cancer J Clin 71: 437-454. https://doi.org/10.3322/caac.21689
[3]	Zhou Q, Liu L, Lin X, et al. (2025) Nicotinamide riboside attenuates radiation-induced intestinal injury by suppressing gasdermin E-mediated pyroptosis in intestinal epithelial cells. J Transl Med 23: 1126. https://doi.org/10.1186/s12967-025-07012-1
[4]	Hauer-Jensen M, Denham JW, Andreyev HJN (2014) Radiation enteropathy—pathogenesis, treatment and prevention. Nat Rev Gastroenterol Hepatol 11: 470-479. https://doi.org/10.1038/nrgastro.2014.46
[5]	Hill MA (2018) Track to the future: Historical perspective on the importance of radiation track structure and DNA as a radiobiological target. Int J Radiat Biol 94: 759-768. https://doi.org/10.1080/09553002.2017.1387304
[6]	Bodgi L, Pujo-Menjouet L, Bouchet A, et al. (2024) Seventy years of dose-response models: From the target theory to the use of big databases involving cell survival and DNA repair. Radiat Res 202: 130-142. https://doi.org/10.1667/RADE-24-00015.1
[7]	McMahon SJ (2018) The linear quadratic model: usage, interpretation and challenges. Phys Med Biol 64: 01TR01. https://doi.org/10.1088/1361-6560/aaf26a
[8]	Albenberg L, Esipova TV, Judge CP, et al. (2014) Correlation between intraluminal oxygen gradient and radial partitioning of intestinal microbiota. Gastroenterology 147: 1055-1063.e8. https://doi.org/10.1053/j.gastro.2014.07.020
[9]	Lee JY, Bays DJ, Savage HP, et al. (2024) The human gut microbiome in health and disease: Time for a new chapter?. Infect Immun 92: e00302-24. https://doi.org/10.1128/iai.00302-24
[10]	Savage HP, Bays DJ, Tiffany CR, et al. (2024) Epithelial hypoxia maintains colonization resistance against Candida albicans. Cell Host Microbe 32: 1103-1113.e6. https://doi.org/10.1016/j.chom.2024.05.008
[11]	Wang Y, Wang X, Chen Z, et al. (2025) Akkermansia muciniphila exacerbates acute radiation–induced intestinal injury by depleting mucin and enhancing inflammation. ISME J 19: wraf084. https://doi.org/10.1093/ismejo/wraf084
[12]	Pujo J, Petitfils C, Le Faouder P, et al. (2021) Bacteria-derived long chain fatty acid exhibits anti-inflammatory properties in colitis. Gut 70: 1088-1097. https://doi.org/10.1136/gutjnl-2020-321173
[13]	Singhal R, Shah YM (2020) Oxygen battle in the gut: Hypoxia and hypoxia-inducible factors in metabolic and inflammatory responses in the intestine. J Biol Chem 295: 10493-10505. https://doi.org/10.1074/jbc.REV120.011188
[14]	Iqbal S, Andersson S, Nesta E, et al. (2025) Fetal-like reversion in the regenerating intestine is regulated by mesenchymal asporin. Cell Stem Cell 32: 613-626.e8. https://doi.org/10.1016/j.stem.2025.02.009
[15]	Parker W, Perkins SE, Harker M, et al. (2012) A prescription for clinical immunology: The pills are available and ready for testing. A review. Curr Med Res Opin 28: 1193-1202. https://doi.org/10.1185/03007995.2012.695731
[16]	Sun R, Li S, Chen Z, et al. (2025) Oral Antioxidant-Engineered Probiotics for the Treatment of Radiation-Induced Colitis. ACS Appl Mater Interfaces 17: 10316-10327. https://doi.org/10.1021/acsami.4c17651
[17]	Cubillos-Ruiz A, Guo T, Sokolovska A, et al. (2021) Engineering living therapeutics with synthetic biology. Nat Rev Drug Discov 20: 941-960. https://doi.org/10.1038/s41573-021-00285-3
[18]	Riglar DT, Silver PA (2018) Engineering bacteria for diagnostic and therapeutic applications. Nat Rev Microbiol 16: 214-225. https://doi.org/10.1038/nrmicro.2017.172
[19]	Litvak Y, Byndloss MX, Bäumler AJ (2018) Colonocyte metabolism shapes the gut microbiota. Science 362: eaat9076. https://doi.org/10.1126/science.aat9076
[20]	Byndloss MX, Bäumler AJ (2018) The germ-organ theory of non-communicable diseases. Nat Rev Microbiol 16: 103-110. https://doi.org/10.1038/nrmicro.2017.158
[21]	Zerfaß C, Chen J, Soyer OS (2018) Engineering microbial communities using thermodynamic principles and electrical interfaces. Curr Opin Biotechnol 50: 121-127. https://doi.org/10.1016/j.copbio.2017.12.004
