International Journal of Toxins and Toxics Review Article
Nutrient-Mediated Activation of Cellular Signaling Pathways: Mechanistic Insights into Attenuation of Toxin Induced Inflammation in Food Animals
Abstract
Dietary and environmental toxins remain a persistent challenge in food animal production, where subclinical and clinical inflammation compromises health, productivity, and food safety. Toxin induced inflammation is driven by oxidative stress, mitochondrial dysfunction, and dysregulated immune signaling, resulting in impaired metabolic efficiency and increased disease susceptibility. Recent advances in nutritional science have revealed that nutrients act not only as substrates for growth but also as signaling molecules capable of modulating key cellular pathways involved in inflammatory regulation. This review synthesizes current knowledge on nutrient mediated activation of cellular signaling pathways and their mechanistic roles in attenuating toxin induced inflammation in food animals. Major nutrient sensing and stress responsive pathways, including AMP activated protein kinase, mechanistic target of rapamycin, nuclear factor erythroid two related factor two, nuclear factor kappa B, and mitogen activated protein kinases, are discussed in the context of toxin exposure. The review highlights how specific nutrients such as amino acids, fatty acids, vitamins, minerals, and functional phytogenic compounds influence these pathways to restore redox balance, regulate cytokine production, enhance cellular detoxification, and maintain mitochondrial integrity. Species specific responses in poultry, ruminants, and swine are also considered, reflecting differences in digestive physiology and metabolic regulation. In addition, emerging tools including nutrigenomics, metabolomics, and systems biology approaches are evaluated for their potential to clarify complex nutrient toxin signaling interactions. By integrating mechanistic insights with applied nutritional strategies, this review provides a framework for 2 | Page developing precision feeding interventions aimed at reducing inflammation, improving resilience to toxins, and enhancing sustainable food animal production. The findings underscore the importance of signaling based nutrition as a promising avenue for mitigating toxin related challenges in modern livestock systems.
Keywords
References (261)
- Debnath I, Ghosh S, Bhunia S, Nayak A, Basak S, Nandi S, Bhattacharjee S.
- Mechanistic insights and therapeutic potential of quercetin in neuroprotection: a
- comprehensive review of pathways and clinical perspectives. BIO Integration. 2025
- Aug 18;6(1):978.
- Moezzi SA, Ramezani S, Rezaei K, Khoei AJ. Mechanisms of Pesticide Toxicity in
- Fish: Insights Into the Ameliorative Role of Plant‐Derived Compounds—A Review.
- Aquaculture Nutrition. 2025;2025(1):5328773.
- Fang M, Hu W, Liu B. Protective and detoxifying effects conferred by selenium
- against mycotoxins and livestock viruses: A review. Frontiers in Veterinary Science.
- 2022 Aug 2;9:956814.
- Patra AK, Amasheh S, Aschenbach JR. Modulation of gastrointestinal barrier and
- nutrient transport function in farm animals by natural plant bioactive compounds–a
- comprehensive review. Critical Reviews in Food Science and Nutrition. 2019 Nov
- 13;59(20):3237-66.
- Sonali S, Ray B, Ahmed Tousif H, Rathipriya AG, Sunanda T, Mahalakshmi AM,
- Rungratanawanich W, Essa MM, Qoronfleh MW, Chidambaram SB, Song BJ.
- Mechanistic insights into the link between gut dysbiosis and major depression: an
- extensive review. Cells. 2022 Apr 16;11(8):1362.
- Ali W, Zhang H, Junaid M, Mao K, Xu N, Chang C, Rasool A, Wajahat Aslam M, Ali
- J, Yang Z. Insights into the mechanisms of arsenic-selenium interactions and the
- associated toxicity in plants, animals, and humans: A critical review. Critical reviews
- in environmental science and technology. 2021 Apr 3;51(7):704-50.
- Vijiyakumar N, Prince SE. A comprehensive review of cadmium-induced toxicity,
- signalling pathways, and potential mitigation strategies. Toxicology and
- Environmental Health Sciences. 2025 Mar;17(1):79-94.
