Abstract
The gastrointestinal (GI) barrier acts as the primary interface between humans and the external environment. It constantly faces the risk of inflammation and oxidative stress due to exposure to foreign substances and microorganisms. Thus, maintaining the structural and functional integrity of the GI barrier is crucial for overall well-being, as it helps prevent systemic inflammation and oxidative stress, which are major contributors to age-related diseases. A healthy gut relies on maintaining gut redox homeostasis, which involves several essential elements. Firstly, it requires establishing a baseline electrophilic tone and an electrophilic mucosal gradient. Secondly, the electrophilic system needs to have sufficient capacity to generate reactive oxygen species, enabling effective elimination of invading microorganisms and rapid restoration of the barrier integrity following breaches. These elements depend on physiological redox signaling mediated by electrophilic pathways such as NOX2 and the H2O2 pathway. Additionally, the nucleophilic arm of redox homeostasis should exhibit sufficient reactivity to restore the redox balance after an electrophilic surge. Factors contributing to the nucleophilic arm include the availability of reductive substrates and redox signaling mediated by the cytoprotective Keap1-Nrf2 pathway. Future research should focus on identifying preventive and therapeutic strategies that enhance the strength and responsiveness of GI redox homeostasis. These strategies aim to reduce the vulnerability of the gut to harmful stimuli and address the decline in reactivity often observed during the aging process. By strengthening GI redox homeostasis, we can potentially mitigate the risks associated with age-related gut dyshomeostasis and optimize overall health and longevity.
Similar content being viewed by others
References
Ahl D, Liu H, Schreiber O et al (2016) Lactobacillus reuteri increases mucus thickness and ameliorates dextran sulphate sodium-induced colitis in mice. Acta Physiol (Oxf) 217:300–310. https://doi.org/10.1111/apha.12695
Alam A, Leoni G, Quiros M et al (2016) The microenvironment of injured murine gut elicits a local pro-restitutive microbiota. Nat Microbiol 1:15021. https://doi.org/10.1038/nmicrobiol.2015.21
Almeida PP, Tavares-Gomes AL, Stockler-Pinto MB (2022) Relaxing the “second brain”: nutrients and bioactive compounds as a therapeutic and preventive strategy to alleviate oxidative stress in the enteric nervous system. Nutr Rev 80:2206–2224. https://doi.org/10.1093/nutrit/nuac030
Aviello G, Knaus UG (2018) NADPH oxidases and ROS signaling in the gastrointestinal tract. Mucosal Immunol 11:1011–1023. https://doi.org/10.1038/s41385-018-0021-8
Aw TY (2005) Intestinal glutathione: determinant of mucosal peroxide transport, metabolism, and oxidative susceptibility. Toxicol Appl Pharmacol 204:320–328. https://doi.org/10.1016/j.taap.2004.11.016
Babbin BA, Jesaitis AJ, Ivanov AI et al (2007) Formyl peptide receptor-1 activation enhances intestinal epithelial cell restitution through phosphatidylinositol 3-kinase-dependent activation of Rac1 and Cdc42. J Immunol 179:8112–8121. https://doi.org/10.4049/jimmunol.179.12.8112
Baird L, Yamamoto M (2020) The molecular mechanisms regulating the KEAP1-NRF2 pathway. Mol Cell Biol 40:e00099–e00020. https://doi.org/10.1128/MCB.00099-20
Beckman JS, Koppenol WH (1996) Nitric oxide, superoxide, and peroxynitrite: the good, the bad, and ugly. Am J Physiol 271:C1424–1437. https://doi.org/10.1152/ajpcell.1996.271.5.C1424
Bedard K, Krause K-H (2007) The NOX family of ROS-generating NADPH oxidases: physiology and pathophysiology. Physiol Rev 87:245–313. https://doi.org/10.1152/physrev.00044.2005
Bellezza I, Giambanco I, Minelli A, Donato R (2018) Nrf2-Keap1 signaling in oxidative and reductive stress. Biochim Biophys Acta Mol Cell Res 1865:721–733. https://doi.org/10.1016/j.bbamcr.2018.02.010