[22]	Imlay JA (2008) Cellular defenses against superoxide and hydrogen peroxide. Annu Rev Biochem 77: 755-776. https://doi.org/10.1146/annurev.biochem.77.061606.161055
[23]	Kam WWY, Banati RB (2013) Effects of ionizing radiation on mitochondria. Free Radic Biol Med 65: 607-619. https://doi.org/10.1016/j.freeradbiomed.2013.07.024
[24]	Wang W, Yu Y, Wang R, et al. (2026) Holdemanella biformis augments washed microbiota transplantation for the treatment of radiation enteritis. Gut 75: 289-301. https://doi.org/10.1136/gutjnl-2025-335230
[25]	He Y, Zhao G, Ouyang X, et al. (2025) Creatine-mediated ferroptosis inhibition is involved in the intestinal radioprotection of daytime-restricted feeding. Gut Microbes 17: 2489072. https://doi.org/10.1080/19490976.2025.2489072
[26]	Rivera-Chávez F, Zhang LF, Faber F, et al. (2016) Depletion of butyrate-producing clostridia from the gut microbiota drives an aerobic luminal expansion of salmonella. Cell Host Microbe 19: 443-454. https://doi.org/10.1016/j.chom.2016.03.004
[27]	Lu Q, Liang Y, Tian S, et al. (2023) Radiation-induced intestinal injury: Injury mechanism and potential treatment strategies. Toxics 11: 1011. https://doi.org/10.3390/toxics11121011
[28]	Winter SE, Bäumler AJ (2023) Gut dysbiosis: Ecological causes and causative effects on human disease. Proc Natl Acad Sci U S A 120: e2316579120. https://doi.org/10.1073/pnas.2316579120
[29]	Winter SE, Thiennimitr P, Winter MG, et al. (2010) Gut inflammation provides a respiratory electron acceptor for Salmonella. Nature 467: 426-429. https://doi.org/10.1038/nature09415
[30]	Moran M, Malmuthuge N, Guan LL (2025) Harnessing gut microbiota to mitigate Salmonella Dublin: Lessons from S. Typhimurium. Virulence 16: 2590844. https://doi.org/10.1080/21505594.2025.2590844
[31]	Borisov VB, Siletsky SA, Paiardini A, et al. (2021) Bacterial oxidases of the cytochrome bd family: Redox enzymes of unique structure, function, and utility as drug targets. Antioxid Redox Signal 34: 1280-1318. https://doi.org/10.1089/ars.2020.8039
[32]	Rottinghaus AG, Amrofell MB, Moon TS (2020) Biosensing in smart engineered probiotics. Biotechnol J 15: e1900319. https://doi.org/10.1002/biot.201900319
[33]	Zhang D, Zhong D, Ouyang J, et al. (2022) Microalgae-based oral microcarriers for gut microbiota homeostasis and intestinal protection in cancer radiotherapy. Nat Commun 13: 1413. https://doi.org/10.1038/s41467-022-28744-4
[34]	Cavaliere M, Feng S, Soyer OS, et al. (2017) Cooperation in microbial communities and their biotechnological applications. Environ Microbiol 19: 2949-2963. https://doi.org/10.1111/1462-2920.13767
[35]	Coyte KZ, Schluter J, Foster KR (2015) The ecology of the microbiome: Networks, competition, and stability. Science 350: 663-666. https://doi.org/10.1126/science.aad2602
[36]	Zhao L (2025) Guild-level response of the gut microbiome to nutritional signals: Advancing precision nutrition for metabolic health. Annu Rev Nutr 45: 197-221. https://doi.org/10.1146/annurev-nutr-122424-022254
[37]	Charbonneau MR, Isabella VM, Li N, et al. (2020) Developing a new class of engineered live bacterial therapeutics to treat human diseases. Nat Commun 11: 1738. https://doi.org/10.1038/s41467-020-15508-1
[38]	Li L, Yang Z, Yi Y, et al. (2025) Gut microbiota and radiation-induced injury: Mechanistic insights and microbial therapies. Gut Microbes 17: 2528429. https://doi.org/10.1080/19490976.2025.2528429
[39]	Tewari N, Dey P (2024) Navigating commensal dysbiosis: gastrointestinal host-pathogen interplay orchestrating opportunistic infections. Microbiol Res 286: 127832. https://doi.org/10.1016/j.micres.2024.127832
[40]	Lei W, Cheng Y, Gao J, et al. (2023) Akkermansia muciniphila in neuropsychiatric disorders: Friend or foe?. Front Cell Infect Microbiol 13: 1224155. https://doi.org/10.3389/fcimb.2023.1224155
