Gut最新文献

Background: Stroke induces complex pathophysiological responses that extend beyond the brain, yet the mechanisms through which peripheral signals influence stroke recovery remain largely unclear.

Objective: Here, we identify a novel gut-brain neural circuit that promotes stroke recovery via kynurenic acid (KYNA) signalling.

Design: In a training cohort (30 patients with acute ischaemic stroke (AIS) and 30 controls), untargeted metabolomics profiled intestinal metabolites and the key metabolite KYNA was validated in an independent cohort (100 patients with AIS and 100 controls) using targeted metabolomics and assessed for its 3-month prognostic value. In stroke mouse models, KYNA was administered to evaluate therapeutic effects. Mechanistic studies combined neuronal calcium imaging, enteric neuron receptor manipulation, vagotomy, neuronal tracing, electrophysiology and immunofluorescence to delineate the KYNA-mediated gut-brain neural circuit regulating stroke recovery.

Results: Our study demonstrates a significant reduction of intestinal KYNA in patients with AIS and validates its prognostic value for neurological recovery at 3 months poststroke in both the training and validation cohorts. Oral KYNA supplementation markedly improves poststroke cerebral injury by activating G protein-coupled receptor 35 (GPR35) on enteric neurons, initiating vagal nerve signalling. Mechanistically, KYNA-GPR35 interaction activates vagal afferents, transmitting signals through the nucleus tractus solitarius to hippocampal and hypothalamic regions. This GPR35-vagus nerve signalling pathway, further validated with the selective GPR35 agonist Zaprinast, confers neuroprotection by shifting microglial polarisation towards the anti-inflammatory M2 phenotype and enhancing neuronal α7 nicotinic acetylcholine receptor activity.

Conclusion: KYNA acts through an intestinal GPR35-vagus neural pathway to influence stroke recovery, highlighting this gut-brain signalling axis as a promising therapeutic avenue.

Background: Chronic visceral pain in IBS with diarrhoea (IBS-D) is a profound therapeutic challenge. While aberrant central processing is implicated, the key brain regions driving this visceral pain and their suitability as neuromodulatory targets remain undefined.

Objective: To identify a central hub of visceral pain in IBS-D and elucidate the mechanism by which repetitive transcranial magnetic stimulation (rTMS) confers analgesic effects.

Design: Combined functional MRI with visceral sensitivity assessments was used to pinpoint hyperactive brain regions of patients with IBS-D. Mechanistic studies were conducted in a well-established IBS mouse model. A clinical trial was performed to validate the therapeutic potential of rTMS in patients with IBS-D.

Results: Clinical observations identified hyperexcitability of the medial prefrontal cortex (mPFC) as strongly correlated with visceral pain in patients with IBS-D. In IBS mice, visceral pain was driven by the hyperactivity of mPFC glutamatergic (mPFC^Glu) neurons, which received nociceptive inputs from the anterior cingulate cortex via an NR2A-dependent mechanism. Low frequency (lf)-rTMS of the mPFC sustainably alleviated visceral pain in IBS mice by inhibiting mPFC^Glu neurons and restoring normal synaptic plasticity. Building on these findings, a clinical trial validated that a 2-week course of mPFC-targeted lf-rTMS in patients with IBS-D effectively alleviated visceral pain and improved bowel habits, effects associated with reduced mPFC activity and sustained for at least 8 weeks.

Conclusions: Hyperexcitability of the mPFC drives chronic visceral pain in patients with IBS-D and lf-rTMS provides analgesia by suppressing this hyperactivity, offering a novel, mechanism-based neuromodulation strategy for IBS-D treatment.

Carbamoyl phosphate synthetase 1 (CPS1) is primarily expressed in hepatocytes as a highly abundant mitochondrial matrix enzyme that catalyses the first step of the urea cycle that leads to renal nitrogen disposal. CPS1 is a member of the CPS family that manifests broad evolutionary expression from bacteria to humans. CPS1 expression and enzyme activity are highly regulated transcriptionally and post-translationally. Its autosomal recessive mutation leads to CPS1 deficiency, which causes encephalopathy and coma, typically neonatally, due to severe hyperammonaemia. CPS1 is physiologically secreted, apically, into bile likely via mitochondria-derived vesicles. Normally absent from serum, it is released by basolateral mistargeting and cellular injury and becomes readily detectable in serum during acute liver failure (ALF). Injury-triggered CPS1 release into blood, or media in cultured hepatocytes, is selective as compared with other mitochondrial proteins. This, coupled with its abundance and short (1-2 hours) serum half-life, renders it a prognostic serum biomarker, particularly in human acetaminophen-related ALF. Its rapid turnover is explained by its non-enzymatic role as an immune modulator via its uptake by circulating monocytes leading to differentiation of anti-inflammatory cells that home to, and protect, the injured liver. CPS1 also plays a growing role in several cancers, by CPS1 upregulation or downregulation, particularly via metabolic reprogramming which alters the tumour microenvironment and impacts cancer growth and progression. Therefore, CPS1 has multiple enzymatic and non-enzymatic touch points spanning a wide range of cellular and extracellular functions and roles, with important physiological, homoeostatic, genetic disease, diagnostic and potential therapeutic clinical implications.