Effects of a Gut Microbiome Toxin, p-Cresol, on the Indices of Social Behavior in Rats

Tevzadze, Gigi; Oniani, N.; Zhuravliova, Elene; Darchia, Nato; Eliozishvili, Marine; Gogichadze, M.; Lortkipanidze, N.; Oniani, T. N.; Kakabadze, Ann; Kakabadze, Zurab; Karalashvili, L; Kikvidze, Zaal; Mikeladze, David

doi:10.1007/s11062-019-09764-1

Cited by 10 publications

(10 citation statements)

References 19 publications

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“…11 Another study revealed ASD-like behavior in rats intraperitoneally administered with p-cresol. 12 Similar results with dysregulation in dopaminergic neurotransmission were demonstrated following oral p-cresol administration in non-mutant mice. 13 Therefore, p-cresol mediated alterations in the dopaminergic pathway appear to be associated with the pathophysiology of ASD.…”

Section: Introductionsupporting

confidence: 58%

“…Previous studies demonstrated that p -cresol is a neurotoxin that can cross the blood brain barrier, impair neurotransmission, and induce behavioral abnormalities. 12 In addition, pcresol is a potent inhibitor of DBH enzyme. [14][15][16] It is also known that the serum DBH is predominantly contributed by the brain tissue, and hence the serum DBH activity meaningfully reflects the brain DBH activity.…”

Section: Difficile Infection Increases Serum P-cresol and Reduces Serum Dbh Activitymentioning

confidence: 99%

“…Increased gut and serum concentrations of p-cresol have been demonstrated to alter dopaminergic neurotransmission, which has been implicated in neurological disorders, including autism. [11][12][13] Two major dopaminergic pathways in brain significant to ASD include the mesocorticolimbic (MCL) circuit, and the nigrostriatal (NS) circuit. 38,39 Substantia nigra and the ventral tegmental area are the two major DA producing areas in the brain.…”

Section: Difficile Infection Increased Da and Its Metabolite Levels In Corpus Striatum And Prefrontal Cortexmentioning

confidence: 99%

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Clostridioides difficileinfection increases circulating p-cresol levels and dysregulates brain dopamine metabolism: linking gut-brain axis to autism spectrum disorders?

Vinithakumari

Padhi

Hernández

et al. 2021

Preprint

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Gastrointestinal illnesses are one of the most common comorbidities reported in patients with neurodevelopmental diseases, including autism spectrum disorders (ASD). Gut dysbiosis, overgrowth of C. difficile in the gut, and gut microbiota-associated alterations in central neurotransmission have been implicated in ASD, where the dopaminergic axis plays an important role in the disease pathogenesis. Human C. difficile strains produce a significant amount of the toxic metabolite p-cresol, an inhibitor of dopamine beta-hydroxylase (DBH), which catalyzes the conversion of dopamine (DA) to norepinephrine (NE). p-cresol is known to precipitate and exacerbate autistic behavior in rodents by increasing DA levels and altering DA receptor sensitivity in brain regions relevant to ASD. Therefore, we hypothesized that C. difficile infection dysregulates dopaminergic metabolism in the brain by increasing p-cresol levels in the gut and circulation and by inhibiting DBH, ultimately leading to elevated DA in the brain. For testing this hypothesis, we induced antibiotic-associated C. difficile in mice and determined the gut and serum p-cresol levels, serum DBH activity, and dopamine and its metabolite levels in different brain regions relevant to ASD. The results showed that C. difficile infection causes significant alterations in the dopaminergic axis in mice (p < 0.05). In addition, significantly increased circulating p-cresol levels and reduced DBH activity was observed in C. difficile infected animals (p < 0.05). Therefore, the results from this study suggest a potential link between C. difficile infection and alterations in the dopaminergic axis implicated in the precipitation and aggravation of ASD.

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Section: Introductionsupporting

confidence: 58%

Section: Difficile Infection Increases Serum P-cresol and Reduces Serum Dbh Activitymentioning

confidence: 99%

Section: Difficile Infection Increased Da and Its Metabolite Levels In Corpus Striatum And Prefrontal Cortexmentioning

confidence: 99%

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Clostridioides difficileinfection increases circulating p-cresol levels and dysregulates brain dopamine metabolism: linking gut-brain axis to autism spectrum disorders?