[41]	Yang Y, Liu F, Zeng D, et al. (2025) Expressing Vitreoscilla hemoglobin in Escherichia coli Nissle 1917 enhances its probiotic potential for alleviating ulcerative colitis. J Control Release 386: 114149. https://doi.org/10.1016/j.jconrel.2025.114149
[42]	Tachon S, Brandsma JB, Yvon M (2010) NoxE NADH oxidase and the electron transport chain are responsible for the ability of lactococcus lactis to decrease the redox potential of milk. Appl Environ Microbiol 76: 1311-1319. https://doi.org/10.1128/AEM.02120-09
[43]	Rivera-Chávez F, Lopez CA, Zhang LF, et al. (2016) Energy taxis toward host-derived nitrate supports a salmonella pathogenicity island 1-independent mechanism of invasion. mBio 7: e00960-16. https://doi.org/10.1128/mbio.00960-16
[44]	Wu J, Huang H, Wang L, et al. (2024) A tailored series of engineered yeasts for the cell-dependent treatment of inflammatory bowel disease by rational butyrate supplementation. Gut Microbes 16: 2316575. https://doi.org/10.1080/19490976.2024.2316575
[45]	Wang L, Cheng X, Bai L, et al. (2022) Positive interventional effect of engineered butyrate-producing bacteria on metabolic disorders and intestinal flora disruption in obese mice. Microbiol Spectr 10: e0114721. https://doi.org/10.1128/spectrum.01147-21
[46]	Lee JS, Kao DJ, Worledge CS, et al. (2025) E. coli genetically modified for purine nucleobase release promotes butyrate generation and colonic wound healing during DSS insult. Gut Microbes 17: 2490211. https://doi.org/10.1080/19490976.2025.2490211
[47]	Liao Z, Hu C, Gao Y (2022) Mechanisms modulating the activities of intestinal stem cells upon radiation or chemical agent exposure. J Radiat Res 63: 149-157. https://doi.org/10.1093/jrr/rrab124
[48]	Kostopoulos I, Aalvink S, Kovatcheva-Datchary P, et al. (2021) A continuous battle for host-derived glycans between a mucus specialist and a glycan generalist in vitro and in vivo. Front Microbiol 12: 632454. https://doi.org/10.3389/fmicb.2021.632454
[49]	Tingler AM, Engevik MA (2025) Breaking down barriers: Is intestinal mucus degradation by Akkermansia muciniphila beneficial or harmful?. Infect Immun 93: e0050324. https://doi.org/10.1128/iai.00503-24
[50]	Li L, Li M, Chen Y, et al. (2024) Function and therapeutic prospects of next-generation probiotic Akkermansia muciniphila in infectious diseases. Front Microbiol 15: 1354447. https://doi.org/10.3389/fmicb.2024.1354447
[51]	Cani PD, Depommier C, Derrien M, et al. (2022) Akkermansia muciniphila: Paradigm for next-generation beneficial microorganisms. Nat Rev Gastroenterol Hepatol 19: 625-637. https://doi.org/10.1038/s41575-022-00631-9
[52]	Everard A, Belzer C, Geurts L, et al. (2013) Cross-talk between Akkermansia muciniphila and intestinal epithelium controls diet-induced obesity. Proc Natl Acad Sci U S A 110: 9066-9071. https://doi.org/10.1073/pnas.1219451110
[53]	Plovier H, Everard A, Druart C, et al. (2017) A purified membrane protein from Akkermansia muciniphila or the pasteurized bacterium improves metabolism in obese and diabetic mice. Nat Med 23: 107-113. https://doi.org/10.1038/nm.4236
[54]	Wang L, Tang L, Feng Y, et al. (2020) A purified membrane protein from Akkermansia muciniphila or the pasteurised bacterium blunts colitis associated tumourigenesis by modulation of CD8+ T cells in mice. Gut 69: 1988-1997. https://doi.org/10.1136/gutjnl-2019-320105
[55]	Bakshani CR, Ojuri TO, Pilgaard B, et al. (2025) Carbohydrate-active enzymes from Akkermansia muciniphila break down mucin O-glycans to completion. Nat Microbiol 10: 585-598. https://doi.org/10.1038/s41564-024-01911-7
[56]	Ioannou A, Berkhout MD, Geerlings SY, et al. (2025) Akkermansia muciniphila: Biology, microbial ecology, host interactions and therapeutic potential. Nat Rev Microbiol 23: 162-177. https://doi.org/10.1038/s41579-024-01106-1