- Hannan MA, Rahman MA, Sohag AA, Uddin MJ, Dash R, Sikder MH, Rahman MS,
- Timalsina B, Munni YA, Sarker PP, Alam M. Black cumin (Nigella sativa L.): A
- comprehensive review on phytochemistry, health benefits, molecular pharmacology,
- and safety. Nutrients. 2021 May 24;13(6):1784.
- Lv Q, Xu W, Yang F, Li J, Wei W, Chen X, Liu Y, Zhang Z. Protective and
- Detoxifying Effects of Resveratrol on Zearalenone-Mediated Toxicity: A Review.
- International Journal of Molecular Sciences. 2024 Oct 13;25(20):11003.
- Duan N, Hu X, Zhou R, Li Y, Wu W, Liu N. A review on dietary flavonoids as
- modulators of the tumor microenvironment. Molecular Nutrition & Food Research.
- 2023 Apr;67(7):2200435.
- Wang L, et al. The biological activity mechanism of chlorogenic acid and its
- applications in food industry: A review. Front Nutr. 2022;9:943911.
- doi:10.3389/fnut.2022.943911.
- Zhang Y, Chen S, Yuan M, Xu Y, Xu H. Gout and diet: A comprehensive review of
- mechanisms and management. Nutrients. 2022;14(17):3525. Available from:
- https://www.mdpi.com/2072-6643/14/17/3525
- Zhang J, et al. Trichothecenes toxicity in humans and animals: Unraveling the
- mechanisms and harnessing phytochemicals for prevention. Comp Biochem Physiol C
- Toxicol Pharmacol. 2025. Available from:
- https://www.sciencedirect.com/science/article/pii/S1532045625001073
- Khuda-Bukhsh AR, Das S, Saha SK. Molecular approaches toward targeted cancer
- prevention with food plants and their products: inflammatory and other signaling
- pathways. Nutr Cancer. 2014;66(2):194–205. doi:10.1080/01635581.2014.864420.
- Zhang ZF, Zhang Y, Fan SH, Zhuang J, et al. Troxerutin protects against BDE-47-
- induced liver inflammation via attenuation of oxidative stress-mediated NAD+
- depletion. J Hazard Mater. 2015;283:98–109. Available from:
- https://www.sciencedirect.com/science/article/pii/S0304389414007419
- Shi L, et al. Chitosan oligosaccharide attenuates LPS-induced inflammation in IPEC-
- J2 cells through the TLR4/NF-κB signaling pathway. Carbohydr Polym.
- 2019;219:1–9. Available from:
- https://www.sciencedirect.com/science/article/pii/S0144861719305430
- Thakur K, Zhu YY, Feng JY, Zhang JG, Hu F, et al. Morin as a functional food
- ingredient: Updated evidence in prevention and treatment of metabolic syndromes.
- Food Funct. 2020;11:6488–6504. Available from:
- https://pubs.rsc.org/en/content/articlehtml/2020/fo/d0fo01444c
- Tao P, Ji J, Wang Q, Cui M, Cao M, Xu Y. Role of gut microbiota-derived short-chain
- fatty acids in diabetic kidney disease. Front Immunol. 2022;13:1080456.
- doi:10.3389/fimmu.2022.1080456.
- Mosadegh M, Goodarzi NN, Erfani Y. Comprehensive insight into apoptosis:
- mechanisms and therapeutic modulation. Cancer Invest. 2025.
- doi:10.1080/07357907.2024.2445528.
- Edo GI, Mafe AN, Ali ABM, Akpoghelie PO, Yousif E, et al. Mechanistic insights
- into β-glucans and gut microbiota interactions for enhancing human health. Discover
- Food. 2025. doi:10.1007/s44187-025-00503-6.
- Mei L, Wang J, Hao Y, Zeng X, Yang Y, et al. Immunoregulatory mechanisms of
- Akkermansia muciniphila: A comprehensive update. Crit Rev Food Sci Nutr. 2025.
- doi:10.1080/10408398.2024.2416481.
- Huo W, Qiao Y, Li E, Li M, Che L. Nutrition, microbiota, and immunity in rotavirus
- infection: Insights from models. Front Vet Sci. 2025;12:1680448.
