P1335 Dietary Carnosic Acid Eases Colitis by Activating NRF2 Signal via Regulating Gut Microbiota and Metabolites
Authors: Xiaohan W , feng T 
Published: January 2025

Abstract

Background
Ulcerative colitis (UC) is a chronic intestinal inflammatory disease, which is closely related to the imbalance of intestinal microbiota and metabolic alterations. We have studied the role of dietary carnosic acid (CA) in alleviating intestinal inflammation through regulating the intestinal microbiota and its metabolites.

Methods
Mice were fed with a diet supplemented with CA or a normal diet, and the enteritis model was established using dextran sulfate sodium (DSS). The feces of mice fed with different diets were transplanted into germ-free mice to determine the direct role of the CA-regulated microbiota in alleviating colitis. The intestinal microbiota was analyzed by 16S rRNA sequencing, serum metabolites were analyzed by liquid chromatography-mass spectrometry (LC-MS) metabolomics, and downstream targets were analyzed by RNA sequencing.

Results
Through the analysis of the microbiota based on the 16S rRNA gene, we found for the first time that the addition of CA to the diet improved the imbalance of the intestinal microbiota induced by DSS. The protective mechanism of CA against DSS-induced colitis is to improve the function of the intestinal mucosal barrier by activating the Nrf2 signaling pathway. It is worth noting that the addition of CA to the diet can enrich the microbe-derived 3-indolepropionic acid, thereby activating the Nrf2 signaling in human colonic epithelial cells. In addition, exogenous 3-indolepropionic acid treatment has a similar protective effect on DSS-induced colitis by improving the Nrf2 signaling-dependent mucosal barrier function.

Conclusion
In conclusion, our research results indicate that the intestinal microbiota - 3-indolepropionic acid - Nrf2 axis plays an important role in maintaining intestinal homeostasis, which may represent a new method for preventing colitis by manipulating the metabolites of the intestinal microbiota.

References
[1]Loussouarn M, Krieger-Liszkay A, Svilar L, et al. Carnosic Acid and Carnosol, Two Major Antioxidants of Rosemary, Act through Different Mechanisms[J]. Plant Physiol, 2017,175(3):1381-1394.
[2]Bahri S, Jameleddine S, Shlyonsky V. Relevance of carnosic acid to the treatment of several health disorders: Molecular targets and mechanisms[J]. Biomed Pharmacother, 2016,84:569-582.
[3]Satoh T, Trudler D, Oh C K, et al. Potential Therapeutic Use of the Rosemary Diterpene Carnosic Acid for Alzheimer's Disease, Parkinson's Disease, and Long-COVID through NRF2 Activation to Counteract the NLRP3 Inflammasome[J]. Antioxidants (Basel), 2022,11(1).
[4]Li X, Zhao L, Han J J, et al. Carnosol Modulates Th17 Cell Differentiation and Microglial Switch in Experimental Autoimmune Encephalomyelitis[J]. Front Immunol, 2018,9:1807.
[5]Veenstra J P, Vemu B, Tocmo R, et al. Pharmacokinetic Analysis of Carnosic Acid and Carnosol in Standardized Rosemary Extract and the Effect on the Disease Activity Index of DSS-Induced Colitis[J]. Nutrients, 2021,13(3).
[6]David L A, Maurice C F, Carmody R N, et al. Diet rapidly and reproducibly alters the human gut microbiome[J]. Nature, 2014,505(7484):559-563.
[7]Guo C, Wang Y, Zhang S, et al. Crataegus pinnatifida polysaccharide alleviates colitis via modulation of gut microbiota and SCFAs metabolism[J]. Int J Biol Macromol, 2021,181:357-368.
[8]Glassner K L, Abraham B P, Quigley E. The microbiome and inflammatory bowel disease[J]. J Allergy Clin Immunol, 2020,145(1):16-27.
[9]He X, Zhang M, Li S T, et al. Alteration of gut microbiota in high-fat diet-induced obese mice using carnosic acid from rosemary[J]. Food Sci Nutr, 2022,10(7):2325-2332.
[10]Ou J, Huang J, Zhao D, et al. Protective effect of rosmarinic acid and carnosic acid against streptozotocin-induced oxidation, glycation, inflammation and microbiota imbalance in diabetic rats[J]. Food Funct, 2018,9(2):851-860.
[11]Li D, Wang P, Wang P, et al. Targeting the gut microbiota by dietary nutrients: A new avenue for human health[J]. Crit Rev Food Sci Nutr, 2019,59(2):181-195.
[12]Welihinda A A, Kaur M, Greene K, et al. The adenosine metabolite inosine is a functional agonist of the adenosine A2A receptor with a unique signaling bias[J]. Cell Signal, 2016,28(6):552-560.
[13]Mager L F, Burkhard R, Pett N, et al. Microbiome-derived inosine modulates response to checkpoint inhibitor immunotherapy[J]. Science, 2020,369(6510):1481-1489.
[14]Rahimian R, Fakhfouri G, Daneshmand A, et al. Adenosine A2A receptors and uric acid mediate protective effects of inosine against TNBS-induced colitis in rats[J]. Eur J Pharmacol, 2010,649(1-3):376-381.
[15]Mabley J G, Pacher P, Liaudet L, et al. Inosine reduces inflammation and improves survival in a murine model of colitis[J]. Am J Physiol Gastrointest Liver Physiol, 2003,284(1):G138-G144.
[16]Peng S, Shen L, Yu X, et al. The role of Nrf2 in the pathogenesis and treatment of ulcerative colitis[J]. Front Immunol, 2023,14:1200111.
[17]Singh R, Chandrashekharappa S, Bodduluri S R, et al. Enhancement of the gut barrier integrity by a microbial metabolite through the Nrf2 pathway[J]. Nat Commun, 2019,10(1):89.
[18]Abdelkader N F, Ibrahim S M, Moustafa P E, et al. Inosine mitigated diabetic peripheral neuropathy via modulating GLO1/AGEs/RAGE/NF-kappaB/Nrf2 and TGF-beta/PKC/TRPV1 signaling pathways[J]. Biomed Pharmacother, 2022,145:112395.