Vinithakumari

Padhi

Hernández

et al. 2021

Preprint

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“…It is well-known that the gut microbiota modulates behavior and contributes to neurological disorders [1] , [2] . Dysbiotic gut microbiota could contribute to the development of autism spectrum disorders (ASD), epilepsy, and anxiety [3] , [4] ; however, the underlying mechanisms that induce these disorders remain unknown. Clostridium difficile is known to play a critical role in the development of emotional and cognitive complications in ASD, epilepsy, and anxiety [3] , [5] , [6] .…”

Section: Introductionmentioning

confidence: 99%

Gut neurotoxin p-cresol induces brain-derived neurotrophic factor secretion and increases the expression of neurofilament subunits in PC-12 cells

Tevzadze

Barbakadze

Kvergelidze

et al. 2021

AIMSN

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<abstract> <p>Increased p-cresol levels reportedly alter brain dopamine metabolism and exacerbate neurological disorders in experimental animals. In contrast to toxic concentrations, low doses of p-cresol may have distinct effects on neuronal metabolism. However, the role of p-cresol in synapse remodeling, neurite outgrowth, and other anabolic processes in neurons remains elusive. We propose that low doses of p-cresol affect neuronal cell structural remodeling compared with the high concentration-mediated harmful effects. Thus, the effects of p-cresol on the secretion of brain-derived neurotrophic factor (BDNF) and neurofilament subunit expression were examined using rat pheochromocytoma cells (PC-12 cells). We observed that low doses of p-cresol potentiated nerve growth factor-induced differentiation via secretion of BDNF in cultured PC-12 cells. Opioidergic compounds modulated these p-cresol effects, which were reversed by oxytocin. We propose that this effect of p-cresol has an adaptive and compensatory character and can be attributed to the induction of oxidative stress. Accordingly, we hypothesize that low doses of p-cresol induce mild oxidative stress, stimulating BDNF release by activating redox-sensitive genes. Given that the intestinal microbiome is the primary source of endogenous p-cresol, the balance between gut microbiome strains (especially Clostridium species) and opioidergic compounds may directly influence neuroplasticity.</p> </abstract>

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“…Prior studies of microbe-host co-metabolites derived from microbial precursors in blood, like hippurate or p-cresol sulfate (i.e., hepatically modified forms of microbially-derived metabolites), hinted that the cross-sectional variance in these molecules might only be associated with the microbiome and not with host genetics 17,38,62,63 . Here we show that those observations do not extrapolate to all microbe-host co-metabolites.…”

Section: Discussionmentioning

confidence: 99%

Genome-microbiome interplay provides insight into the determinants of the human blood metabolome

Diener

Wilmanski

et al. 2022

Preprint

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Variation in the blood metabolome is intimately related to human health. Prior work has shown that host genetics and gut microbiome composition, combined, explain sizable, but orthogonal, components of the overall variance in blood metabolomic profiles. However, few details are known about the interplay between genetics and the microbiome in explaining variation on a metabolite-by-metabolite level. Here, we performed analyses of variance for each of the 945 blood metabolites that were robustly detected across a cohort of 2,049 individuals, while controlling for a number of relevant covariates, like sex, age, and genetic ancestry. Over 60% of the detected blood metabolites were significantly associated with either host genetics or the gut microbiome, with more than half of these associations driven solely by the microbiome and around 30% under hybrid genetic-microbiome control. The variances explained by genetics and the microbiome for each metabolite were indeed largely additive, although subtle, but significant, non-additivity was detected. We found that interaction effects, where a metabolite-microbe association was specific to a particular genetic background, were quite common, albeit with modest effect sizes. The outputs of our integrated genetic-microbiome regression models provide novel biological insights into the processes governing the composition of the blood metabolome. For example, we found that unconjugated secondary bile acids were solely associated with the microbiome, while their conjugated forms were under strong host genetic control. Overall, our results reveal which components of the blood metabolome are under strong genetic control, which are more dependent on gut microbiome composition, and which are dependent upon both. This knowledge will help to guide targeted interventions designed to alter the composition of the blood metabolome.

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Effects of a Gut Microbiome Toxin, p-Cresol, on the Indices of Social Behavior in Rats

Cited by 10 publications

References 19 publications

Clostridioides difficileinfection increases circulating p-cresol levels and dysregulates brain dopamine metabolism: linking gut-brain axis to autism spectrum disorders?

Clostridioides difficileinfection increases circulating p-cresol levels and dysregulates brain dopamine metabolism: linking gut-brain axis to autism spectrum disorders?

Gut neurotoxin p-cresol induces brain-derived neurotrophic factor secretion and increases the expression of neurofilament subunits in PC-12 cells

Genome-microbiome interplay provides insight into the determinants of the human blood metabolome

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