Aberrant branched‐chain amino acid accumulation along the microbiota–gut–brain axis: Crucial targets affecting the occurrence and treatment of ischaemic stroke

Abstract

Background and Purpose Although increasing evidence illustrated that the bidirectional communication between the brain and the gut is closely related to the occurrence of various complex diseases. Limited effort has been made to explore the influence of intestinal flora on the risk of ischaemic stroke. The present study aims to identify microbiota and specialized microbiota metabolites related to the occurrence and treatment of ischaemic stroke. Experimental Approach The role of microbiota in the occurrence and the treatment of ischaemic stroke was evaluated on ischaemia/reperfusion (I/R), pseudo‐germ‐free and faecal transplantation animals. The target microbiota and specialized metabolites were identified by comparing their distribution in flora and metabolomic profiles in ischaemic stroke patients and animals with compared with healthy controls. The effects and mechanisms involved of the targeted metabolites in ischaemic stroke were explored in ischaemia/reperfusion rats, hypoxia/reoxygenation PC12 cells and LPS‐induced inflammatory BV2 cells. Key Results Both ischaemic stroke patients and I/R rats had significant accumulation of branched‐chain amino acids, which were closely associated with gut microflora dysbiosis and the development of ischaemic stroke. Lactobacillus helveticus (L.hel) and Lactobacillus brevis (L.bre) are identified as the microbiota most affected by ischaemia/reperfusion modelling and treatment. L.hel and L.bre colonization exhibited significant neuroprotective activity and could greatly alleviate the accumulation of branched‐chain amino acids. In addition, branched‐chain amino acid (BCAA) accumulation was shown to exacerbate microglia‐induced neuroinflammation by activating AKT/STAT3/NF‐κB signalling. Conclusion and Implications Our findings demonstrated the crucial role of intestinal flora and microbiota metabolites in the occurrence and treatment of ischaemic stroke.

Early metabolic disruption and predictive biomarkers of delayed-cerebral ischemia in aneurysmal subarachnoid haemorrhage

“…Note that rat studies have found a relationship between aberrant branched-chain amino acid metabolism and ischemic stroke. This relationship was due to a dysregulation of the microbiota-gutbrain axis (36). No such mechanism associating BCAA and microbiota has yet been reported for aSAH and DCI, but our finding that BCAA metabolism is linked to microbiota metabolism potentially involving bacterial species is consistent with (36).…”

“…This relationship was due to a dysregulation of the microbiota-gutbrain axis (36). No such mechanism associating BCAA and microbiota has yet been reported for aSAH and DCI, but our finding that BCAA metabolism is linked to microbiota metabolism potentially involving bacterial species is consistent with (36). Most previous studies on aSAH and DCI have focused on brain metabolic issues.…”

Interventional strategies for ischemic stroke based on the modulation of the gut microbiota

“…Restoration of the L. helveticus and L. brevis colonies had strong neuroprotective effects. It significantly alleviated the accumulation of branched-chain amino acids (BCAAs), which aggravated microglia-induced neuroinflammation through the AKT/STAT3/NF-kB signaling pathway in the development of IS (Shen et al, 2023). Additionally, as an aged biome can increase the systemic proinflammatory cytokine levels (Spychala et al, 2018), which in turn contributes to the pathogenesis of IS, replenishing the gut microbiome with fresh microorganisms can reverse agerelated poor stroke recovery through host immunologic, microbial, and metabolomic modulation.…”

“…Therefore, many researchers are investigating novel approaches for treating IS. In the past two decades, more than 1,000 potential neuroprotectants have been found to attenuate ischemic brain injury by promoting neuronal survival, neural plasticity, neurogenesis, and synaptogenesis (Liberale et al, 2018;Shen et al, 2023). However, the studies were mainly conducted on experimental IS animal models, and only a few agents targeting these molecules could be administered in the clinic (Gauberti et al, 2018;Gan et al, 2020;Mani et al, 2023).…”

Cohort Profile: A Prospective Study of Gut Microbiota in Patients with Acute Ischemic Stroke

“…GM could influence neuropsychiatric disease, such as Alzheimer's disease, Parkinson's disease, depression, and AIS. The correlation between ischemic stroke and GM is widely concerned [9]. A large number of evidences showed the link between GM and AIS.…”