- doi:10.3389/fvets.2025.1680448.
- Zhao Z, Yang Q, Sun Y, Ruan X. Antioxidant and anti-inflammatory potential of
- syringic acid: Mechanistic insights. Front Pharmacol. 2025.
- doi:10.3389/fphar.2025.1615294.
- Umapathy S, Pan I, Issac PK, Kumar MSK, Giri J, et al. Selenium nanoparticles as
- neuroprotective agents in Parkinson’s disease. Mol Neurobiol. 2025.
- doi:10.1007/s12035-024-04253-x.
- Chinonso AD, Kayode AA, Adondua MA, et al. Biochemistry of traditional herbal
- compounds and their molecular targets. 2025. Available from: ResearchGate
- Saadat YR, Barzegari A, Saadatian Z, et al. Gut microbiota and kidney aging: Current
- research insights. Lipids Health Dis. 2025. doi:10.1186/s12986-025-01032-w.
- Murtaza B, Li X, Nawaz MY, Saleemi MK, et al. Toxicodynamics of combined
- mycotoxins: Diagnostic biomarkers. Compr Rev Food Sci Food Saf. 2024.
- doi:10.1111/1541-4337.13338.
- Liao C, Xu F, Yu Z, Ding K, Jia Y. Role of NLRP3 inflammasome in mycotoxin-
- induced toxicity. Vet Sci. 2024;11(7):291. Available from:
- https://www.mdpi.com/2306-7381/11/7/291
- Zhou Y, Wang D, Yan W. Natural products in inflammatory bowel disease:
- Mechanistic evidence from animal studies. Nutrients. 2023;15(4):1031. Available
- from: https://www.mdpi.com/2072-6643/15/4/1031
- Jan AT, Azam M, Siddiqui K, Ali A, Choi I, et al. Heavy metals and human health:
- Mechanisms and antioxidant defenses. Int J Mol Sci. 2015;16(12):29592–29630.
- Available from: https://www.mdpi.com/1422-0067/16/12/29592
- Davinelli S, Maes M, Corbi G, Zarrelli A, Willcox DC, et al. Dietary phytochemicals
- and neuro-inflammaging. Immun Ageing. 2016;13:16. doi:10.1186/s12979-016-0070-
- Parasramka MA, Ho E, Williams DE, et al. MicroRNAs, diet, and cancer: Epigenetic
- actions of phytochemicals. Mol Carcinog. 2012;51(3):213–230.
- doi:10.1002/mc.20822.
- Puah BP, Jalil J, Attiq A, Kamisah Y. Molecular mechanisms behind anticancer
- activity of lycopene. Molecules. 2021;26(13):3888. Available from:
- https://www.mdpi.com/1420-3049/26/13/3888
- Lou-Bonafonte JM, et al. Biological action of squalene: Current insights. Mol Nutr
- Food Res. 2018;62:e1800136. doi:10.1002/mnfr.201800136.
- Aslam M, Aslam A, Sheraz M, Ali B, et al. Lead toxicity in cereals: Mechanisms and
- management. Front Plant Sci. 2021;11:587785. doi:10.3389/fpls.2020.587785.
- Hussain T, Kandeel M, Metwally E, Murtaza G, et al. Oxidative stress and male
- fertility: Mechanistic insights. Front Endocrinol. 2023;14:1070692.
- doi:10.3389/fendo.2023.1070692.
- Rudrapal M, Khairnar SJ, Khan J, Dukhyil AB, et al. Polyphenols in oxidative stress-
- induced diseases. Front Pharmacol. 2022;13:806470. doi:10.3389/fphar.2022.806470.
- Rajesh M, Mukhopadhyay P, Bátkai S, Patel V, et al. Cannabidiol attenuates diabetic
- cardiomyopathy. J Am Coll Cardiol. 2010;56(25):2115–2125.
- doi:10.1016/j.jacc.2010.07.033.
- Wen ZQ, Lin J, Xie WQ, Shan YH, Zhen GH, et al. Endoplasmic reticulum stress in
- degenerative musculoskeletal diseases. J Orthop Surg Res. 2023;18:850.
