Oleanolic acid ameliorates intestinal alterations associated with EAE

Abstract

Background Multiple sclerosis (MS) is a chronic demyelinating autoimmune disease affecting the CNS. Recent studies have indicated that intestinal alterations play key pathogenic roles in the development of autoimmune diseases, including MS. The triterpene oleanolic acid (OA), due to its anti-inflammatory properties, has shown to beneficially influence the severity of the experimental autoimmune encephalomyelitis (EAE), a preclinical model of MS. We herein investigate EAE-associated gut intestinal dysfunction and the effect of OA treatment. Methods Mice with MOG35–55-induced EAE were treated with OA or vehicle from immunization day and were daily analyzed for clinical deficit. We performed molecular and histological analysis in serum and intestinal tissues to measure oxidative and inflammatory responses. We used Caco-2 and HT29-MTX-E12 cells to elucidate OA in vitro effects. Results We found that OA protected from EAE-induced changes in intestinal permeability and preserved the mucin-containing goblet cells along the intestinal tract. Serum levels of the markers for intestinal barrier damage iFABP and monocyte activation sCD14 were consistently and significantly reduced in OA-treated EAE mice. Beneficial OA effects also included a decrease of pro-inflammatory mediators both in serum and colonic tissue of treated-EAE mice. Moreover, the levels of some immunoregulatory cytokines, the neurotrophic factor GDNF, and the gastrointestinal hormone motilin were preserved in OA-treated EAE mice. Regarding oxidative stress, OA treatment prevented lipid peroxidation and superoxide anion accumulation in intestinal tissue, while inducing the expression of the ROS scavenger Sestrin-3. Furthermore, short-chain fatty acids (SCFA) quantification in the cecal content showed that OA reduced the high iso-valeric acid concentrations detected in EAE-mice. Lastly, using in vitro cell models which mimic the intestinal epithelium, we verified that OA protected against intestinal barrier dysfunction induced by injurious agents produced in both EAE and MS. Conclusion These findings reveal that OA ameliorates the gut dysfunction found in EAE mice. OA normalizes the levels of gut mucosal dysfunction markers, as well as the pro- and anti-inflammatory immune bias during EAE, thus reinforcing the idea that OA is a beneficial compound for treating EAE and suggesting that OA may be an interesting candidate to be explored for the treatment of human MS.

Oleanolic Acid: Extraction, Characterization and Biological Activity

“…Anyway, it is generally accepted that OA and related triterpenoids exhibit a very moderate aptitude as radical scavengers [ 158 ]. Still, Gutierrez et al [ 159 ] found that treatment with OA prevented lipid peroxidation and superoxide anion accumulation in the gut, while inducing the expression of the ROS scavenger Sestrin-3, which was associated with a normalization of the levels of intestinal mucosal dysfunction markers, as well as the pro- and anti-inflammatory immune bias in a murine model of experimental autoimmune encephalomyelitis.…”

“…Although many mechanisms have been proposed to underlie their effects, a unifying proposal is that oxidative stress and inflammation represent a common pathway of injury. In this review, we have presented evidence indicating that OA plays an efficient role in preventing lipid peroxidation and superoxide anion accumulation [ 159 ] and reinforces the endogenous intracellular antioxidant. On the other hand, investigations in cell cultures and experimental animals have demonstrated that OA significantly inhibits pro-inflammatory cytokine production (IL-1β, IL-6, IL-8, TNF-α, MCP-1) in a number of inflammation and oxidative stress scenarios [ 102 , 189 , 190 ].…”

The Gut-Brain Axis in Multiple Sclerosis. Is Its Dysfunction a Pathological Trigger or a Consequence of the Disease?

“…Altogether these studies clearly demonstrate the importance of the microbiota composition in determining the inflammatory environment in the gut, and its consequences on the CNS. It is highly relevant to MS that dysbiosis in patients is frequently associated with an increased intestinal permeability (84) and both alterations have been also demonstrated in EAE (85)(86)(87). That such conditions might promote a systemic inflammatory condition is supported by the increased plasma levels of LPS observed in both MS patients and EAE-affected mice (88,89), as well as by the increased anti-microbiota systemic IgG responses observed in MS patients, which suggest an enhanced bacterial translocation from the gut lumen to systemic circulation in MS (90).…”

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“…[32] Anti SARS-CoV-2 (COVID-19) [33,34] normalise the levels of gut mucosal dysfunction markers, reshape the gut microbiota [35], treatment of human Multiple schlerosis [36], Suppress liver carcinogenesis [37] Improves obesity-related inflammation and insulin resistance [38] Antidiabetic [39], α-glucosidase inhibitor [40], protect skin aging [41] Peripheral anti-nociceptive and anti-inflammation effect…”