Reducing the amount of <em>Clostridium difficile</em> in the gut microbiome reduces the behavioral projection of cognitive activity in rats

Tevzadze,Gigi; Kiknadze,Natalia; Zhuravliova,Elene; Barbakadze,Tamar; Shanshiashvili,Lali; Narmania,Nana; Mikeladze,David

doi:10.3892/wasj.2023.207

Reducing the amount of Clostridium difficile in the gut microbiome reduces the behavioral projection of cognitive activity in rats

Authors:
- Gigi Tevzadze
- Natalia Kiknadze
- Elene Zhuravliova
- Tamar Barbakadze
- Lali Shanshiashvili
- Nana Narmania
- David Mikeladze
View Affiliations

Affiliations: 4‑D Research Institute, Ilia State University, Tbilisi 0162, Georgia, Institute of Chemical Biology, Ilia State University, Tbilisi 0162, Georgia
Published online on: October 17, 2023 https://doi.org/10.3892/wasj.2023.207
Article Number: 30
Copyright : © Tevzadze et al. This is an open access article distributed under the terms of Creative Commons Attribution License [CC BY 4.0].

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

It is already known that the gut microbiome bacteria colony of Clostridium difficile produces 10‑1,000‑fold more para‑cresol (p‑cresol) than other known p‑cresol‑producing bacteria in the gut. A notable link between a high concentration of p‑cresol, a phenolic compound produced by Clostridium difficile, and its penetration into the brain and various neurological disorders has been demonstrated over the past decades. The present study demonstrates a possible link between the amounts of Clostridium difficile in the gut microbiome and p‑cresol levels in the brain with cognitive activity. Herein, the amount of Clostridium difficile in the gut microbiome of rats was decreased through administration of vancomycin, a well‑known antibiotic used for eliminating the effects of gut infections caused by the growth of the colony of Clostridium difficile. In these rats in the experimental group, the behavioral projection of cognitive activity was significantly decreased, compared to the rats in the control group. These data may thus indicate a potential link between Clostridium difficile colonies in the gut and cognitive functions of the brain. It is suggested that this interaction is carried out through the dopaminergic activity of the brain.