- doi:10.1186/s40779-023-00485-5.
- Krawczyk M, Burzynska-Pedziwiatr I, Wozniak LA, et al. Polyphenols and oxidative
- stress in diabetes. Biomolecules. 2023;13(9):1402. Available from:
- https://www.mdpi.com/2218-273X/13/9/1402
- Liu Q, Hu Y, Cao Y, Song G, Liu Z, et al. Chicoric acid attenuates LPS-induced
- oxidative stress via Keap1/Nrf2 pathway. J Agric Food Chem. 2017;65(5):1081–1089.
- doi:10.1021/acs.jafc.6b04873.
- Hassan FU, Arshad MA, Li M, Rehman MSU, Loor JJ, Huang J. Mulberry leaf
- biomass improves ruminant production and health. Animals. 2020;10(11):2076.
- doi:10.3390/ani10112076.
- Hong Y, Boiti A, Vallone D, Foulkes NS. ROS signaling and oxidative stress
- regulation. Antioxidants. 2024;13(3):312. Available from:
- https://www.mdpi.com/2076-3921/13/3/312
- Yao C, et al. Mycotoxin contamination: Mechanisms and nutritional intervention
- strategies. Toxins. 2025. Available from: PMC database.
- Attallah NGM, Mokhtar FA, Elekhnawy E, Heneidy SZ, et al. Antibacterial and
- hepatoprotective effects of Salvinia auriculata. Pharmaceuticals. 2022;15(5):549.
- Available from: https://www.mdpi.com/1424-8247/15/5/549
- Mishra A, Mishra PS, Bandopadhyay R, Khurana N, et al. Neuroprotective potential
- of chrysin. Molecules. 2021;26(21):6456. Available from:
- https://www.mdpi.com/1420-3049/26/21/6456
- Ahmed MAE, Mohanad M, Ahmed AAE, Aboulhoda BE, et al. Chlorogenic acid
- protects against gastric ulcer in rats. Life Sci. 2021;277:119473. Available from:
- https://www.sciencedirect.com/science/article/pii/S0024320521003556
- Tao W, Yu Y, Tan D, Huang X, Huang J, et al. Microbiota–enteric nervous system
- crosstalk in diabetic gastroenteropathy. Front Cell Infect Microbiol. 2025;15:1603442.
- doi:10.3389/fcimb.2025.1603442.
- Zhang T, et al. Clostridium perfringens α-toxin impairs intestinal health via
- PLCγ1/AMPK/mTOR pathway. Heliyon. 2024. Available from: Cell Press database.
- Kalra P, Khan H, Kaur A, Singh TG. Autophagy pathways in cerebral ischemic injury.
- Neurochem Res. 2022;47:247–262. doi:10.1007/s11064-021-03500-0.
- Charles-Messance H, Mitchelson KAJ, et al. Regulating metabolic inflammation by
- nutritional modulation. J Allergy Clin Immunol. 2020. Available from: ScienceDirect.
- Zhou J, et al. Mechanisms of regulated cell death in cancer. Biomedicines.
- 2025;13(8):1880. Available from: https://www.mdpi.com/2227-9059/13/8/1880
- Ucar BI, Ucar G, Saha S, Buttari B, Profumo E, et al. Pharmacological regulation of
- Nrf2-Keap1-ARE signaling in ischemia-reperfusion injury. Antioxidants.
- 2021;10:922. Available from: PMC database.
- Zhao Y, et al. Alginate oligosaccharides attenuate ochratoxin A liver injury via
- Nrf2/NF-κB pathways. Food Front. 2025. doi:10.1002/fft2.70177.
- Zhi Y, Xie S, Sun Y. Naringenin and brain health: Mechanistic insights. Front Nutr.
- 2025. doi:10.3389/fnut.2025.1680349.
- Fatima I, Sahar A, Tariq A, Naz T, et al. Role of licorice derivatives in NF-κB and
- MAPK signaling. J Nutr Metab. 2024;2024:9988167. doi:10.1155/2024/9988167.
- Li Z, et al. Cadmium induces renal inflammation via ROS/MAPK/NF-κB pathways.
