Background: Major depressive disorder (MDD) is a serious mental illness. Compelling evidence from both mouse and human found the microbiome are actively involved in driving depression. Gut microbiota could result in long-term changes in metabolites of host, but changes at the protein level were rarely reported. Methods: To improving understanding the protein changes induced by the gut microbiota via gut-brain axis in depression, germ-free (GF) mice were transplanted the gut microbiota of MDD patients to induce depression-like behaviors. Afterwards, the iTRAQ-based quantitative proteomics approach was used to explore protein expression alteration of the PFC, liver, cecum and serum. Findings: More than 5,000 proteins were identified in all the four tissues. The proportion of various functional proteins in the cecum was similar with the liver, but was different from the PFC and serum. Comparison to DE proteins of the traditional rodent models of depression, gut microbiota recipient mice also showed distinct characters. The pathway enrichment analysis revealed that the NRF2-mediated oxidative stress response was activity in the PFC, cecum and serum. Notably, cascade reactions of ILK/AMPK/mTOR between the PFC and peripheral tissues may contribute to the influence of gut microbiota on behaviors. Interpretation: The gut microbiota can result in distinct impact on multiple components of gut-brain axis at protein level in depression. The oxidative stress response and cascade reactions may be potential sensing mechanisms of gut microbiota influence the behaviors. Funding Statement: This project was supported by grants from the National Key Research and Development Program of China (2017YFA0505700). Declaration of Interests: The authors have no conflicts of interest to declare. Ethics Approval Statement: All animal handling and procedures followed the recommendations of the Guide for the Care and Use of Laboratory Animals, and were approved by the Ethics Committee of Chongqing Medical University (Chongqing, China).