View Figures

View References

1	Russell WR, Duncan SH, Scobbie L, Duncan G, Cantlay L, Calder AG, Anderson SE and Flint HJ: Major phenylpropanoid-derived metabolites in the human gut can arise from microbial fermentation of protein. Mol Nutr Food Res. 57:523–535. 2013.PubMed/NCBI View Article : Google Scholar
2	Lin L and Zhang J: Role of intestinal microbiota and metabolites on gut homeostasis and human diseases. BMC Immunol. 18(2)2017.PubMed/NCBI View Article : Google Scholar
3	Persico AM and Napolioni V: Urinary p-cresol in autism spectrum disorder. Neurotoxicol Teratol. 36:82–90. 2013.PubMed/NCBI View Article : Google Scholar
4	Saito Y, Sato T, Nomoto K and Tsuji H: Identification of phenol- and p-cresol-producing intestinal bacteria by using media supplemented with tyrosine and its metabolites. FEMS Microbiol Ecol. 94(fiy125)2018.PubMed/NCBI View Article : Google Scholar
5	Morinaga Y, Fuke C, Arao T and Miyazaki T: Quantitative analysis of cresol and its metabolites in biological materials and distribution in rats after oral administration. Leg Med (Tokyo). 6:32–40. 2004.PubMed/NCBI View Article : Google Scholar
6	Gabriele S, Sacco R, Cerullo S, Neri C, Urbani A, Tripi G, Malvy J, Barthelemy C, Bonnet-Brihault F and Persico AM: Urinary p-cresol is elevated in young French children with autism spectrum disorder: A replication study. Biomarkers. 19:463–470. 2014.PubMed/NCBI View Article : Google Scholar
7	Tevzadze G, Shanshiashvilli L and Mikeladze D: Children with epilepsy and autistic spectrum disorders show similarly high levels of urinary p-cresol. J Biol Phys Chem. 17:77–80. 2017.
8	DeWolf WE Jr, Carr SA, Varrichio A, Goodhart PJ, Mentzer MA, Roberts GD, Southan C, Dolle RE and Kruse LI: Inactivation of dopamine .beta.-hydroxylase by p-cresol: Isolation and characterization of covalently modified active site peptides. Biochemistry. 27:9093–9101. 1988.PubMed/NCBI View Article : Google Scholar
9	Goodhart PJ, DeWolf WE and Kruse LI: Mechanism-based inactivation of dopamine beta.-hydroxylase by p-cresol and related alkylphenols. Biochemistry. 26:2576–2583. 1987.PubMed/NCBI View Article : Google Scholar
10	Sun Z, Bo Q, Mao Z, Li F, He F, Pao C, Li W, He Y, Ma X and Wang C: Reduced plasma dopamine-β-hydroxylase activity is associated with the severity of bipolar disorder: A pilot study. Front Psychiatry. 12(566091)2021.PubMed/NCBI View Article : Google Scholar
11	Robinson PD, Schutz CK, Macciardi F, White BN and Holden JJA: Genetically determined low maternal serum dopamine b-hydroxylase levels and the etiology of autism spectrum disorders. Am J Med Genet. 100:30–36. 2001.PubMed/NCBI View Article : Google Scholar
12	Perkovic MN, Erjavec GN, Stefulj J, Muck-Seler D, Pivac N, Hercigonja DK, Hranilovic D, Curkovic M and Dodig-Curkovic K: Association between the polymorphisms of the selected genes encoding dopaminergic system with ADHD and autism. Psychiatry Res. 215:260–261. 2014.PubMed/NCBI View Article : Google Scholar
13	Peláez T, Alcalá L, Alonso R, Rodríguez-Créixems M, García-Lechuz JM and Bouza E: Reassessment of Clostridium difficile susceptibility to metronidazole and vancomycin. Antimicrob Agents Chemother. 46:1647–1650. 2002.PubMed/NCBI View Article : Google Scholar
14	Johnson S: Recurrent Clostridium difficile infection: A review of risk factors, treatments, and outcomes. J Infect. 58:403–410. 2009.PubMed/NCBI View Article : Google Scholar
15	Settanni CR, Bibbò S, Ianiro G, Rinninella E, Cintoni M, Mele MC, Cammarota G and Gasbarrini A: Gastrointestinal involvement of autism spectrum disorder: Focus on gut microbiota. Expert Rev Gastroenterol Hepatol. 15:599–622. 2021.PubMed/NCBI View Article : Google Scholar
16	Alharthi A, Alhazmi S, Alburae N and Bahieldin A: The human gut microbiome as a potential factor in autism spectrum disorder. Int J Mol Sci. 23(1363)2022.PubMed/NCBI View Article : Google Scholar
17	Tevzadze G, Barbakadze T, Kvergelidze E, Zhuravliova E, Shanshiashvili L and Mikeladze D: Gut neurotoxin p-cresol induces brain-derived neurotrophic factor secretion and increases the expression of neurofilament subunits in PC-12 cells. AIMS Neurosci. 9:12–23. 2021.PubMed/NCBI View Article : Google Scholar
18	Saribas Z, Ergun H, Mamuk S, Köseoglu-Eser O and Melli M: Critical appraisal of air pouch infection model in rats. Ann Clin Lab Sci. 42:50–56. 2012.PubMed/NCBI
19	Gonzales M, Pepin J, Frost EH, Carrier JC, Sirard S, Fortier LC and Valiquette L: Faecal pharmacokinetics of orally administered vancomycin in patients with suspected Clostridium difficile infection. BMC Infect Dis. 10(363)2010.PubMed/NCBI View Article : Google Scholar
20	Rajizadeh MA, Sheibani V, Bejeshk MA, Borzadaran FM, Saghari H and Esmaeilpour K: The effects of high intensity exercise on learning and memory impairments followed by combination of sleep deprivation and demyelination induced by etidium bromide. Int J Neurosci. 129:1166–1178. 2019.PubMed/NCBI View Article : Google Scholar
21	Rajizadeh MA, Esmaeilpour K, Masoumi-Ardakani Y, Bejeshk MA, Shabani M, Nakhaee N, Ranjbar MP, Borzadaran FM and Sheibani V: Voluntary exercise impact on cognitive impairments in sleep-deprived intact female rats. Physiol Behav. 188:58–66. 2018.PubMed/NCBI View Article : Google Scholar
22	Esmaeilpour K, Sheibani V, Shabani M and Mirnajafi-Zadeh J: Low frequency electrical stimulation has time dependent improving effect on kindling-induced impairment in long-term potentiation in rats. Brain Res. 1668:20–27. 2017.PubMed/NCBI View Article : Google Scholar
23	Iulita MF, Allard S, Richter L, Munter LM, Ducatenzeiler A, Weise C, Do Carmo S, Klein WL, Multhaup G and Cuello AC: Intracellular Aβ pathology and early cognitive impairments in a transgenic rat overexpressing human amyloid precursor protein: A multidimensional study. Acta Neuropathol Commun. 2(61)2014.PubMed/NCBI View Article : Google Scholar
24	Lueptow LM: Novel object recognition test for the investigation of learning and memory in mice. J Vis Exp. 126(55718)2017.PubMed/NCBI View Article : Google Scholar
25	Ennaceur A: One-trial object recognition in rats and mice: Methodological and theoretical issues. Behav Brain Res. 215:244–254. 2010.PubMed/NCBI View Article : Google Scholar
26	Public Health England. Clostridioides difficile: guidance, data and analysis. Available from: https://www.gov.uk/government/collections/clostridium-difficile-guidance-data-and-analysis.
27	Krijger IM, Meerburg BG, Harmanus C and Burt SA: Clostridium difficile in wild rodents and insectivores in the Netherlands. Lett Appl Microbiol. 69:35–40. 2019.PubMed/NCBI View Article : Google Scholar
28	Chiu CY, Sarwal A, Feinstein A and Hennessey K: Effective dosage of oral vancomycin in treatment for initial episode of clostridioides difficile infection: A systematic review and meta-analysis. Antibiotics. 8(173)2019.PubMed/NCBI View Article : Google Scholar
29	Nazzal L, Soiefer L, Chang M, Tamizuddin F, Schatoff D, Cofer L, Aguero-Rosenfeld ME, Matalon A, Meijers B, Holzman R and Lowenstein J: Effect of vancomycin on the gut microbiome and plasma concentrations of gut-derived uremic solutes. Kidney Int Rep. 6:2122–2133. 2021.PubMed/NCBI View Article : Google Scholar
30	Koyama N, Inokoshi J and Tomoda H: Anti-infectious agents against MRSA. Molecules. 18:204–224. 2012.PubMed/NCBI View Article : Google Scholar
31	Kirk JA, Banerji O and Fagan RP: Characteristics of the Clostridium difficile cell envelope and its importance in therapeutics. Microb Biotechnol. 10:76–90. 2017.PubMed/NCBI View Article : Google Scholar
32	Eubank TA, Gonzales-Luna AJ, Hurdle JG and Garey KW: Genetic mechanisms of vancomycin resistance in clostridioides difficile: A systematic review. Antibiotics (Basel). 11(258)2022.PubMed/NCBI View Article : Google Scholar