Ma Xiancang (L2), Zhu Feng (L3), Gao Yuan (R1), Fan Yajuan (R3)

A research team led by Ma Xiancang and Zhu Feng, professors of the First Affiliated Hospital of Xi'an Jiaotong University (XJTU), issued a paper titled Systems biological assessment of altered cytokine responses to bacteria and fungi reveals impaired immune functionality in schizophrenia on Nov 2 in Molecular Psychiatry, a top international mental illness journal.

XJTU doctoral students Gao Yuan and Fan Yajuan are first authors. Ma and Zhu are corresponding authors. The First Affiliated Hospital of XJTU is the only signed unit.

The researchers systematically compared the immune response of peripheral blood mononuclear cells (PBMCs) of schizophrenia patients and healthy controls to 10 pathogenic stimulants, including bacteria, fungi and microbial ligands, and revealed the abnormal cytokine response pattern of PBMCs in patients with schizophrenia to pathogen stimulation.

They found that cytokines induced by the same type of stimulants have a more obvious correlation after stimulation by 10 pathogens or microbial ligands. In addition, in healthy controls, monocyte-derived and T-cell-derived cytokines formed two relatively independent clusters. In patients with schizophrenia, the difference between the two clusters is significantly reduced, and many correlations between cytokines are weakened or even disappear.

It is noteworthy that the PBMCs of patients with schizophrenia produced cytokine levels after stimulation by the microbial product muramyl dipeptide (MDP), which was significantly lower than that of healthy controls.

In addition, the result that the MDP level in the patient's serum is elevated and is positively correlated with the course of the disease, indicating that as the disease progresses, the bacterial translocation in the patient's body increases and the immune response is weakened.

This also suggests that MDP may be one of the upstream mediators of immune activation in patients with schizophrenia. The low-level inflammation caused by MDP may lead to changes in the permeability of the intestinal barrier and the entry of microbial products into the peripheral circulation and potential interactions.

In the study, the researchers performed single-cell transcriptome sequencing on the PBMCs of schizophrenia patients before and after MDP stimulation and the control group, and found that antiviral and inflammatory programs were generally inhibited in each immune cell subgroup of schizophrenia patients after MDP stimulation and the chemokine/cytokine-receptor interaction network is damaged.

The team describes in the study the molecular and cellular basis of impaired immune function in patients with schizophrenia, and proposes a relationship between innate immune damage, reduced pathogen clearance, increased translocation of bacterial metabolites during the development of schizophrenia, and inactivation of innate immune response.

The interaction provides a new perspective and theoretical basis for the pathological mechanism of systemic immune activation, neuroinflammation and brain abnormalities in patients with schizophrenia.

In recent years, the team has focused on the genetic variation of the international frontier scientific issues of mental illness, intestinal bacteria, immunity, and brain axis research, and has conducted more in-depth research on the relationship between intestinal microbe-mediated immune changes and schizophrenia.

The research was financed by the National Natural Science Foundation of China.

Link to the paper: https://www.nature.com/articles/s41380-021-01362-0