Bhattacharyya A, Chattopadhyay R, Mitra S, Crowe SE (2014) Oxidative stress: an essential factor in the pathogenesis of gastrointestinal mucosal diseases. Physiol Rev 94:329–354. https://doi.org/10.1152/physrev.00040.2012
Bischoff SC, Barbara G, Buurman W et al (2014) Intestinal permeability – a new target for disease prevention and therapy. BMC Gastroenterol 14:189. https://doi.org/10.1186/s12876-014-0189-7
Bradshaw PC (2019) Cytoplasmic and mitochondrial NADPH-Coupled redox systems in the regulation of aging. Nutrients 11:504. https://doi.org/10.3390/nu11030504
Branca JJV, Gulisano M, Nicoletti C (2019) Intestinal epithelial barrier functions in ageing. Ageing Res Rev 54:100938. https://doi.org/10.1016/j.arr.2019.100938
Campbell EL, Colgan SP (2019) Control and dysregulation of redox signalling in the gastrointestinal tract. Nat Rev Gastroenterol Hepatol 16:106–120. https://doi.org/10.1038/s41575-018-0079-5
Chassaing B, Kumar M, Baker MT et al (2014) Mammalian gut immunity. Biomed J 37:246–258. https://doi.org/10.4103/2319-4170.130922
Chu FF, Doroshow JH, Esworthy RS (1993) Expression, characterization, and tissue distribution of a new cellular selenium-dependent glutathione peroxidase, GSHPx-GI. J Biol Chem 268:2571–2576
Circu ML, Aw TY (2011) Redox biology of the intestine. Free Radic Res 45:1245–1266. https://doi.org/10.3109/10715762.2011.611509
Clark RI, Salazar A, Yamada R et al (2015) Distinct shifts in microbiota composition during drosophila aging impair intestinal function and drive mortality. Cell Rep 12:1656–1667. https://doi.org/10.1016/j.celrep.2015.08.004
Corcionivoschi N, Alvarez LAJ, Sharp TH et al (2012) Mucosal reactive oxygen species decrease virulence by disrupting Campylobacter jejuni phosphotyrosine signaling. Cell Host Microbe 12:47–59. https://doi.org/10.1016/j.chom.2012.05.018
Dent E, Wright ORL, Woo J, Hoogendijk EO (2023) Malnutrition in older adults. Lancet 401:951–966. https://doi.org/10.1016/S0140-6736(22)02612-5
Ferrucci L, Fabbri E (2018) Inflammageing: chronic inflammation in ageing, cardiovascular disease, and frailty. Nat Rev Cardiol 15:505–522. https://doi.org/10.1038/s41569-018-0064-2
Finkel T (2011) Signal transduction by reactive oxygen species. J Cell Biol 194:7–15. https://doi.org/10.1083/jcb.201102095
Forman HJ, Davies KJA, Ursini F (2014a) How do nutritional antioxidants really work: nucleophilic tone and para-hormesis versus free radical scavenging in vivo. Free Radic Biol Med 66:24–35. https://doi.org/10.1016/j.freeradbiomed.2013.05.045
Forman HJ, Ursini F, Maiorino M (2014b) An overview of mechanisms of redox signaling. J Mol Cell Cardiol 0:2–9. https://doi.org/10.1016/j.yjmcc.2014.01.018
Franceschi C, Campisi J (2014) Chronic inflammation (inflammaging) and its potential contribution to age-associated diseases. J Gerontol A Biol Sci Med Sci 69(Suppl 1):S4–9. https://doi.org/10.1093/gerona/glu057
Funk MC, Zhou J, Boutros M (2020) Ageing, metabolism and the intestine. EMBO Rep 21:e50047. https://doi.org/10.15252/embr.202050047
González-Bosch C, Boorman E, Zunszain PA, Mann GE (2021) Short-chain fatty acids as modulators of redox signaling in health and disease. Redox Biol 47:102165. https://doi.org/10.1016/j.redox.2021.102165
Grasberger H, El-Zaatari M, Dang DT, Merchant JL (2013) Dual oxidases control release of hydrogen peroxide by the gastric epithelium to prevent helicobacter felis infection and inflammation in mice. Gastroenterology 145:1045–1054. https://doi.org/10.1053/j.gastro.2013.07.011
Guo W, Liu J, Sun J et al (2020) Butyrate alleviates oxidative stress by regulating NRF2 nuclear accumulation and H3K9/14 acetylation via GPR109A in bovine mammary epithelial cells and mammary glands. Free Radic Biol Med 152:728–742. https://doi.org/10.1016/j.freeradbiomed.2020.01.016
