Base On The Brain-gut-microbiota Axis Through Tryptophan Pathway To Explore The Mechanism Of Immune Tolerance Induced By Oral Brain Antigen Combined With Probiotics In The Treatment Of Traumatic Brain Injury

After traumatic brain injury(TBI),immunosuppressive and immune tolerance therapy have attracted the attention of the academic community.The common physiological and anatomical basis of these studies is that the brain injury leads to the destruction of the blood-brain barrier and alteration of the internal environment of the brain tissue,which in turn causes the brain antigens to be recognized by immune system as well as triggers autoimmune aggression,and excessive immune damage exacerbates the secondary inflammatory response,further affecting the patient's brain recovery process.There are some disadvantages of immunosuppressive agents,such as,expensiveness,narrow safety spectrum,and poor immunity to cause infection Drawing on the theory of immune tolerance,oral autologous brain antigens(derived from the necrotic brain tissue and drained cerebrospinal fluid that clear the brain contusion and laceration)induce oral tolerance in the intestinal mucosa,so that the body does not cause an immune response to the antigen.Mucosa is a key component of immune tolerance,which not only solves the immune response to brain antigens but does not reduce other immune functions of the body.Due to the regulation of the brain-gut axis,patients with TBI cause intestinal flora imbalance.In clinical treatment,patients with severe TBI are often faced with extremely high incidence of diarrhea,stress ulcers,and postoperative use of antibiotics to control lung and urinary tract infections etc.,meanwhile,the composition of the intestinal flora and the structure and function of the intestinal tract will change significantly.Intestinal dysfunction will damage the immune tolerance of TBI patients,affect the establishment of immune tolerance,and then affect the therapeutic effect of brain antigen.Therefore,we orally administer brain protein(BP)combined with probiotics to induce immune tolerance,and explore the mechanism by which the homeostasis of the gut microbiota helps to improve the efficacy of brain protein.Through experiments,we proved that TBI patients and surgical brain injury(SBI)rat models have obvious microbiota dysregulation.It is worth noting that the intestinal mucosal permeability,serum pro-inflammatory cytokine levels,and the activation of glial cells and microglia showed that the combined group(BP combined with probiotics orally administered)much better suppressed secondary immune damage than the BP group(BP oral administered).Quantitative proteomic analysis based on TMT(Tandem mass tag)showed that the combined group induced immune tolerance by activating the tryptophan(Try)metabolic pathway.A series of experiments further confirmed that in the BP group,indoleamine 2,3 dioxygenase(IDO)/kynurenine(Kyn)/arene receptor(Ah R)expression was higher,while tryptophan hydroxylation Enzyme 1(Tp H1)/serotonin(5-HT)was only changed in the combination group.Therefore,this study shows that probiotics can enhance the efficacy of BP-induced immune tolerance through the Try-5-HT pathway.