Patients with chronic postsurgical pain (CPSP) frequently exhibit comorbid cognitive deficits. Recent observations have emphasized the critical effects of gut microbial metabolites, like short-chain fatty acids (SCFAs), in regulating cognitive function. However, the underlying mechanisms and effective interventions remain unclear. According to hierarchical clustering and 16S rRNA analysis, over two-thirds of the CPSP rats had cognitive impairment, and the CPSP rats with cognitive impairment had an aberrant composition of gut SCFA-producing bacteria. Then, using feces microbiota transplantation, researchers identified a causal relationship between cognitive-behavioral and microbic changes. Similarly, the number of genera that generated SCFAs was decreased in the feces from recipients of cognitive impairment microbiota. Moreover, treatment with the SCFAs alleviated the cognitive-behavioral deficits in the cognitively compromised pain rats. Finally, we observed that SCFA supplementation improved histone acetylation and abnormal synaptic transmission in the medial prefrontal cortex (mPFC), hippocampal CA1, and central amygdala (CeA) area via the ACSS2 (acetyl-CoA synthetase2)-HDAC2 (histone deacetylase 2) axis. These findings link pain-related cognition dysfunction, gut microbiota, and short-chain fatty acids, shedding fresh insight into the pathogenesis and therapy of pain-associated cognition dysfunction.

The pathogenesis of Hepatic Encephalopathy (HE) is complex and multifactorial. The development of metagenomics sequencing technology led to show the significant role of gut microbiota in the pathogenesis of cognitive dysfunction, which paved the way for further research in this field. However, it is unknown whether gut microbiota plays a role in bile duct ligation (BDL)-evoked cholestatic liver disease-related cognitive dysfunction. The aim of this investigation is to assess BDL mice induced cognitive dysfunction and meanwhile to delineate the alteration of gut microbiota in cognitive dysfunction mice, which may underline the role of gut microbiota in BDL mice induced cognitive dysfunction. Our study was carried out in male C57BL/6 J mice with bile duct ligation. The liver functions were assessed via different biochemical markers [alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), total bilirubin (TBIL), and total bile acid (TBA)] and a histopathological examination of the liver tissue. We used the novel object recognition test (NORT) to assess cognitive dysfunction. And BDL mice were divided into BDL with cognitive dysfunction (BDL-CD) or BDL without cognitive dysfunction (BDL-NCD groups) by the result of hierarchical cluster analysis of NORT. Then, 16S ribosomal RNA (rRNA) gene sequencing was used to compare the gut bacterial composition between BDL-CD and BDL-NCD groups. According to our results, we concluded that bile duct ligation can significantly change the gut microbiota composition, and Bacteroides fragilis, Bacteroides ovatus V975, and Bacteroides thetaiotaomicron play a vital role in BDL-evoked cholestatic liver disease-related cognitive dysfunction.

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.