Ha E-M, Oh C-T, Bae YS, Lee W-J (2005) A direct role for dual oxidase in drosophila gut immunity. Science 310:847–850. https://doi.org/10.1126/science.1117311
Ha E-M, Oh C-T, Ryu J-H et al (2005b) An antioxidant system required for host protection against gut infection in Drosophila. Dev Cell 8:125–132. https://doi.org/10.1016/j.devcel.2004.11.007
Hickson M (2006) Malnutrition and ageing. Postgrad Med J 82:2–8. https://doi.org/10.1136/pgmj.2005.037564
Homolak J (2022) Redox homeostasis in Alzheimer’s Disease. In: Çakatay U (ed) Redox signaling and biomarkers in ageing. Springer, Cham, pp 323–348
Homolak J (2023) Targeting the microbiota-mitochondria crosstalk in neurodegeneration with senotherapeutics. Senescence, Mitochondria and Senotherapeutics. Elsevier
Homolak J, Babic Perhoc A, Knezovic A et al (2021) Is galactose a hormetic sugar? An exploratory study of the rat hippocampal redox regulatory network. Mol Nutr Food Res 65:e2100400. https://doi.org/10.1002/mnfr.202100400
Homolak J, Babic Perhoc A, Knezovic A et al (2021) The effect of acute oral galactose administration on the redox system of the rat small intestine. Antioxid (Basel) 11:37. https://doi.org/10.3390/antiox11010037
Jones RM, Neish AS (2017) Redox signaling mediated by the gut microbiota. Free Radic Biol Med 105:41–47. https://doi.org/10.1016/j.freeradbiomed.2016.10.495
Jones RM, Luo L, Ardita CS et al (2013) Symbiotic lactobacilli stimulate gut epithelial proliferation via Nox-mediated generation of reactive oxygen species. EMBO J 32:3017–3028. https://doi.org/10.1038/emboj.2013.224
Jones RM, Desai C, Darby TM et al (2015) Lactobacilli modulate epithelial cytoprotection through the Nrf2 pathway. Cell Rep 12:1217–1225. https://doi.org/10.1016/j.celrep.2015.07.042
Knaus UG (2020) Chap. 33 - ROS signaling in complex systems: The gut. In: Sies H (ed) Oxidative stress. Academic Press, Cambridge, pp 695–712
Knaus UG, Hertzberger R, Pircalabioru GG et al (2017) Pathogen control at the intestinal mucosa – H2O2 to the rescue. Gut Microbes 8:67–74. https://doi.org/10.1080/19490976.2017.1279378
Kovač Z (2021) Pathophysiological body reactivity and interactions in comorbidities. Synergism Versus antagonism of disease pathways and etiopathogenetic clusters in comorbidity conditions. Psychiatr Danub 33:414–426
Kruidenier L, Kuiper I, van Duijn W et al (2003) Differential mucosal expression of three superoxide dismutase isoforms in inflammatory bowel disease. J Pathol 201:7–16. https://doi.org/10.1002/path.1407
Kunst C, Schmid S, Michalski M et al (2023) The influence of gut microbiota on oxidative stress and the Immune System. Biomedicines 11:1388. https://doi.org/10.3390/biomedicines11051388
Liguori I, Russo G, Curcio F et al (2018) Oxidative stress, aging, and diseases. Clin Interv Aging 13:757–772. https://doi.org/10.2147/CIA.S158513
Loguercio C, Taranto D, Beneduce F et al (1996a) Age affects glutathione content and glutathione-transferase activity in human gastric mucosa. Ital J Gastroenterol 28:477–481
Loguercio C, Taranto D, Vitale LM et al (1996b) Effect of liver cirrhosis and age on the glutathione concentration in the plasma, erythrocytes, and gastric mucosa of man. Free Radic Biol Med 20:483–488. https://doi.org/10.1016/0891-5849(96)02057-6
Luo J, Mills K, le Cessie S et al (2020) Ageing, age-related diseases and oxidative stress: what to do next? Ageing Res Rev 57:100982. https://doi.org/10.1016/j.arr.2019.100982
Maher P (2005) The effects of stress and aging on glutathione metabolism. Ageing Res Rev 4:288–314. https://doi.org/10.1016/j.arr.2005.02.005
Mármol F, Sánchez J, López D et al (2009) Oxidative stress, nitric oxide and prostaglandin E2 levels in the gastrointestinal tract of aging rats. J Pharm Pharmacol 61:201–206. https://doi.org/10.1211/jpp/61.02.0009
McCord JM (1987) Radical explanations for old observations. Gastroenterology 92:2026–2028. https://doi.org/10.1016/0016-5085(87)90640-8