[57]	Luis AS, Jin C, Pereira GV, et al. (2021) A single sulfatase is required to access colonic mucin by a gut bacterium. Nature 598: 332-337. https://doi.org/10.1038/s41586-021-03967-5
[58]	Soheilipour M, Noursina A, Nekookhoo M, et al. (2025) The pathobiont role of Akkermansia muciniphila in colorectal cancer: A systematic review. BMC Gastroenterol 25: 702. https://doi.org/10.1186/s12876-025-04293-0
[59]	Panzetta ME, Valdivia RH (2024) Akkermansia in the gastrointestinal tract as a modifier of human health. Gut Microbes 16: 2406379. https://doi.org/10.1080/19490976.2024.2406379
[60]	Davey LE, Malkus PN, Villa M, et al. (2023) A genetic system for Akkermansia muciniphila reveals a role for mucin foraging in gut colonization and host sterol biosynthesis gene expression. Nat Microbiol 8: 1450-1467. https://doi.org/10.1038/s41564-023-01407-w
[61]	Steidler L, Neirynck S, Huyghebaert N, et al. (2003) Biological containment of genetically modified Lactococcus lactis for intestinal delivery of human interleukin 10. Nat Biotechnol 21: 785-789. https://doi.org/10.1038/nbt840
[62]	Kunjapur AM, Napolitano MG, Hysolli E, et al. (2021) Synthetic auxotrophy remains stable after continuous evolution and in coculture with mammalian cells. Sci Adv 7: eabf5851. https://doi.org/10.1126/sciadv.abf5851
[63]	Foo GW, Leichthammer CD, Saita IM, et al. (2024) Intein-based thermoregulated meganucleases for containment of genetic material. Nucleic Acids Res 52: 2066-2077. https://doi.org/10.1093/nar/gkad1247
[64]	Chin YW, Kim JY, Kim JH, et al. (2017) Improved production of 2′-fucosyllactose in engineered Escherichia coli by expressing putative α-1,2-fucosyltransferase, WcfB from Bacteroides fragilis. J Biotechnol 257: 192-198. https://doi.org/10.1016/j.jbiotec.2016.11.033
[65]	Praveschotinunt P, Duraj-Thatte AM, Gelfat I, et al. (2019) Engineered E. coli Nissle 1917 for the delivery of matrix-tethered therapeutic domains to the gut. Nat Commun 10: 5580. https://doi.org/10.1038/s41467-019-13336-6
[66]	Zhang FL, Yang YL, Zhang Z, et al. (2021) Surface-displayed Amuc_1100 from Akkermansia muciniphila on lactococcus lactis ZHY1 improves hepatic steatosis and intestinal health in high-fat-fed zebrafish. Front Nutr 8: 726108. https://doi.org/10.3389/fnut.2021.726108
[67]	Di W, Zhang Y, Zhang X, et al. (2024) Heterologous expression of P9 from Akkermansia muciniphila increases the GLP-1 secretion of intestinal L cells. World J Microbiol Biotechnol 40: 199. https://doi.org/10.1007/s11274-024-04012-z
[68]	Kruger AG, Brucks SD, Yan T, et al. (2021) Stereochemical control yields mucin mimetic polymers. ACS Cent Sci 7: 624-630. https://doi.org/10.1021/acscentsci.0c01569
[69]	Alty JW, Barnes CE, Nicoli AM, et al. (2025) Synthetic mucins as glycan-defined prebiotics. ACS Cent Sci 11: 918-926. https://doi.org/10.1021/acscentsci.5c00317
[70]	Ottman N, Reunanen J, Meijerink M, et al. (2017) Pili-like proteins of Akkermansia muciniphila modulate host immune responses and gut barrier function. PLoS One 12: e0173004. https://doi.org/10.1371/journal.pone.0173004
[71]	Wheeler KM, Carcamo-Oyarce G, Turner BS, et al. (2019) Mucin glycans attenuate the virulence of Pseudomonas aeruginosa in infection. Nat Microbiol 4: 2146-2154. https://doi.org/10.1038/s41564-019-0581-8
[72]	Sheinboim D, Parikh S, Manich P, et al. (2022) An exercise-induced metabolic shield in distant organs blocks cancer progression and metastatic dissemination. Cancer Res 82: 4164-4178. https://doi.org/10.1158/0008-5472.CAN-22-0237
[73]	Wang L, Lynch C, Pitroda SP, et al. (2024) Radiotherapy and immunology. J Exp Med 221: e20232101. https://doi.org/10.1084/jem.20232101
[74]	Cheng J, Wu H, Cui Y (2024) WNT4 promotes the symmetric fission of crypt in radiation-induced intestinal epithelial regeneration. Cell Mol Biol Lett 29: 158. https://doi.org/10.1186/s11658-024-00677-4
