Table 1.

Analysis of selected articles.

Reference	Study Design	Objectives	Mains Results	Limitations
Shetty S et al., 2014 [18]	Cross-sectional epidemiological study 250 patients (140 males and 110 females) with a positive history of schizophrenia	To explore the possible bidirectional link between periodontal disease and schizophrenia.	The study shows that patients who were schizophrenic for a longer duration of time (p < 0.001) have increased evidence of poor periodontal condition, demonstrated by gingival and plaque indexes. The findings suggest that the role of periodontal disease in the pathogenesis of schizophrenia cannot be ruled out.	Further long-term interventional studies involving periodontal management of PWS and monitoring the cytokine profile followed by assessment of changes in the schizophrenic status of these patients need to be undertaken.
Yolken RH et al., 2015 [19]	Case control 41 PWS and 33 control individuals without a psychiatric disorder	To analyze to characterize bacteriophage genomes in the oral pharynx of PWS and control individuals without a psychiatric disorder	LPP, with PWS, was significantly greater than the number of matches in the controls. The level of LPP was correlated with an increased rate of comorbid immunological disorders with PWS.	The level of LPP was found to be associated with the administration of valproate, commonly used in the treatment of epilepsy or as a mood stabilizer in schizophrenics.
Castro–Nallar E et al., 2015 [20]	Case control 16 individuals with schizophrenia and 16 controls	To characterize the schizophrenia microbiome by interrogating the oropharyngeal microbiome structure regarding its taxonomic and functional diversity.	Lactic acid bacteria were relatively more abundant in schizophrenia including Lactobacillus and Bifidobacterium with the largest effect found in Lactobacillus gasseri, which appeared to be at least 400 times more abundant in PWS than in controls. PWS showed decreased oral microbial biodiversity and an increased number of metabolic pathways related to metabolite transport systems including siderophores, glutamate, and vitamin B12 in PWS. In contrast, carbohydrate and lipid pathways and energy metabolism were abundant in controls.	The fact that all controls were non-smokers, although statistically accounted for in inferences, might confound the effects of schizophrenia from those of smoking on microbiome composition.
Dickerson F et al., 2017 [5]	Review	To summarize what is known about immune alterations and the microbiome based on human studies in schizophrenia and bipolar disorder.	The part on the oral microbiota takes up the results of the studies by Robert H. Yolken et al. and Eduardo Castro–Nallar et al.	Observational study.
Nguyen TT et al., 2018 [21]	Review	To highlight gaps in our knowledge, potential implications for diagnosis and therapeutic interventions, and outline future directions for microbiome research in psychiatry.	PWS showed decreased oral microbial biodiversity. At the genus level, lactic acid bacteria (Lactobacillus and Bifidobacterium) were relatively more abundant in schizophrenia, particularly species Lactobacillus gasseri. Notably, lactic acid bacteria are often considered health-promoting and anti-inflammatory. LPP in PWS, which is a bacteriophage that preferentially infects the bacteria Lactobacillus gasseri. This study also observed a positive association between colonization with LPP and comorbid immunological diseases. These conflicting results may be due to differences between populations, as schizophrenia is a very heterogeneous disease, or underscore the complexity of community relationships within the microbiota.	Observational study.
Hashioka S et al., 2019 [22]	Review	To focus on the biological and epidemiological evidence of possible causal links of periodontitis to the selected neuropsychiatric disorders, namely Alzheimer, Depression, Schizophrenia, Ischemia, Stroke, Parkinson	The study showed that evidence of a significant relationship between periodontitis and schizophrenia is not yet accumulated. Only one cross-sectional study with a small sample size concluded that patients with schizophrenia have a high risk of periodontitis and there is an even higher risk in those who are taking antipsychotics that reduce salivary secretion and cause xerostomia.	A small sample size with schizophrenia. This review article focuses on possible causal links of periodontitis to schizophrenia but other neuropsychiatric disorders.
Cui G et al., 2020 [23]	Case control 54 with metabolic profile of schizophrenia 54 healthy controls	To characterize metabolites in the peripheral circulation to deepen our understanding of the pathogenesis of schizophrenia (using Fourier transform-ion cyclotron resonance-mass spectrometry (FT-ICR-MS))	The authors discovered two dysregulated metabolic pathways in schizophrenia: an upregulation arachidonic acid-related pathway, and a downregulation aromatic amino acid-related pathway. The carnitine was identified as a promising diagnostic biomarker for schizophrenia with an area under the curve of 0.997. An imbalance of the redox homeostasis in schizophrenia	Low level of evidence
Yolken R et al.,2021 [24]	Case control 316 individuals, including 121 PWS, 62 with mania, 48 with major depressive disorder, and 85 controls without a psychiatric disorder	To confirm the link between PWS and altered oropharyngeal microbiome with a larger sample of PWS.	The study showed that the oropharyngeal microflora of PWS and individuals with mania differed from controls. Three of the taxa, Neisseria subflava, Weeksellaceae, and Prevotella, were decreased in PWS or mania as compared to that of controls, while Streptococci wereincreased in these groups. Neisseria subflava was also positively associated with cognitive functioning. Altered beta-diversity in PWS and mania as compared to control individuals without a psychiatric disorder.	There are a number of environmental exposures which might be increased in individuals with psychiatric disorders, and which were not directly measured in this study. Inhaled drugs such as cannabis, increased exposure to sexually transmitted diseases, to respiratory viruses, to effects of alcohol and to medications such as anticholinergic agents. Patients with inadequate periodontal care may not have detailed dietary. This study was cross-sectional and did not measure changes over time
Qing Y et al., 2021 [25]	Case control 85 patients with first episode schizophrenia (FES) 43 with clinical high risk (CHR) 80 healthy controls (HCs)	To investigate the salivary microbiome in the context of schizophrenia. To characterize the microbial profiles at different clinical stages of the schizophrenia. To gain understanding of the function of salivary microbes in the initiation of schizophrenia.	The authors found a high ratio Firmicutes/Proteobacteria in PWS in the salivary microbiome. They added that H2S-producing bacteria could be potential diagnostic biomarkers for FES and CHR and precede the onset of the trouble. The study showed that the metabolic functions of the salivary microbiome were disturbed in schizophrenia.	It is an observational study. It cannot prove the causal relationship between the salivary microbiome and schizophrenia. Lack of metagenomic data to determine the actual microbial gene content in the salivary microbiome. The dental status and oral hygiene not sufficiently considered

LPP: Lactobacillus phage phiadh; PWS: Persons with schizophrenia.