Morampudi V, Dalwadi U, Bhinder G et al (2016) The goblet cell-derived mediator RELM-β drives spontaneous colitis in Muc2-deficient mice by promoting commensal microbial dysbiosis. Mucosal Immunol 9:1218–1233. https://doi.org/10.1038/mi.2015.140
Nauseef WM (2019) The phagocyte NOX2 NADPH oxidase in microbial killing and cell signaling. Curr Opin Immunol 60:130–140. https://doi.org/10.1016/j.coi.2019.05.006
Norman K, Haß U, Pirlich M (2021) Malnutrition in older adults—recent advances and remaining Challenges. Nutrients 13:2764. https://doi.org/10.3390/nu13082764
Parvez S, Long MJC, Poganik JR, Aye Y (2018) Redox Signaling by reactive electrophiles and oxidants. Chem Rev 118:8798–8888. https://doi.org/10.1021/acs.chemrev.7b00698
Patlevič P, Vašková J, Švorc P et al (2016) Reactive oxygen species and antioxidant defense in human gastrointestinal diseases. Integr Med Res 5:250–258. https://doi.org/10.1016/j.imr.2016.07.004
Pawelec G, Goldeck D, Derhovanessian E (2014) Inflammation, ageing and chronic disease. Curr Opin Immunol 29:23–28. https://doi.org/10.1016/j.coi.2014.03.007
Pircalabioru G, Aviello G, Kubica M et al (2016) Defensive mutualism rescues NADPH oxidase inactivation in gut infection. Cell Host Microbe 19:651–663. https://doi.org/10.1016/j.chom.2016.04.007
Pomatto LCD, Davies KJA (2017) The role of declining adaptive homeostasis in ageing. J Physiol 595:7275–7309. https://doi.org/10.1113/JP275072
Pomatto LCD, Davies KJA (2018) Adaptive homeostasis and the free radical theory of ageing. Free Radic Biol Med 124:420–430. https://doi.org/10.1016/j.freeradbiomed.2018.06.016
Rada B, Leto TL (2008) Oxidative innate immune defenses by Nox/Duox family NADPH oxidases. Contrib Microbiol 15:164–187. https://doi.org/10.1159/000136357
Rera M, Clark RI, Walker DW (2012) Intestinal barrier dysfunction links metabolic and inflammatory markers of aging to death in drosophila. Proc Natl Acad Sci USA 109:21528–21533. https://doi.org/10.1073/pnas.1215849110
Roberts SB, Rosenberg I (2006) Nutrition and aging: changes in the regulation of energy metabolism with aging. Physiol Rev 86:651–667. https://doi.org/10.1152/physrev.00019.2005
Salazar AM, Resnik-Docampo M, Ulgherait M et al (2018) Intestinal snakeskin limits microbial dysbiosis during aging and promotes longevity. iScience 9:229–243. https://doi.org/10.1016/j.isci.2018.10.022
Salazar AM, Aparicio R, Clark RI et al (2023) Intestinal barrier dysfunction: an evolutionarily conserved hallmark of aging. Dis Model Mech 16:dmm049969. https://doi.org/10.1242/dmm.049969
Sasabe J, Miyoshi Y, Rakoff-Nahoum S et al (2016) Interplay between microbial d-amino acids and host d-amino acid oxidase modifies murine mucosal defence and gut microbiota. Nat Microbiol 1:16125. https://doi.org/10.1038/nmicrobiol.2016.125
Sastre J, Pallardó FV, Viña J (1996) Glutathione, oxidative stress and aging. AGE 19:129–139. https://doi.org/10.1007/BF02434082
Schafer FQ, Buettner GR (2001) Redox environment of the cell as viewed through the redox state of the glutathione disulfide/glutathione couple. Free Radic Biol Med 30:1191–1212. https://doi.org/10.1016/s0891-5849(01)00480-4
Sekhar RV, Patel SG, Guthikonda AP et al (2011) Deficient synthesis of glutathione underlies oxidative stress in aging and can be corrected by dietary cysteine and glycine supplementation. Am J Clin Nutr 94:847–853. https://doi.org/10.3945/ajcn.110.003483
Shin J, Noh J-R, Choe D et al (2021) Ageing and rejuvenation models reveal changes in key microbial communities associated with healthy ageing. Microbiome 9:240. https://doi.org/10.1186/s40168-021-01189-5
Sies H, Jones DP (2020) Reactive oxygen species (ROS) as pleiotropic physiological signalling agents. Nat Rev Mol Cell Biol 21:363–383. https://doi.org/10.1038/s41580-020-0230-3
