Lowering propionic acid levels by regulating gut microbiota with ursodeoxycholic acid appears to regress autism symptoms: an animal study

Year 2023, Volume: 6 Issue: 4, 791 - 799, 30.07.2023

Levent Karakaş , Volkan Solmaz , Erman Bağcıoğlu , Bahattin Ozkul İbrahim Söğüt , Yiğit Uyanıkgil , Oytun Erbaş

https://doi.org/10.32322/jhsm.1286838

Cited By: 1

Abstract

Aims: Patients with autism have altered gut microbiata, including higher frequency of bacteroidetes and clostridiales that produce of propionic acid (PPA) –a compound that is established as an autism-inducing agent. We hypothesized that lowering the PPA levels by regulating gut microbiata with ursodeoxycholic acid (UDCA) can regress the autism symptoms. The aim of this study is to examine the potential ameliorating effects of UDCA on a PPA-induced rat model of autism.
Methods: Thirty male Wistar albino rats were divided into three groups: controls, PPA-induced (5 days of intraperitoneal 250 mg/kg/day dosage) autism model receiving oral saline, and PPA-induced autism model receiving oral UDCA (100 mg/kg/day). Oral treatments were applied for 15 days. At the end of the 15th day, all rats underwent behavioral tests and MR spectroscopy. At the end of the study, all animals were sacrificed and brain tissue / blood samples were collected for histopathological and biochemical analyses.
Results: Sociability test, open field test and passive avoidance learning tests were impaired, similar to the autism behavioral pattern, in PPA recipients; however, results were closer to normal patterns in the PPA+UDCA group. Biochemically, MDA, TNF-alpha, IL-2, IL-17, NF-kB, lactate, NGF and NRF2 levels in brain tissues showed significant differences between controls and the PPA+Saline group, and between the PPA+Saline group and the PPA+UDCA group (p< 0.05, for all). Histopathology showed that PPA injection caused increased glial activity, neural body degeneration, decreased neural count and dysmorphic changes in hippocampal and cerebellar tissues (p<0.01, for all). UDCA treatment significantly ameliorated these changes.
Conclusion: UDCA administration has ameliorating effects on PPA-induced autism-like behavioral, biochemical and histopathological changes in rats.

Keywords

Autism, ursodeoxycholic acid, propionic acid, gut microbiota

Thanks

No funds were used in the study. All expenses were covered by the researchers.