- Arch Toxicol. 2021;95:3725–3738. doi:10.1007/s00204-021-03157-2.
- Mahto K, Kuwar OK, Maloo A, Kumar A. Therapeutic potential of Boswellia serrata
- in arthritis management. Inflammopharmacology. 2025. doi:10.1007/s10787-025-
- He F, et al. Bacteriostatic potential of melatonin: Mechanistic insights. Front
- Immunol. 2021;12:683879. doi:10.3389/fimmu.2021.683879.
- Ma Z, Du B, Li J, Yang Y, Zhu F. Anti-inflammatory activities of anthocyanins. Int J
- Mol Sci. 2021;22(20):11076. Available from: https://www.mdpi.com/1422-
- 0067/22/20/11076
- Wang XL, et al. Gastrodin prevents motor deficits and oxidative stress in the MPTP
- mouse model of Parkinson’s disease via the ERK1/2–Nrf2 signaling pathway. Life
- Sci. 2014;114(2):77–85. Available from:
- https://www.sciencedirect.com/science/article/pii/S0024320514006766
- Zhang Y, et al. Assessing and mitigating foodborne acetochlor-induced ileum toxicity
- in broiler chicks: role of omega-3 polyunsaturated fatty acid supplementation and
- molecular pathway modulation. Pestic Biochem Physiol. 2024;199:105761.
- Palomer X, Pizarro-Delgado J, Barroso E, Vázquez-Carrera M. Palmitic and oleic
- acid: the yin and yang of fatty acids in type 2 diabetes mellitus. Trends Endocrinol
- Metab. 2018;29(3):178–190. Available from:
- https://www.cell.com/trends/endocrinology-metabolism/fulltext/S1043-
- 2760(17)30170-4
- Chen X, et al. Fatty acid supplementation attenuates microglia-induced
- neuroinflammation by inhibiting the HMGB1/TLR4/NF-κB pathway following
- experimental traumatic brain injury. J Neuroinflammation. 2017;14:206.
- doi:10.1186/s12974-017-0917-3
- Sozen E, Demirel T, Ozer NK. Vitamin E: regulatory role in the cardiovascular
- system. IUBMB Life. 2019;71(4):507–515. doi:10.1002/iub.2020
- Abubakar MB, Sanusi KO, Ugusman A, et al. Alzheimer’s disease: an update and
- insights into pathophysiology. Front Aging Neurosci. 2022;14:742408.
- doi:10.3389/fnagi.2022.742408
- Nitulescu GM, Paunescu H, et al. Comprehensive analysis of drugs to treat SARS-
- CoV-2 infection: mechanistic insights into current COVID-19 therapies. Int J Mol
- Med. 2020;46(2):467–488. Available from: https://www.spandidos-
- publications.com/ijmm/46/2/467
- Gao Y, et al. Alginate oligosaccharide attenuates lipopolysaccharide-induced
- intestinal barrier dysfunction in BALB/c mice: mechanistic insights. J Agric Food
- Chem. 2025. doi:10.1021/acs.jafc.4c12136
- Wang J, et al. Lycopene supplementation attenuates lipopolysaccharide-induced
- amyloidogenesis and cognitive impairment via modulation of neuroinflammation and
- oxidative stress. J Nutr Biochem. 2018;54:136–146. Available from:
- https://www.sciencedirect.com/science/article/pii/S0955286317309543
- Yang D, et al. Luteolin attenuates mercuric chloride-induced hepatotoxicity by
- regulating the Sirt1/Nrf2/TNF-α signaling pathway. Sci Rep. 2016;6:37157. Available
- from: https://www.nature.com/articles/srep37157
- Hui P, Xu C, Li J, Wu S, Bao W, et al. Curcumin activates the Wnt/β-catenin/PPARD
- signaling axis to attenuate ochratoxin A-induced enterotoxicity. J Agric Food Chem.
- 2025. doi:10.1021/acs.jafc.5c12569
- Subedi L, Ji E, Shin D, Jin J, Yeo JH, Kim SY. Equol, a dietary daidzein gut
- metabolite, attenuates microglial activation and enhances neuroprotection in vitro.