Stolfi C, Maresca C, Monteleone G, Laudisi F (2022) Implication of intestinal barrier dysfunction in gut dysbiosis and diseases. Biomedicines 10:289. https://doi.org/10.3390/biomedicines10020289
Stone JR, Yang S (2006) Hydrogen peroxide: a signaling messenger. Antioxid Redox Signal 8:243–270. https://doi.org/10.1089/ars.2006.8.243
Thrasivoulou C, Soubeyre V, Ridha H et al (2006) Reactive oxygen species, dietary restriction and neurotrophic factors in age-related loss of myenteric neurons. Aging Cell 5:247–257. https://doi.org/10.1111/j.1474-9726.2006.00214.x
Uchiyama J, Akiyama M, Hase K et al (2022) Gut microbiota reinforce host antioxidant capacity via the generation of reactive sulfur species. Cell Rep 38:110479. https://doi.org/10.1016/j.celrep.2022.110479
Untersmayr E, Brandt A, Koidl L, Bergheim I (2022) The intestinal barrier dysfunction as driving factor of inflammaging. Nutrients 14:949. https://doi.org/10.3390/nu14050949
Ursini F, Maiorino M, Forman HJ (2016) Redox homeostasis: the golden mean of healthy living. Redox Biol 8:205–215. https://doi.org/10.1016/j.redox.2016.01.010
Vaccaro A, Kaplan Dor Y, Nambara K et al (2020) Sleep loss can cause death through accumulation of reactive oxygen species in the gut. Cell 181:1307-1328e15. https://doi.org/10.1016/j.cell.2020.04.049
Wang Y, Yang J, Yi J (2012) Redox sensing by proteins: oxidative modifications on cysteines and the consequent events. Antioxid Redox Signal 16:649–657. https://doi.org/10.1089/ars.2011.4313
Wang R-S, Oldham WM, Maron BA, Loscalzo J (2018) Systems biology approaches to redox metabolism in stress and disease states. Antioxid Redox Signal 29:953–972. https://doi.org/10.1089/ars.2017.7256
Wen Z, Liu W, Li X et al (2019) A protective role of the NRF2-Keap1 pathway in maintaining intestinal barrier function. Oxid Med Cell Longev. https://doi.org/10.1155/2019/1759149
Wentworth CC, Jones RM, Kwon YM et al (2010) Commensal-epithelial signaling mediated via formyl peptide receptors. Am J Pathol 177:2782–2790. https://doi.org/10.2353/ajpath.2010.100529
Wingler K, Müller C, Schmehl K et al (2000) Gastrointestinal glutathione peroxidase prevents transport of lipid hydroperoxides in CaCo-2 cells. Gastroenterology 119:420–430. https://doi.org/10.1053/gast.2000.9521
Wolach B, Gavrieli R, de Boer M et al (2017) Chronic granulomatous disease: clinical, functional, molecular, and genetic studies. The israeli experience with 84 patients. Am J Hematol 92:28–36. https://doi.org/10.1002/ajh.24573
Wu G, Lupton JR, Turner ND et al (2004) Glutathione metabolism and its implications for Health. J Nutr 134:489–492. https://doi.org/10.1093/jn/134.3.489
Ying J, Clavreul N, Sethuraman M et al (2007) Thiol oxidation in signaling and response to stress. Free Radic Biol Med 43:1099–1108. https://doi.org/10.1016/j.freeradbiomed.2007.07.014
Yu C, Xiao J-H (2021) The Keap1-Nrf2 system: a mediator between oxidative stress and aging. Oxid Med Cell Longev 2021:6635460. https://doi.org/10.1155/2021/6635460
Zampino M, AlGhatrif M, Kuo P-L et al (2020) Longitudinal changes in resting metabolic rates with aging are accelerated by diseases. Nutrients 12:3061. https://doi.org/10.3390/nu12103061
Zuo J, Zhang Z, Luo M et al (2022) Redox signaling at the crossroads of human health and disease. MedComm 3:e127. https://doi.org/10.1002/mco2.127
Funding
None.
Author information
Authors and Affiliations
Contributions
JH wrote the manuscript.
Corresponding author
Ethics declarations
Conflict of interest
The authors declare no conflict of interest.
Ethical approval
This article does not contain any studies with human participants or animals performed the author.
Additional information
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Homolak, J. Gastrointestinal redox homeostasis in ageing. Biogerontology 24, 741–752 (2023). https://doi.org/10.1007/s10522-023-10049-8
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10522-023-10049-8