References

• American Psychiatric Association. and American Psychiatric Association. DSM-5 Task Force., Diagnostic and statistical manual of mental disorders: DSM-5. Fifth edition. ed. 2013, Washington, DC:American Psychiatric Publishing. xliv, 947 pages.
• Krishnan A, Zhang R, Yao V, et al. Genome-wide prediction and functional characterization of the genetic basis of autism spectrum disorder. Nat Neurosci. 2016;19(11):1454-62.
• Hollowood-Jones K, Adams JB, Coleman DM, et al. Altered metabolism of mothers of young children with Autism Spectrum Disorder:a case control study. BMC Pediatr. 2020;20(1):557.
• Samadi A, Sabuncuoglu S, Samadi M, et al. A Comprehensive Review on Oxysterols and Related Diseases. Curr Med Chem. 2021;28(1):110-36.
• Yalcinkaya A, Samadi A, Lay I, Unal S, Sabuncuoglu S, Oztas Y. Oxysterol concentrations are associated with cholesterol concentrations and anemia in pediatric patients with sickle cell disease. Scand J Clin Lab Invest. 2019;79(6):381-7.
• Dowman JK, Tomlinson JW, Newsome PN. Pathogenesis of non-alcoholic fatty liver disease. QJM. 2010;103(2):71-83.
• Gątarek P, Rosiak A, Borowczyk K, Głowacki R, Kałużna-Czaplińska J. Higher levels of low molecular weight sulfur compounds and homocysteine thiolactone in the urine of autistic children. Molecules. 2020;25(4).
• El-Ansary A, Chirumbolo S, Bhat RS, Dadar M, Ibrahim EM, Bjørklund G. The role of lipidomics in autism spectrum disorder. Mol Diagn Ther. 2020;24(1):31-48.
• Fujiwara T, Morisaki N, Honda Y, Sampei M, Tani Y. Chemicals, nutrition, and autism spectrum disorder: a mini-review. Front Neurosci. 2016;10:174.
• Pulikkan J, Mazumder A, Grace T. Role of the gut microbiome in autism spectrum disorders. Adv Exp Med Biol. 2019;1118:253-269.
• El-Ansary AK, Ben Bacha A, Kotb M. Etiology of autistic features:the persisting neurotoxic effects of propionic acid. J Neuroinflammation. 2012;9:74.
• Finegold SM, Dowd SE, Gontcharova V, et al. Pyrosequencing study of fecal microflora of autistic and control children. Anaerobe. 2010;16(4):444-453.
• Cannizzaro C, Monastero R, Vacca M, Martire M. [3H]-DA release evoked by low pH medium and internal H+ accumulation in rat hypothalamic synaptosomes:involvement of calcium ions. Neurochem Int. 2003;43(1):9-17.
• Shultz SR, MacFabe DF. Propionic acid animal model of autism. New York, NY:755-1778.: Springer New York; 2014:1755-1778.
• Shultz SR, MacFabe DF, Ossenkopp KP, et al. Intracerebroventricular injection of propionic acid, an enteric bacterial metabolic end-product, impairs social behavior in the rat:implications for an animal model of autism. Neuropharmacology. 2008;54(6):901-911.
• Choi J, Lee S, Won J, et al. Pathophysiological and neurobehavioral characteristics of a propionic acid-mediated autism-like rat model. PLoS One. 2018;13(2):e0192925.
• Ridlon JM, Kang DJ, Hylemon PB, Bajaj JS. Bile acids and the gut microbiome. Curr Opin Gastroenterol. 2014;30(3):332-338.
• Chávez-Talavera O, Tailleux A, Lefebvre P, Staels B. Bile acid control of metabolism and inflammation in obesity, type 2 diabetes, dyslipidemia, and nonalcoholic fatty liver disease. Gastroenterology. 2017;152(7):1679-1694.e3.
• Mahmoudian Dehkordi S, Arnold M, Nho K, et al. Altered bile acid profile associates with cognitive impairment in Alzheimer's disease-An emerging role for gut microbiome. Alzheimers Dement. 2019;15(1):76-92.
• Grobe S, Badenhorst CPS, Bayer T, et al. Engineering regioselectivity of a P450 monooxygenase enables the synthesis of ursodeoxycholic acid via 7β-hydroxylation of lithocholic acid. Angew Chem Int Ed Engl. 2021;60(2):753-757.
• Fattorusso A, Di Genova L, Dell'Isola GB, Mencaroni E, Esposito S. Autism spectrum disorders and the gut microbiota. Nutrients. 2019;11(3).
• Kim SH, Chun HJ, Choi HS, et al. Ursodeoxycholic acid attenuates 5-fluorouracil-induced mucositis in a rat model. Oncol Lett. 2018;16(2):2585-2590.
• Garcia-Gutierrez E, Narbad A, Rodríguez JM. Autism spectrum disorder associated with gut microbiota at immune, metabolomic, and neuroactive level. Front Neurosci. 2020;14:578666.
• Pearson BL, Defensor EB, Blanchard DC, Blanchard RJ. C57BL/6J mice fail to exhibit preference for social novelty in the three-chamber apparatus. Behav Brain Res. 2010;213(2):189-194.
