**1. Introduction**

Major depression (MD) is described as "a global crisis" by the World Health Organization (WHO) [1]. Major depression can affect anyone from young people to seniors, and it is one of the most widespread illnesses, often co-existing with other serious illnesses [2]. According to the WHO, MD was ranked as the third leading cause of the global burden of disease in 2004 and will likely have moved to the first place by 2030 [3]. It is now estimated that 350 million people are affected by MD worldwide, which poses a significant health and economic burden to society [4–6]. In 2016, MD was the first source of disability, accounting for 1059 worldwide disability-adjusted life years (DALYs)/100,000 habitants, thereby noticeably preceding ischemic and hemorrhagic stroke (787 and 923 respectively), hypertensive heart disease (242), Alzheimer disease (470), cancers (liver (295), colon (249), breast (208), and HIV (169)) [7]. Major depression was responsible for 48.7% of all worldwide DALYs related to mental and substance use disorders [7]. This alarming figure is a wakeup call for researchers and should encourage them to address this global non-communicable disease.

Major depression is heterogeneous and improving its treatment may require isolating more specific subgroups in the so-called precision medicine approach. Major depressionv has been identified as a frequent comorbidity of other major psychiatric disorders including schizophrenia (SZ). A half of SZ patients have been identified with MD that has been associated with impaired quality of life which suggests a 5 times higher risk of MD in this population compared to non-SZ individuals. Yet MD remains poorly diagnosed and poorly treated in this population [8–10]. Some studies suggest that MD-SZ may be different from non-SZ MD with lower placebo response and higher impact on functioning [9,11–13]. Major depression in schizophrenia (MD-SZ) has been also associated with other poor illness outcomes including pain, metabolic disturbances, less adherence and lower quality of life [8,14,15]. Treating depression is thus needed to improve the SZ prognosis [16]. Conventional antidepressants are partly effective, but 44% of the subjects remain unremitted under treatment [9]. Yet, funding for research directed to improving diagnosis and treatment of MD-SZ is sadly lacking [17].

Though conventional treatments have improved MD prognosis, they still remain unsatisfactory. The response rate of antidepressants amounts to only 17.7% in the general population [18]. An explanation for this high rate of non-response and relapses relies on the observation that current pharmacological treatments are primarily based on the monoaminergic hypothesis, without involving the personalized medicine approach. According to this hypothesis, MD is principally due to the fact of a deficit of three neurotransmitters in the brain (i.e., serotonin, norepinephrine, and dopamine). All current antidepressants target serotonin, norepinephrine, or dopamine deficits. The high rate of therapeutic failure in psychiatry can most likely be accounted for by the limitations pertaining to brain-orientated treatments. Current treatments do improve neurotransmitters deficits, yet without addressing the source of these deficits. This may explain the high relapsing rates and chronic illness course.

The key to breaking the deadlock of SZ-MD treatment may be found in the intestinal microbiota [19]. The links between gut microbiota disturbances and brain dysfunction have clearly been demonstrated in rodents. The so-called "gut-brain axis" has already been extensively described in humans with six pathways [19,20]: vagal nerve stimulation; inflammation and cytokine modulation; decreased gut permeability; short-chain fatty acid and neurotransmitter synthesis; nutrient absorption; Hypothalamic–pituitary–adrenal (HPA) stress axis (cortisol) modulation (Figure 1). Moreover, microbiota dysfunctions have been associated with peripheral immune inflammation as well as neuro-inflammation (also called microglia activation) [21].

**Figure 1.** The gut–brain axis in major depression.

Several clues indicate that targeting microbiota may be particularly relevant in schizophrenia (SZ). Schizophrenia patients are treated by antipsychotics that induce gastrointestinal disorders (including constipation) that may impact their gut microbiota. More than one quarter of SZ stabilized outpatients have abdominal obesity, which is a clinical marker of disturbed microbiota, and MD has been found to be the best predictor of rapid high weight gain in SZ [14]. Abnormal bacterial markers have been identified in the blood of SZ patients [22,23]. Emerging data show that about 30% of SZ people have elevated antigliadin antibodies (AGA) of the IgG type, representing a possible subgroup of schizophrenia patients with increased gut permeability [24]. Also, recent data have shown a high correlation of IgG-mediated antibodies between the periphery and cerebral spinal fluid in schizophrenia but not healthy controls, particularly AGA IgG suggesting that these antibodies may be crossing the blood-brain barrier with resulting neuroinflammation [25]. Schizophrenia has been extensively associated with other abnormal translational markers, suggesting an increased gut permeability in this illness [23,25–29]. More than one in five SZ patients are identified with metabolic syndrome [30], and one-third with chronic low-grade peripheral inflammation [31–34]. This inflammation is a good marker of central inflammation and has also been associated with SZ-MD [35].

Our hypothesis is that replacing the whole microbiota of SZ-MD patients (the so-called fecal microbiota transplantation (FMT)) may improve their mental and physical health, and more specifically their depressive symptoms and quality of life. Schizophrenia combined with MD and/or inflammation may be a target of choice for microbiota-orientated therapies.

The objective was to synthetize current data for testing microbiota-orientated treatments and to explore the benefit/risk ratio of FMT in major depression and schizophrenia.