[75]	Li Q, Liu X, Shao L, et al. (2025) Efficacy and safety of local glucocorticoids for the treatment of acute radiation-induced intestinal injury: Protocol of a multicenter randomized controlled trial. Front Pharmacol 16: 1529977. https://doi.org/10.3389/fphar.2025.1529977
[76]	Sadhu S, Paul T, Yadav N (2025) Therapeutic engineering of the gut microbiome using synthetic biology and metabolic tools: A comprehensive review with E. coli Nissle 1917 as a model case study. Arch Microbiol 207: 213. https://doi.org/10.1007/s00203-025-04417-w
[77]	Rutter JW, Dekker L, Owen KA, et al. (2022) Microbiome engineering: engineered live biotherapeutic products for treating human disease. Front Bioeng Biotechnol 10: 1000873. https://doi.org/10.3389/fbioe.2022.1000873
[78]	Srivastava R, Lesser CF (2024) Living engineered bacterial therapeutics: Emerging affordable precision interventions. Microb Biotechnol 17: e70057. https://doi.org/10.1111/1751-7915.70057
[79]	Boopathi E, Den RB, Thangavel C (2023) Innate immune system in the context of radiation therapy for cancer. Cancers (Basel) 15: 3972. https://doi.org/10.3390/cancers15153972
[80]	Wu W, Cai Y, Yang Z, et al. (2025) Radiation-induced intestinal injury: From molecular mechanisms to clinical translation. Oncol Rev 19: 1613704. https://doi.org/10.3389/or.2025.1613704
[81]	Harding SM, Benci JL, Irianto J, et al. (2017) Mitotic progression following DNA damage enables pattern recognition within micronuclei. Nature 548: 466-470. https://doi.org/10.1038/nature23470
[82]	Leibowitz BJ, Zhao G, Wei L, et al. (2021) Interferon β drives intestinal regeneration after radiation. Sci Adv 7: eabi5253. https://doi.org/10.1126/sciadv.abi5253
[83]	McMahon RA, D'Souza C, Neeson PJ, et al. (2023) Innate immunity: Looking beyond T-cells in radiation and immunotherapy combinations. Neoplasia 46: 100940. https://doi.org/10.1016/j.neo.2023.100940
[84]	Ablasser A, Chen ZJ (2019) cGAS in action: Expanding roles in immunity and inflammation. Science 363: eaat8657. https://doi.org/10.1126/science.aat8657
[85]	Kumar S, Kumar K, Angdisen J, et al. (2025) cGAS/STING pathway mediates accelerated intestinal cell senescence and SASP after GCR exposure in mice. Cells 14: 1767. https://doi.org/10.3390/cells14221767
[86]	Moretti J, Roy S, Bozec D, et al. (2017) STING senses microbial viability to orchestrate stress-mediated autophagy of the endoplasmic reticulum. Cell 171: 809-823.e13. https://doi.org/10.1016/j.cell.2017.09.034
[87]	Lv C, Hu X, Li X, et al. (2025) Engineered probiotic alleviates ulcerative colitis by inhibiting M1 macrophage polarization via glycolytic reprogramming. Bioeng Transl Med 10: e70067. https://doi.org/10.1002/btm2.70067
[88]	Merk LN, Shur AS, Jena S, et al. (2024) Diagnostic and Therapeutic Microbial Circuit with Application to Intestinal Inflammation. ACS Synth Biol 13: 3885-3896. https://doi.org/10.1021/acssynbio.3c00668
[89]	Daeffler KNM, Galley JD, Sheth RU, et al. (2017) Engineering bacterial thiosulfate and tetrathionate sensors for detecting gut inflammation. Mol Syst Biol 13: 923. https://doi.org/10.15252/msb.20167416
[90]	Aboelella NS, Brandle C, Kim T, et al. (2021) Oxidative Stress in the Tumor Microenvironment and Its Relevance to Cancer Immunotherapy. Cancers (Basel) 13: 986. https://doi.org/10.3390/cancers13050986
[91]	Armstrong A, Isalan M (2024) Engineering bacterial theranostics: From logic gates to in vivo applications. Front Bioeng Biotechnol 12: 1437301. https://doi.org/10.3389/fbioe.2024.1437301
[92]	Chien T, Doshi A, Danino T (2017) Advances in bacterial cancer therapies using synthetic biology. Curr Opin Syst Biol 5: 1-8. https://doi.org/10.1016/j.coisb.2017.05.009
[93]	Weibel N, Curcio M, Schreiber A, et al. (2024) Engineering a novel probiotic toolkit in Escherichia coli Nissle 1917 for sensing and mitigating gut inflammatory diseases. ACS Synth Biol 13: 2376-2390. https://doi.org/10.1021/acssynbio.4c00036
