Akkermansia muciniphila-Nlrp3 is involved in the neuroprotection of phosphoglycerate mutase 5 deficiency in traumatic brain injury mice

Abstract

IntroductionGut-microbiota-brain axis is a potential treatment to decrease the risk of chronic traumatic encephalopathy following traumatic brain injury (TBI). Phosphoglycerate mutase 5 (PGAM5), a mitochondrial serine/threonine protein phosphatase, resides in mitochondrial membrane and regulates mitochondrial homeostasis and metabolism. Mitochondria mediates intestinal barrier and gut microbiome.ObjectivesThis study investigated the association between PGAM5 and gut microbiota in mice with TBI.MethodsThe controlled cortical impact injury was established in mice with genetically-ablated Pgam5 (Pgam5−/−) or wild type, and WT male mice were treated with fecal microbiota transplantation (FMT) from male Pgam5−/− mice or Akkermansia muciniphila (A. muciniphila). Then the gut microbiota abundance, blood metabolites, neurological function, and nerve injury were detected.ResultsTreated with antibiotics for suppressing gut microbiota in Pgam5−/− mice partially relieved the role of Pgam5 deficiency in the improvement of initial inflammatory factors and motor dysfunction post-TBI. Pgam5 knockout exhibited an increased abundance of A. muciniphila in mice. FMT from male Pgam5−/− mice enabled better maintenance of amino acid metabolism and peripherial environment than that in TBI-vehicle mice, which suppressed neuroinflammation and improved neurological deficits, and A. muciniphila was negatively associated with intestinal mucosal injury and neuroinflammation post-TBI. Moreover, A. muciniphila treatment ameliorated neuroinflammation and nerve injury by regulating Nlrp3 inflammasome activation in cerebral cortex with TBI.ConclusionThus, the present study provides evidence that Pgam5 is involved in gut microbiota-mediated neuroinflammation and nerve injury, with A. muciniphila-Nlrp3 contributing to peripheral effects.

Remote burn injury in aged mice induces colonic lymphoid aggregate expansion and dysbiosis of the fecal microbiome which correlates with neuroinflammation

“…This suggests that reduction in Akkermansia is exacerbated by high levels of colonic inflammation, which is seen in either combined age and burn injury or inflammatory bowel disease. A recent study demonstrated that Akkermansia is negatively associated with intestinal injury after traumatic brain injury (39), which agrees with our data showing that Akkermansia is negatively associated with intestinal barrier dysfunction (Fig. 3).…”

“…In addition to being gut protective, Akkermansia colonization correlates negatively with neuroinflammation and neurological dysfunction after traumatic brain injury ( 39 ), primarily by decreasing inflammasome activation within the brain. Furthermore, increasing the amount of acetate, the primary short-chain fatty acid product of Akkermansia , after traumatic brain injury in experimental animals significantly improved motor performance ( 41 ).…”

Fecal microbiota transplantation inhibited neuroinflammation of traumatic brain injury in mice via regulating the gut–brain axis

“…In this study, Bacteroidota and Muribaculaceae were the dominant bacterial taxa in TBI mice, while FMT treatment could decrease the abundance of Bacteroidota and Muribaculaceae . Additionally, the study has shown the increased abundance of Muribaculum , the genus type of the family Muribaculaceae , order Bacteroidales , and phylum Bacteroidota in TBI mice ( Chen Y. et al., 2023 ). In addition, our results showed that FMT treatment decreased the relative abundances of Patescibacteria , Saccharimonadaceae , Rikenellaceae , Alistipes , Ruminococcaceae , and Eggerthellaceae in TBI mice, which was consistent with previous studies.…”

“…Akkermansia , belonging to the family Akkermansiaceae of the phylum Verrucomicrobiota , exerted anti-inflammatory effects ( Qu et al., 2021 ). The study has shown that the relative abundance of A. muciniphila was negatively correlated with intestinal injury and neurological dysfunction, as well as the levels of TNF-α and IL-1β in cortical tissue after TBI, and A. muciniphila treatment improved intestinal injury, neurological dysfunction, and neuroinflammation in the cerebral cortex of TBI mice ( Chen Y. et al., 2023 ). To sum up, the enrichment of inflammation-related bacteria, such as Rikenellaceae and Alistipes , and the reduction of anti-inflammatory-related bacteria Akkermansia might participate in the process of TBI, and these changes in the relative abundance of bacteria could be reversed by FMT, which contributed to the explanation of the specific therapeutic mechanism of FMT in TBI.…”

“…Remarkably, gut microbiota dysbiosis was considered to be the main risk factor of TBI, which was likely to be alleviated by probiotic therapy. It was reported that antibiotic treatment could inhibit the gut microbiota of PGAM5(-/-) mice, partially alleviating post-TBI inflammatory response and motor dysfunction in mice, and Akkermansia muciniphila treatment inhibited neuroinflammation in the cerebral cortex after TBI ( Chen Y. et al., 2023 ). Moreover, our previous study revealed that probiotic Clostridium butyricum treatment significantly improved neurological dysfunction, brain edema, and BBB impairment; reduced colonic IL-6 level; and protected the integrity of the intestinal barrier in the TBI mice ( Li et al., 2018 ).…”