**1. Introduction**

More than 21 million people worldwide suffer from schizophrenia (SZ) [1]. A growing body of studies has shown the role of the gut–brain axis dysregulation in the pathophysiology of SZ. Subclinical inflammation, aberrant monoamine metabolism, and abnormal hypothalamic–pituitary–adrenal axis

activation have been widely reported in patients with SZ [2–5] and are associated with microbiota alterations [6–9]. For instance, Schwartz et al. [10] found elevated abundance of Lactobacillaceae, Halothiobacillaceae, Brucellaceae, and Micrococcineae and lowered counts of Veillonellaceae in a cohort of SZ patients; in addition, greater microbial abnormalities, lower remission rates, and poorer responses to therapy, as well as decreased microbiome α-diversity index and altered gu<sup>t</sup> microbial composition, were observed in SZ patients [11]. Although mechanisms underlying the potential effect of microbiota on the pathogenesis and course of SZ are ye<sup>t</sup> to be determined, chronic inflammation [12] and altered tryptophan metabolism [13,14] have been suggested to be implicated in the pathogenesis of SZ. However, gu<sup>t</sup> microbiota-associated biomarkers that would hold clinical utility have not been indicated to date.

Olanzapine (OLZ), one of the most widely used second-generation antipsychotics (SGAs) [15], has multiple adverse effects, including weight gain, dyslipidemia, impaired glucose metabolism, and hypertension [16–19]. These metabolic adversities may occur shortly after treatment implementation and progress with treatment duration [20–22]. Importantly, the first year of antipsychotic treatment is a critical period for weight gain and other metabolic adverse effects [23]. Notably, weight gain at the beginning of OLZ therapy can be used to predict long-term outcomes related to cardiovascular comorbidity. Therefore, dietary counseling and weight management, including regular bodyweight measurements, should be implemented as soon as the OLZ therapy begins [24,25]. However, weight gain is of multifactorial nature [20,26–28], and, to date, no effective therapeutic strategies could prevent weight gain in patients treated with OLZ.

A few studies have demonstrated that OLZ administration plays a role in weight gain and metabolic malfunctions. Davey et al. [29] found that OLZ treatment induced metabolic alterations via microbiota changes, and the metabolic alterations could be reversed by treatment with antibiotics; in addition, microbial, inflammatory, and metabolic adversities related to OLZ treatment were sex-dependent [30]. Moreover, Morgan et al. [31] observed that weight gain depended on gu<sup>t</sup> microbiota, and specific bacteria were responsible for weight gain. Furthermore, Flowers et al. [32] revealed that clusters of gu<sup>t</sup> microbiota were associated with pharmacological treatment in patients with bipolar disorder. However, to the best of our knowledge, the effects of OLZ on gu<sup>t</sup> microbiota in patients with SZ have not been investigated. We hypothesized that short-term treatment with OLZ in controlled conditions (unified dietary intake and environmental factors) affects fecal microbiota compositions, and microbiota can affect body weight and treatment efficacy. Accordingly, this study analyzed microbiota compositions of stool samples collected from a cohort of SZ inpatients. The cohort comprised of acutely-relapsed SZ inpatients who were followed-up for six weeks during OLZ treatment.

#### **2. Materials and Methods**