[94]	Zhu D, Galley J, Pizzini J, et al. (2025) Microbial biosensor for sensing and treatment of intestinal inflammation. Adv Sci 12: 2504364. https://doi.org/10.1002/advs.202504364
[95]	Chowdhury S, Castro S, Coker C, et al. (2019) Programmable bacteria induce durable tumor regression and systemic antitumor immunity. Nat Med 25: 1057-1063. https://doi.org/10.1038/s41591-019-0498-z
[96]	Woo SG, Kim SK, Lee SG, et al. (2025) Engineering probiotic Escherichia coli for inflammation-responsive indoleacetic acid production using RiboJ-enhanced genetic circuits. J Biol Eng 19: 10. https://doi.org/10.1186/s13036-025-00479-y
[97]	Piraner DI, Abedi MH, Moser BA, et al. (2017) Tunable thermal bioswitches for in vivo control of microbial therapeutics. Nat Chem Biol 13: 75-80. https://doi.org/10.1038/nchembio.2233
[98]	Liu S, Tang FL, Yan XL, et al. (2025) Succinate promotes M1 polarization of intestinal macrophages in mice with necrotizing enterocolitis through the PI3K/AKT pathway. Pediatr Discov 3: e70026. https://doi.org/10.1002/pdi3.70026
[99]	Che M, Wei W, Yang X, et al. (2025) Radiation-induced upregulation of itaconate in macrophages promotes the radioresistance of non-small cell lung cancer by stabilizing NRF2 protein and suppressing immune response. Redox Biol 85: 103711. https://doi.org/10.1016/j.redox.2025.103711
[100]	Huangfu S, Lan C, Li S, et al. (2025) Itaconate suppresses neonatal intestinal inflammation via metabolic reprogramming of M1 macrophage. Clin Transl Med 15: e70419. https://doi.org/10.1002/ctm2.70419
[101]	Liu Y, Zhan J, Wang J, et al. (2025) Ferroptosis: A double-edged sword that enhances radiation sensitivity and facilitates radiation-induced injury in tumors. Front Immunol 16: 1591172. https://doi.org/10.3389/fimmu.2025.1591172
[102]	Xie LW, Cai S, Lu HY, et al. (2024) Microbiota-derived I3A protects the intestine against radiation injury by activating AhR/IL-10/Wnt signaling and enhancing the abundance of probiotics. Gut Microbes 16: 2347722. https://doi.org/10.1080/19490976.2024.2347722
[103]	Ji Q, Fu S, Zuo H, et al. (2022) ACSL4 is essential for radiation-induced intestinal injury by initiating ferroptosis. Cell Death Discov 8: 332. https://doi.org/10.1038/s41420-022-01127-w
[104]	Li K, Zhou R, Yin Z, et al. (2025) Role of ferroptosis in the redox biology of mycotoxins. FASEB J 39: e70916. https://doi.org/10.1096/fj.202501371R
[105]	Ozkan A, Merry G, Piatok J, et al. (2025) Discovery of a radiation countermeasure therapeutic for intestinal injury enabled by human organ chips combined with AI. medRxiv : 2025.10.03.25337298. https://doi.org/10.1101/2025.10.03.25337298
[106]	Zhao X, Ji K, Zhang M, et al. (2023) NMN alleviates radiation-induced intestinal fibrosis by modulating gut microbiota. Int J Radiat Biol 99: 823-834. https://doi.org/10.1080/09553002.2023.2145029
[107]	Xue H, Lei S, Wang Q, et al. (2025) The mechanism of action of NMN in inhibiting NLRP3 acetylation-mediated granulosa cell pyroptosis to improve ovarian reserve function in ionizing radiation-exposed mice. FASEB J 39: e71335. https://doi.org/10.1096/fj.202503167R
[108]	Audrito V, Messana VG, Deaglio S (2020) NAMPT and NAPRT: Two metabolic enzymes with key roles in inflammation. Front Oncol 10: 358. https://doi.org/10.3389/fonc.2020.00358
[109]	Huang Z, Li N, Yu S, et al. (2022) Systematic engineering of Escherichia coli for efficient production of nicotinamide mononucleotide from nicotinamide. ACS Synth Biol 11: 2979-2988. https://doi.org/10.1021/acssynbio.2c00100
[110]	Zelante T, Iannitti RG, Cunha C, et al. (2013) Tryptophan catabolites from microbiota engage aryl hydrocarbon receptor and balance mucosal reactivity via interleukin-22. Immunity 39: 372-385. https://doi.org/10.1016/j.immuni.2013.08.003