- Nutrients. 2017;9(3):207. doi:10.3390/nu9030207
- Chen M, et al. Resveratrol attenuates vascular endothelial inflammation by inducing
- autophagy via the cAMP signaling pathway. Autophagy. 2013;9(12):2033–2045.
- doi:10.4161/auto.26336
- Wang ME, Chen YC, Chen IS, Hsieh SC, et al. Curcumin protects against
- thioacetamide-induced hepatic fibrosis by suppressing inflammation and inducing
- apoptosis of damaged hepatocytes. J Nutr Biochem. 2012;23(10):1351–1360.
- Available from:
- https://www.sciencedirect.com/science/article/pii/S0955286311002415
- Rungratanawanich W, Qu Y, Wang X, et al. Advanced glycation end products and
- related adducts in aging-associated diseases and alcohol-mediated tissue injury. Exp
- Mol Med. 2021;53(2):168–188. Available from:
- https://www.nature.com/articles/s12276-021-00561-7
- Hirsova P, Ibrahim SH, Bronk SF, Yagita H, Gores GJ. Vismodegib suppresses
- TRAIL-mediated liver injury in a mouse model of nonalcoholic steatohepatitis. PLoS
- One. 2013;8(7):e70599. doi:10.1371/journal.pone.0070599
- Yoo GS. Development of vaccine adjuvants and mechanistic insights for combating
- Salmonella infection in chickens. Seoul: Seoul National University; 2025. Available
- from: https://s-space.snu.ac.kr/handle/10371/228615
- Liu W, et al. Glycolysis and reactive oxygen species production contribute to T-2
- toxin–induced chicken heterophil extracellular trap formation. J Agric Food Chem.
- 2021;69(46):13784–13794. doi:10.1021/acs.jafc.1c05371
- Dugershaw BB, Aengenheister L, Hansen SSK, et al. Recent insights into indirect
- mechanisms underlying developmental toxicity of nanomaterials. Arch Toxicol.
- 2020;94(7):2307–2330. doi:10.1186/s12989-020-00359-x
- Pistol GC, Gras MA, Marin DE, et al. Zearalenone reduces expression of key pro- and
- anti-inflammatory mediators and MAPK/NF-κB signaling molecules in pigs. Br J
- Nutr. 2014;111(3):450–460. Available from:
- https://www.cambridge.org/core/journals/british-journal-of-nutrition
- Chirivi M, Contreras GA. Endotoxin-induced alterations of adipose tissue function:
- pathways leading to bovine metabolic stress. J Anim Sci Biotechnol. 2024;15:13.
- doi:10.1186/s40104-024-01013-8
- Vinayagam R, Xu B. Antidiabetic properties of dietary flavonoids: cellular and
- molecular mechanisms. Nutr Metab (Lond). 2015;12:60. doi:10.1186/s12986-015-
- Singh S, Singh TG, Rehni AK. Molecular mechanisms and emerging therapeutic
- strategies in epileptogenesis. CNS Neurol Disord Drug Targets. 2020;19(10):756–772.
- Available from: https://www.ingentaconnect.com
- Tu S, et al. Sarcopenia: current insights into molecular mechanisms, diagnostics, and
- emerging interventional approaches. Int J Mol Sci. 2025;26(14):6740.
- doi:10.3390/ijms26146740
- Mustafa AM, Atwa AM, Elgindy AM, Alkabbani MA, et al. Targeting psoriatic
- inflammation with natural compounds: mechanistic insights and therapeutic promise.
- Inflammopharmacology. 2025. doi:10.1007/s10787-025-01851-6
- Adebiyi MG, Manalo JM, Xia Y. Metabolomic and molecular insights into sickle cell
- disease and emerging therapeutic strategies. Blood Adv. 2019;3(8):1347–1356.
- Available from: https://ashpublications.org/bloodadvances
- Liu A, Zhu K, Song C, Sun L, Cai F. Natural phenolic compounds against
- trichothecenes: protective mechanisms and future perspectives. J Agric Food Chem.
- 2025. doi:10.1021/acs.jafc.4c12790