Clostridioides difficile Infection Dysregulates Brain Dopamine Metabolism

Vinithakumari, Akhil A; Padhi, Piyush; Hernández, Belén; Lin, Susanne Je-Han; Dunkerson-Kurzhumov, Aaron; Showman, Lucas; Breitzman, Matthew W.; Sulaiman, Yousuf; Tangudu, Chandra S.; Kuttappan, Deepa; Muyyarikkandy, Muhammed Shafeekh; Willette, Auriel A.; Phillips, Gregory J; Anantharam, Vellareddy; Perera, Ann; Sponseller, Brett A.; Kanthasamy, Anumantha G.; Mooyottu, Shankumar

doi:10.1128/spectrum.00073-22

Cited by 13 publications

(9 citation statements)

References 53 publications

(71 reference statements)

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“…DA dysregulation indeed occurs in several human diseases in cells of adaptive immunity [11, 15, 53], as well as of innate immunity. Interestingly, studies on animal models show that infective conditions reduce DAβ hydroxylase activity [54] and that viral disease such as HIV infection can affect DA pathways [55].…”

Section: Discussionmentioning

confidence: 99%

Dopaminergic inhibition of human neutrophils is exerted through D1‐like receptors and affected by bacterial infection

et al. 2022

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Dopamine (DA) affects immune functions in healthy subjects (HS) and during disease by acting on D1-like (D1 and D5) and D2-like (D2, D3 and D4) dopaminergic receptors (DR); however, its effects on human polymorphonuclear leukocytes (PMN) are still poorly defined. We investigated DR expression in human PMN and the ability of DA to affect cell migration and reactive oxygen species (ROS) production. Experiments were performed on cells from HS and from patients (Pts) with bacterial infections as well, during the acute phase and after recovery. Some experiments were also performed in mice knockout (KO) for the DRD5 gene. PMN from HS express both D1-like and D2-like DR, and exposure to DA results in inhibition of activation-induced morphological changes, migration and ROS production which depend on the activation of D1-like DR.

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Section: Discussionmentioning

confidence: 99%

Dopaminergic inhibition of human neutrophils is exerted through D1‐like receptors and affected by bacterial infection

et al. 2022

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“…Reports of seizures following the administration of reuptake catecholamine inhibitors, such as tramadol, are well established in clinical practice 40 . Clostridioides has been reported to significantly affect catecholamine metabolism within the intracranial region of mice and exhibited significantly reduced dopamine beta‐hydroxylase (DBH) activity 41 . Our study found a negative correlation between Clostridioides and vanillylmandelic acid levels (i.e., as the former increased, the latter decreased) in the non‐responsive group.…”

Section: Discussionmentioning

confidence: 46%

Abnormalities in Clostridioides and related metabolites before ACTH treatment may be associated with its efficacy in patients with infantile epileptic spasm syndrome

Wan

Shi

et al. 2023

CNS Neurosci Ther

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ObjectiveAdrenocorticotropic hormone (ACTH) is the first‐line treatment of infantile epileptic spasm syndrome (IESS). Its reported effectiveness varies, and our current understanding regarding the role of gut microbiota composition in IESS treatment response is limited. This study assessed the microbiome–metabolome association to understand the role and mechanism of gut microbiota composition in IESS treatment outcomes.MethodsChildren with IESS undergoing ACTH treatment were enrolled. Pre‐treatment stool and serum samples were collected for 16S rRNA gene sequencing and liquid chromatography–tandem mass spectrometry, respectively. The children were divided into “responsive” and “non‐responsive” groups, and gut microbiota and serum metabolome differences were analyzed.ResultsOf the 30 patients with IESS, 14 responded to ACTH and 16 did not. The “non‐responsive” group had larger maleficent Clostridioides and Peptoclostridium_phage_p630P populations (linear discriminant analysis >2; false discovery rate q < 0.05). Ten metabolites were upregulated (e.g., xanthurenic acid) and 15 were downregulated (e.g., vanillylmandelic acid) (p < 0.05). Association analysis of the gut microbiome and serum metabolome revealed that Clostridioides and Peptoclostridium_phage_p630P2 were positively correlated with linoleic and xanthurenic acids, while Clostridioides was negatively correlated with vanillylmandelic acid (p < 0.05). A classifier using differential gut bacteria and metabolites achieved an area under the receiver operating characteristic curve of 0.906 to distinguish responders from non‐responders.ConclusionThis study found significant differences in pre‐treatment gut microbiota and serum metabolome between children with IESS who responded to ACTH and those who did not. Additional exploration may provide valuable information for treatment selection and potential interventions. Our results suggest that varying ACTH responses in patients with IESS may be associated with increased gut Clostridioides bacteria and kynurenine pathway alteration, but additional experiments are needed to verify this association.