[111]	Zhu Y, Hua Y, Zhang B, et al. (2017) Metabolic engineering of indole pyruvic acid biosynthesis in Escherichia coli with tdiD. Microb Cell Fact 16: 2. https://doi.org/10.1186/s12934-016-0620-6
[112]	Zhang LS, Davies SS (2016) Microbial metabolism of dietary components to bioactive metabolites: Opportunities for new therapeutic interventions. Genome Med 8: 46. https://doi.org/10.1186/s13073-016-0296-x
[113]	Gilbert JA, Azad MB, Bäckhed F, et al. (2025) Clinical translation of microbiome research. Nat Med 31: 1099-1113. https://doi.org/10.1038/s41591-025-03615-9
[114]	Ozdemir T, Fedorec AJH, Danino T, et al. (2018) Synthetic biology and engineered live biotherapeutics: Toward increasing system complexity. Cell Syst 7: 5-16. https://doi.org/10.1016/j.cels.2018.06.008
[115]	Foo GW, Uruthirapathy AS, Zhang CQ, et al. (2025) Genetic entanglement enables ultrastable biocontainment in the mammalian gut. ACS Synth Biol 14: 3696-3708. https://doi.org/10.1021/acssynbio.5c00412
[116]	Xu C, Shi Z, Shao J, et al. (2019) Metabolic engineering of Lactococcus lactis for high level accumulation of glutathione and S-adenosyl-L-methionine. World J Microbiol Biotechnol 35: 185. https://doi.org/10.1007/s11274-019-2759-x
[117]	Burgardt A, Pelosi L, Chehade MH, et al. (2022) Rational engineering of non-ubiquinone containing Corynebacterium glutamicum for enhanced coenzyme Q10 production. Metabolites 12: 428. https://doi.org/10.3390/metabo12050428
[118]	Li H, Wu Y, Qin D, et al. (2025) Phase-driven rewiring in Escherichia coli enhances coenzyme Q10 biosynthesis via temporal and energetic coordination. Appl Microbiol Biotechnol 109: 248. https://doi.org/10.1007/s00253-025-13619-7
[119]	Yan X, Liu XY, Zhang D, et al. (2021) Construction of a sustainable 3-hydroxybutyrate-producing probiotic Escherichia coli for treatment of colitis. Cell Mol Immunol 18: 2344-2357. https://doi.org/10.1038/s41423-021-00760-2
[120]	Parweez F, Palou R, Li R, et al. (2025) Engineered spermidine-secreting Saccharomyces boulardii enhances olfactory memory in Drosophila melanogaster. Front Neurosci 19: 1628160. https://doi.org/10.3389/fnins.2025.1628160
[121]	Xia M, Mu S, Fang Y, et al. (2023) Genetic and probiotic characteristics of urolithin A producing Enterococcus faecium FUA027. Foods 12: 1021. https://doi.org/10.3390/foods12051021
[122]	Xiao HW, Cui M, Li Y, et al. (2020) Gut microbiota-derived indole 3-propionic acid protects against radiation toxicity via retaining acyl-CoA-binding protein. Microbiome 8: 69. https://doi.org/10.1186/s40168-020-00845-6
[123]	Shi S, Li B, Zhang Y, et al. (2025) Probiotic-based self-crosslinking bio-coating for the treatment of colitis by increasing probiotic colonization. Mater Today Bio 35: 102447. https://doi.org/10.1016/j.mtbio.2025.102447
[124]	Fan H, Li C, Zhang Z, et al. (2025) pH-responsive probiotic-liposome hybrid system synergistically treats radiation-induced injury via dual mechanisms of anti-inflammatory and microbiome modulation. Adv Healthc Mater 14: e2501642. https://doi.org/10.1002/adhm.202501642
[125]	Geng Z, Wang X, Wu F, et al. (2023) Biointerface mineralization generates ultraresistant gut microbes as oral biotherapeutics. Sci Adv 9: eade0997. https://doi.org/10.1126/sciadv.ade0997
[126]	Deng Q, Zhang L, Liu X, et al. (2023) COF-based artificial probiotic for modulation of gut microbiota and immune microenvironment in inflammatory bowel disease. Chem Sci 14: 1598-1605. https://doi.org/10.1039/d2sc04984h
[127]	Nguyen N, Wang M, Li L, et al. (2025) A genetic safeguard for eliminating target genes in synthetic probiotics in a gut environment. iScience 28: 113027. https://doi.org/10.1016/j.isci.2025.113027
[128]	Hedin KA, Kruse V, Vazquez-Uribe R, et al. (2023) Biocontainment strategies for in vivo applications of Saccharomyces boulardii. Front Bioeng Biotechnol 11: 1136095. https://doi.org/10.3389/fbioe.2023.1136095