• Sestakova N, Puzserova A, Kluknavsky M, Bernatova I. Determination of motor activity and anxiety-related behaviour in rodents: methodological aspects and role of nitric oxide. Interdiscip Toxicol. 2013;6(3):126-35.
• Afshar S, Shahidi S, Rohani AH, Komaki A, Asl SS. The effect of NAD-299 and TCB-2 on learning and memory, hippocampal BDNF levels and amyloid plaques in Streptozotocin-induced memory deficits in male rats. Psychopharmacology (Berl). 2018;235(10):2809-2822.
• Bradford MM. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem. 1976;72:248-254.
• Sharma R, Rahi S, Mehan S. Neuroprotective potential of solanesol in intracerebroventricular propionic acid induced experimental model of autism:Insights from behavioral and biochemical evidence. Toxicol Rep. 2019;6:1164-1175.
• Maigoro AY, Lee S. Gut microbiome-based analysis of lipid a biosynthesis in individuals with autism spectrum disorder: an in silico evaluation. Nutrients. 2021;13(2).
• Zhang M, Ma W, Zhang J, He Y, Wang J. Analysis of gut microbiota profiles and microbe-disease associations in children with autism spectrum disorders in China. Sci Rep. 2018;8(1):13981.
• Krigsman A, Walker SJ. Gastrointestinal disease in children with autism spectrum disorders: etiology or consequence? World J Psychiatry. 2021;11(9):605-618.
• Vuong HE, Hsiao EY. Emerging roles for the gut microbiome in autism spectrum disorder. Biol Psychiatry. 2017;81(5):411-423.
• Wei H, Chadman KK, McCloskey DP, et al. Brain IL-6 elevation causes neuronal circuitry imbalances and mediates autism-like behaviors. Biochim Biophys Acta. 2012;1822(6):831-842.
• Ashwood P, Krakowiak P, Hertz-Picciotto I, Hansen R, Pessah I, Van de Water J. Elevated plasma cytokines in autism spectrum disorders provide evidence of immune dysfunction and are associated with impaired behavioral outcome. Brain Behav Immun. 2011;25(1):40-5.
• Crawley JN. Mouse behavioral assays relevant to the symptoms of autism. Brain Pathol. 2007;17(4):448-459.
• Tomova A, Husarova V, Lakatosova S, et al. Gastrointestinal microbiota in children with autism in Slovakia. Physiol Behav. 2015;138:179-187.
• Varesio C, Grumi S, Zanaboni MP, et al. Ketogenic dietary therapies in patients with autism spectrum disorder: facts or fads? a scoping review and a proposal for a shared protocol. Nutrients. 2021;13(6).
• Wahlström A, Sayin SI, Marschall HU, Bäckhed F. Intestinal crosstalk between bile acids and microbiota and its impact on host metabolism. Cell Metab. 2016;24(1):41-50.
• Tang R, Wei Y, Li Y, et al. Gut microbial profile is altered in primary biliary cholangitis and partially restored after UDCA therapy. Gut. 2018;67(3):534-541.
• Bambini-Junior V, Rodrigues L, Behr GA, Moreira JC, Riesgo R, Gottfried C. Animal model of autism induced by prenatal exposure to valproate: behavioral changes and liver parameters. Brain Res. 2011;1408:8-16.
• Buffington SA, Di Prisco GV, Auchtung TA, Ajami NJ, Petrosino JF, Costa-Mattioli M. Microbial reconstitution reverses maternal diet-induced social and synaptic deficits in offspring. Cell. 2016;165(7):1762-1775.
• Xiao G, Zhang M, Peng X, Jiang G. Protocatechuic acid attenuates cerebral aneurysm formation and progression by inhibiting TNF-alpha/Nrf-2/NF-kB-mediated inflammatory mechanisms in experimental rats. Open Life Sci. 2021;16(1):128-141.
• Bjørklund G, Meguid NA, El-Bana MA, et al. Oxidative stress in autism spectrum disorder. Mol Neurobiol. 2020;57(5):2314-2332.
• Forbes CE, Grafman J. The role of the human prefrontal cortex in social cognition and moral judgment. Annu Rev Neurosci. 2010;33:299-324.
• Zhu H, Barker PB. MR spectroscopy and spectroscopic imaging of the brain. Methods Mol Biol. 2011;711:203-226.
• Sever IH, Ozkul B, Bozkurt MF, Erbas O. Therapeutic effect of finasteride through its antiandrogenic and antioxidant role in a propionic acid-induced autism model: demonstrated by behavioral tests, histological findings and MR spectroscopy. Neurosci Lett. 2022;779:136622.
• Goh S, Dong Z, Zhang Y, DiMauro S, Peterson BS. Mitochondrial dysfunction as a neurobiological subtype of autism spectrum disorder: evidence from brain imaging. JAMA Psychiatry. 2014; 71(6):665-671.