Brain-gut microbiota multimodal predictive model in patients with bipolar depression

Bipolar disorder (BD) is a common mental illness characterized by recurrent depressive or manic/hypomania episodes (Alonso et al., 2011; Grande et al., 2016). In addition, the cognitive and social function of a significant proportion of patients with BD is severely impaired, with a high risk of disability and suicide. So far, the pathophysiology of BD has not yet to be fully understood.

In recent years, it has become widely accepted that BD was characterized by abnormal functional connections within and between internal brain networks,including the default mode network (DMN), attention network (AN), frontoparietal network (FPN), etc. (Lippard et al., 2021; Lois et al., 2017; Pavuluri et al., 2012; Wang et al., 2020). And the voxel-based morphometry (VBM) studies of BD have consistently reported regional GMV reductions in brain areas such as the prefrontal cortex, insular cortex, and anterior cingulate cortex (Phillips and Swartz, 2014). Meanwhile, depressed BD patients harbored a distinct gut microbial composition that significantly differed from HCs, suggesting that gut microorganism may play a role in the pathological mechanisms of BD (Hu et al., 2019; Sublette et al., 2021). The gut dysbiosis might be related to a variety of factors such as brain circuits, metabolic pathways, susceptibility genes, and medical treatment (Li et al., 2019; Moreira et al., 2017; Stahl et al., 2019) et al. in BD. Among these, the “microbiota-gut-brain axis” (Wang and Wang, 2016), a two-way modulation system that connects the brain and gut microbiota has been supposed to associated with the development of major mental illnesses (Sharon et al., 2016). However, the mechanism of interaction between brain and gut microbes in bipolar individuals is still unknown.

Quetiapine has been recommended as the first-line treatment for bipolar depression in 2018 Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorder (ISBD) Bipolar Disorder Guideline, but many patients do not achieve relief following the initial treatment. Understanding the biological markers that are beneficial to the outcomes of quetiapine treatment is essential for BD. The previous studies mainly focus on the impacts of antipsychotics on gut ecosystem (Hu et al., 2019; Lu et al., 2019), neuroimaging measures (Nusslock et al., 2014; O’Neill et al., 2019; Berk et al., 2017; Zhang et al., 2018), or symptom improvement. However, few studies have focused on whether combined pre-treatment neuroimaging and gut microbial characteristics may predict personalized quetiapine efficacy. Based on our prior study, it has developed the notion of the brain-gut balance coefficient and discovered that following quetiapine therapy, the composition of the gut microbiome and its association with brain function altered in BD patients (Lu et al., 2019) which might provide some evidences.

In this study, we adopted the correlation network approach which linked the relative abundance of gut microbiota to the neuroimaging measures including GMV and network-based FC, to explore the specific brain-gut associations in bipolar depression patients and healthy individuals. Furthermore, the multimodal predictive model which combined pre-treatment gut microbiota- neuroimaging characteristics for clinical accurate diagnosis and treatment outcome prediction was also investigated. The kernel fusion SVM prediction model was chosen because it provided a unifying mechanism to incorporate heterogeneous data when different formats of data could not be directly concatenated and it allows additional flexibility by placing different weights on biomarkers from different modalities (Zhang et al., 2011). This kernel combination method can also be easily embedded in a traditional SVM and solved efficiently. Fig. 1 depicted a methodical flowchart of the study design. Altogether, our study explored the potential of integrating gut microbiota and neuroimaging endophenotypes in precision clinical diagnosis and treatment of BD.

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