[129]	Zheng C, Niu M, Kong Y, et al. (2024) Oral administration of probiotic spore ghosts for efficient attenuation of radiation-induced intestinal injury. J Nanobiotechnology 22: 303. https://doi.org/10.1186/s12951-024-02572-8
[130]	Zhang F, Zeng L, Zuo J, et al. (2025) Polydopamine/chitosan layer-by-layer coating of Bacillus cereus enhances the robustness of live anti-oxidation materials for the treatment of radiation enteritis. Mater Today Bio 35: 102545. https://doi.org/10.1016/j.mtbio.2025.102545
[131]	Kurtz CB, Millet YA, Puurunen MK, et al. (2019) An engineered E. coli Nissle improves hyperammonemia and survival in mice and shows dose-dependent exposure in healthy humans. Sci Transl Med 11: eaau7975. https://doi.org/10.1126/scitranslmed.aau7975
[132]	Ahmad K, Zhang Y, Chen P, et al. (2024) Chitosan interaction with stomach mucin layer to enhances gastric retention and mucoadhesive properties. Carbohydr Polym 333: 121926. https://doi.org/10.1016/j.carbpol.2024.121926
[133]	U.S. Department of Health and Human Services, Food and Drug AdministrationEarly clinical trials with live biotherapeutic products: Chemistry, manufacturing, and control information (Guidance for Industry) (2016).
[134]	Yang B, Luo H, Yan X, et al. (2025) Lyophilized apoptotic vesicles restore DNA damage and mitochondria dysfunction to ameliorate radiation enteritis. J Nanobiotechnology 23: 521. https://doi.org/10.1186/s12951-025-03592-8
[135]	Golan ME, Stice SL (2024) Extracellular vesicle lyophilization for enhanced distribution to the point of care. J Extracell Vesicles 13: e12411. https://doi.org/10.1016/j.vesic.2024.100041
[136]	Ma S, Li X, Shang S, et al. (2025) Targeting gut microbiota and metabolites in cancer radiotherapy. Clin Transl Med 15: e70481. https://doi.org/10.1002/ctm2.70481
[137]	Valiei A, Aminian-Dehkordi J, Mofrad MRK (2023) Gut-on-a-chip models for dissecting the gut microbiology and physiology. APL Bioeng 7: 011502. https://doi.org/10.1063/5.0126541
[138]	Jalili-Firoozinezhad S, Prantil-Baun R, Jiang A, et al. (2018) Modeling radiation injury-induced cell death and countermeasure drug responses in a human Gut-on-a-Chip. Cell Death Dis 9: 223. https://doi.org/10.1038/s41419-018-0304-8
[139]	Drost J, Clevers H (2018) Organoids in cancer research. Nat Rev Cancer 18: 407-418. https://doi.org/10.1038/s41568-018-0007-6
[140]	Vlachogiannis G, Hedayat S, Vatsiou A, et al. (2018) Patient-derived organoids model treatment response of metastatic gastrointestinal cancers. Science 359: 920-926. https://doi.org/10.1126/science.aao2774
[141]	Dijkstro KK, Monkhorst K, Schipper LJ, et al. (2020) Challenges in establishing pure lung cancer organoids limit their utility for personalized medicine. Cell Rep 31: 107588. https://doi.org/10.1016/j.celrep.2020.107588
[142]	Hamade DF, Epperly MW, Fisher R, et al. (2024) Genetically engineered probiotic Limosilactobacillus reuteri releasing IL-22 (LR-IL-22) modifies the tumor microenvironment, enabling irradiation in ovarian cancer. Cancers (Basel) 16: 474. https://doi.org/10.3390/cancers16030474
[143]	Kim DY, Lee SY, Lee JY, et al. (2024) Gut microbiome therapy: Fecal microbiota transplantation vs live biotherapeutic products. Gut Microbes 16: 2412376. https://doi.org/10.1080/19490976.2024.2412376
[144]	Zhong HJ, Xie X, Chen WJ, et al. (2023) Washed microbiota transplantation improves renal function in patients with renal dysfunction: a retrospective cohort study. J Transl Med 21: 740. https://doi.org/10.1186/s12967-023-04570-0
[145]	Tang B, Cao Y, Li J, et al. (2025) Whole microbiota transplantation restores gut homeostasis throughout the gastrointestinal tract. iMeta 4: e70091. https://doi.org/10.1002/imt2.70091

Reader Comments

Your name:*

Email:*
© 2026 the Author(s), licensee AIMS Press. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0)