Oral Administration of Brain Protein Combined With Probiotics Induces Immune Tolerance Through the Tryptophan Pathway.

Yongxin Hou,Lixia Xu,Hua Yan,Qiaoli Wu,Sirong Song,Weijia Fan,Xiaoguang Tong

doi:10.3389/fnmol.2021.634631

Yongxin Hou, Lixia Xu + Show 5 more

Open Access

https://doi.org/10.3389/fnmol.2021.634631

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Abstract

Excessive inflammation leads to secondary immune damage after traumatic brain injury (TBI). The intestinal mucosa is a key component of immune tolerance due to gut-brain axis regulation, but the curative effect is not optimal. Intestinal dysfunction impairs the establishment of immune tolerance in patients with TBI. Therefore, we orally administered brain protein (BP) combined with probiotics to induce immune tolerance and explored the mechanism by which the homeostasis of the microbiota contributes to the enhancement of curative effects by BPs. Herein, we demonstrated that patients with TBI and surgical brain injury (SBI) models of rats had obvious dysbiosis. Notably, the intestinal barrier, proinflammatory cytokines, and activation of microglia demonstrated that excessive inflammatory damage was better controlled in the combined group (oral administration of BP combined with probiotics) than in the BP group (oral administration of BP). Fundamentally, tandem mass tag (TMT)-based quantitative proteomics analysis revealed that BP and probiotics preferentially affect Try-related pathways. A series of experiments further confirmed that Indoleamine 2,3 dioxygenase (IDO)/Kynurenine (Kyn)/Aryl hydrocarbon receptor (AhR) expression was high in the BP group, while Tryptophan hydroxylase 1(TpH1)/5-hydroxytryptamine (5-HT) only changed in the combined group. This study suggests that probiotics can enhance the efficacy of oral BP-induced immune tolerance through the Try pathway.

Highlights

Head injuries and their sequelae have become increasingly important public health issues (Sundman et al, 2017)
A comparison of the abundance of the predominant genera showed that Enterococcus, Parabacteroides, Akkermansia, and Lachnoclostridium were significantly enriched, whereas Bifidobacterium and Faecalibacterium were depleted in the patients with traumatic brain injury (TBI) (Figure 1E)
We found that Glial fibrillary acid protein (GFAP) expression in the surgical brain injury (SBI) group was significantly higher than those in the brain protein (BP) and combined groups (P < 0.05), similar to the Ionized calcium binding adaptor molecule (Iba)-1 results (Figure 3C), indicating that the oral administration of BP or BP combined with probiotics significantly reduced the activation of astrocytes and microglia

Summary

Introduction

Head injuries and their sequelae have become increasingly important public health issues (Sundman et al, 2017). Intestinal wall damage leads to inflammation of the mucosal barrier (Winter et al, 2013; Albenberg et al, 2014; Dickson, 2016); intestinal permeability increases, and substances can aberrantly penetrate the barrier to disrupt normal physiological functions. Such deficits in intestinal permeability typically lead to an innate immune response that underpins chronically elevated levels of inflammation, which are known to promote disease (Turner, 2009; Gallo and Hooper, 2012). Probiotics can fortify the intestinal barrier to mitigate neurotraumainduced endotoxemia and inhibit systemic dysregulation of the immune system that may otherwise peripherally hyperactivate the brain’s microglia (Lamprecht et al, 2012; de Punder and Pruimboom, 2015)

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