Gut Microbiota Dysbiosis after Traumatic Brain Injury Contributes to Persistent Microglial Activation Associated with Upregulated Lyz2 and Shifted Tryptophan Metabolic Phenotype

Abstract

Traumatic brain injury (TBI) is a common cause of disability and mortality, affecting millions of people every year. The neuroinflammation and immune response post-TBI initially have neuroprotective and reparative effects, but prolonged neuroinflammation leads to secondary injury and increases the risk of chronic neurodegenerative diseases. Persistent microglial activation plays a critical role in chronic neuroinflammation post-TBI. Given the bidirectional communication along the brain–gut axis, it is plausible to suppose that gut microbiota dysbiosis post-TBI influences microglial activation. In the present study, hippocampal microglial activation was observed at 7 days and 28 days post-TBI. However, in TBI mice with a depletion of gut microbiota, microglia were activated at 7 days post-TBI, but not at 28 days post-TBI, indicating that gut microbiota contributes to the long-term activation of microglia post-TBI. In addition, in conventional mice colonized by the gut microbiota of TBI mice using fecal microbiota transplant (FMT), microglial activation was observed at 28 days post-TBI, but not at 7 days post-TBI, supporting the role of gut microbiota dysbiosis in persistent microglial activation post-TBI. The RNA sequencing of the hippocampus identified a microglial activation gene, Lyz2, which kept upregulation post-TBI. This persistent upregulation was inhibited by oral antibiotics and partly induced by FMT. 16s rRNA gene sequencing showed that the composition and function of gut microbiota shifted over time post-TBI with progressive dysbiosis, and untargeted metabolomics profiling revealed that the tryptophan metabolic phenotype was differently reshaped at 7 days and 28 days post-TBI, which may play a role in the persistent upregulation of Lyz2 and the activation of microglia. This study implicates that gut microbiota and Lyz2 are potential targets for the development of novel strategies to address persistent microglial activation and chronic neuroinflammation post-TBI, and further investigations are warranted to elucidate the specific mechanism.

Acute gastrointestinal permeability after traumatic brain injury in mice precedes a bloom in Akkermansia muciniphila supported by intestinal hypoxia

“…An early increase in A. muciniphila may be part of a compensatory response to systemic damage initiated by TBI. Recently, A. muciniphila levels were shown to be reduced at 1 wk and 4 wk in mice receiving CCI of a similar severity to the present study 82 , suggesting that trauma-induced changes in A. muciniphila may be biphasic.…”

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

“…For instance, it was reported that the abundance of Patescibacteria , Saccharimonadales , and Saccharimonadia was increased in patients with Alzheimer’s disease and mild cognitive impairment ( Zhu et al., 2022 ), and Patescibacteria was enriched in mice with neurobehavioral impairments ( Diao et al., 2021 ). Furthermore, Rikenellaceae was the main dominant bacteria in mice after 28 days of TBI injury ( Zheng et al., 2022 ), and the abundance of Alistipes increased in patients with chronic TBI ( Urban et al., 2020 ). Moreover, the levels of Rikenellaceae and Alistipes were increased in rats with anxietylike behavior, accompanied by the activation of neuroinflammatory microglia and the increase of IL-1β expression in the hippocampus ( Wu L. et al., 2021 ).…”

Host–Microbiome Interactions: Tryptophan Metabolism and Aromatic Hydrocarbon Receptors after Traumatic Brain Injury

“…Similarly, Urban RJ et al [ 58 ] reported significant reductions in tryptophan metabolites in TBI patients even years later. Our team [ 66 ] noted altered intestinal metabolism in mice post-TBI and particularly marked changes in tryptophan metabolism at 7 and 28 days post-injury. Specifically, the indole pathway of tryptophan metabolism demonstrated shifts at 7 days post-injury, returning to baseline at 28 days.…”

“…Zheng et al [ 70 ] observed, in a rabbit TBI model, increased mRNA expression of vital enzymes in the tryptophan-kynurenine pathway, highlighted by significant upregulation of IDO1 mRNA expression in the TBI group at all time points post-injury ( p < 0.05). Our own investigation [ 66 ] unveiled that at 7 days post-TBI, kynurenine significantly rose and KYNA decreased, but by 28 days post-TBI, kynurenine remained unchanged, KYNA increased, and both xanthinic acid (XA) and 8-methoxy-kynurenic acid consistently decreased. The first human evidence of post-TBI abnormalities in KP was from QuinA analysis in the cerebrospinal fluid (CSF) of patients with severe TBI, showing a substantial increase around 72–83 h post-injury [ 71 ].…”