Gut microbiota-generated short-chain fatty acids are involved in para-chlorophenylalanine-induced cognitive disorders

Abstract

Neurocognitive disorders (NCDs) include complex and multifactorial diseases that affect many patients. The 5-hydroxytryptamine (5-HT) neuron system plays an important role in NCDs. Existing studies have reported that para-chlorophenylalanine (PCPA), a 5-HT scavenger, has a negative effect on cognitive function. However, we believe that PCPA may result in NCDs through other pathways. To explore this possibility, behavioral tests were performed to evaluate the cognitive function of PCPA-treated mice, suggesting the appearance of cognitive dysfunction and depression-like behavior. Furthermore, 16S rRNA and metabolomic analyses revealed that dysbiosis and acetate alternation could be related to PCPA-induced NCDs. Our results suggest that not only 5-HT depletion but also dysbiosis and acetate alternation contributed to PCPA-related NCDs. Specifically, the latter promotes NCDs by reducing short-chain fatty acid levels. Together, these findings provide an alternative perspective on PCPA-induced NCDs.

Gut microbiota regulates hepatic ischemia–reperfusion injury‐induced cognitive dysfunction via the HDAC2‐ACSS2 axis in mice

“…Previous studies have implicated alterations in hippocampal SCFA levels (e.g., significantly reduced acetate levels in the experimental group compared to the control group) in cognitive impairment models induced by various factors, which is related to the gut microbial SCFA metabolism. [44][45][46] The results of this study differ somewhat from the aforementioned findings, suggesting that the impact of…”

“…Firstly, the precise reasons behind the gut microbiota‐induced HDAC2‐ACSS2 axis imbalance are not extensively explored. Previous studies have implicated alterations in hippocampal SCFA levels (e.g., significantly reduced acetate levels in the experimental group compared to the control group) in cognitive impairment models induced by various factors, which is related to the gut microbial SCFA metabolism 44–46 . The results of this study differ somewhat from the aforementioned findings, suggesting that the impact of gut microbial metabolites, such as SCFAs, on cognitive function may vary under different conditions.…”

Metronidazole-induced neurotoxicity: Possible central serotonergic and noradrenergic system involvement

“…To establish the effect of metronidazole on the serotonergic and noradrenergic mechanisms of depression, PCPA and labetalol were used to disrupt the central serotonergic and noradrenergic pathways respectively. P-chlorophenylalanine, an established inhibitor of tryptophan, hydroxylase is known to cause depletion of 5-HT levels [22], resulting in various neuro-cognitive deficitsand depression-like behaviour in animal models [23][24][25][26].…”

“…This behavior is akin to a state of despair and suggestive of depression-like behavior. 18,27,26 Interestingly, the effect of metronidazole on immobility and swimming activity was not reversed by coadministration with fluoxetine, a selective serotonin reuptake inhibitor that mediates the reuptake of serotonin into the presynaptic terminal, thus enhancing and prolonging serotonergic neurotransmission [28]. This infers that metronidazole does not directly inhibit the serotonin transporter (SERT) but may have effect on postsynaptic mechanisms that alter serotonergic transmission to induce depression-like behavior in the treated rats.…”

The role of gut microbiota in diabetic peripheral neuropathy rats with cognitive dysfunction

“…The NORTs conducted in our study were based on relevant literature (Tarragon et al, 2014;Liu et al, 2022;Sun et al, 2022;Yang et al, 2022;He et al, 2023). Twenty-four hours before testing or training, the animals were placed in the testing room to acclimatize to the testing environment.…”