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“…Changes in metabolites are also common to both gut dysbiosis and chemoconvulsant-induced epilepsy (Meldrum and Chapman, 1999;Agus et al, 2021). For example, in a recent study, we observed an increased concentration of cresols and alterations in dopaminergic neurotransmission within two days of induction of gut dysbiosis and the resultant secondary proliferation of major cresol-producing bacteria (Vinithakumari et al, 2022). In addition, acute gut permeability changes could increase serum toxic metabolite concentrations (Chakaroun et al, 2020;Ghosh et al, 2020;Ma et al, 2022).…”

Section: Discussionmentioning

confidence: 70%

Gut dysbiosis following organophosphate, diisopropylfluorophosphate (DFP), intoxication and saracatinib oral administration

et al. 2022

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Organophosphate nerve agents (OPNAs) act as irreversible inhibitors of acetylcholinesterase and can lead to cholinergic crisis including salivation, lacrimation, urination, defecation, gastrointestinal distress, respiratory distress, and seizures. Although the OPNAs have been studied in the past few decades, little is known about the impact on the gut microbiome which has become of increasing interest across fields. In this study, we challenged animals with the OPNA, diisopropylfluorophosphate (DFP, 4mg/kg, s.c.) followed immediately by 2mg/kg atropine sulfate (i.m.) and 25mg/kg 2-pralidoxime (i.m.) and 30 minutes later by 3mg/kg midazolam (i.m.). One hour after midazolam, animals were treated with a dosing regimen of saracatinib (SAR, 20mg/kg, oral), a src family kinase inhibitor, to mitigate DFP-induced neurotoxicity. We collected fecal samples 48 hours, 7 days, and 5 weeks post DFP intoxication. 16S rRNA genes (V4) were amplified to identify the bacterial composition. At 48 hours, a significant increase in the abundance of Proteobacteria and decrease in the abundance of Firmicutes were observed in DFP treated animals. At 7 days there was a significant reduction in Firmicutes and Actinobacteria, but a significant increase in Bacteroidetes in the DFP groups compared to controls. The taxonomic changes at 5 weeks were negligible. There was no impact of SAR administration on microbial composition. There was a significant DFP-induced reduction in alpha diversity at 48 hours but not at 7 days and 5 weeks. There appeared to be an impact of DFP on beta diversity at 48 hours and 7 days but not at 5 weeks. In conclusion, acute doses of DFP lead to short-term gut dysbiosis and SAR had no effect. Understanding the role of gut dysbiosis in long-term toxicity may reveal therapeutic targets.

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Clostridioides difficile Infection Dysregulates Brain Dopamine Metabolism

Cited by 13 publications

References 53 publications

Dopaminergic inhibition of human neutrophils is exerted through D1‐like receptors and affected by bacterial infection

Dopaminergic inhibition of human neutrophils is exerted through D1‐like receptors and affected by bacterial infection

Abnormalities in Clostridioides and related metabolites before ACTH treatment may be associated with its efficacy in patients with infantile epileptic spasm syndrome

Gut dysbiosis following organophosphate, diisopropylfluorophosphate (DFP), intoxication and saracatinib oral administration

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