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Stress and the Role of the Gut–Brain Axis in the Pathogenesis of Schizophrenia: a Literature Review

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Stress and the Role of the Gut–Brain Axis in the Pathogenesis of Schizophrenia: a Literature Review International Journal of Molecular Sciences Review Stress and the Role of the Gut–Brain Axis in the Pathogenesis of Schizophrenia: A Literature Review Behnam Vafadari Clinic for Anesthesiology, University Medical Center Göttingen, Georg-August-University, 37073 Göttingen, Germany; [email protected] Abstract: Schizophrenia is a severe neuropsychiatric disorder, and its etiology remains largely un- known. Environmental factors have been reported to play roles in the pathogenesis of schizophrenia, and one of the major environmental factors identified for this disorder is psychosocial stress. Several studies have suggested that stressful life events, as well as the chronic social stress associated with city life, may lead to the development of schizophrenia. The other factor is the gut–brain axis. The composition of the gut microbiome and alterations thereof may affect the brain and may lead to schizophrenia. The main interest of this review article is in overviewing the major recent findings on the effects of stress and the gut–brain axis, as well as their possible bidirectional effects, in the pathogenesis of schizophrenia. Keywords: schizophrenia; neuropsychiatric; stress; gut–brain axis; psychosocial 1. Introduction Citation: Vafadari, B. Stress and the Around 792 million people in the world live with mental disorders, which is more Role of the Gut–Brain Axis in the than one in ten people (10.7%) globally [1]. Neuropsychiatry is a discipline that deals with Pathogenesis of Schizophrenia: A mental disorders that are attributable to diseases of the nervous system; these are related Literature Review. Int. J. Mol. Sci. to cognitive and behavioral diseases caused by direct cerebral dysfunctions or indirect 2021, 22, 9747. https://doi.org/ extra-cerebral diseases [2]. In spite of major advances in neurobiology and neuroscience 10.3390/ijms22189747 research, the prevalence of neuropsychiatric diseases has not decreased. Our knowledge in Academic Editor: the basic and clinical pathophysiology of neuropsychiatric diseases, such as schizophrenia, Alberto Fernandez-Teruel is still limited. “Schizophrenia is a severe neuropsychiatric disease that is characterized by impairments in perception, cognition, and avolition, leading to positive, cognitive, and Received: 19 July 2021 negative symptoms, respectively” [3]. The etiology of schizophrenia remains unknown [4]. Accepted: 31 August 2021 As a result, the objective of this review is to assess the newly emerging paradigm of the Published: 9 September 2021 brain–gut–microbiota axis, in which imbalances are risk factors for the pathogenesis of schizophrenia, in addition to the effects of other environmental factors (e.g., stress) on the Publisher’s Note: MDPI stays neutral pathogenesis of schizophrenia. Several studies focused on the risk factors for schizophrenia with regard to jurisdictional claims in separately, and we mention the important findings in this review article. For example, published maps and institutional affil- there is increasing evidence that disorders such as schizophrenia are associated with an iations. imbalance in the gut microbiome [5,6]. Another important factor is stress. Stress can induce changes in the gut microbiome [7] and it is well known that stress is one of the risk factors for the pathogenesis of schizophrenia [3,8–11]. Finally, several lines of evidence support the notion that gut microbiota can affect stress-related behaviors [12]. Copyright: © 2021 by the author. The effects of environmental factors (stress) together with those of the dysregulation Licensee MDPI, Basel, Switzerland. of the gut–brain axis on the pathogenesis of schizophrenia will be discussed in this review This article is an open access article (Figure1). This can be interesting due to the fact that there are few studies that show the distributed under the terms and bidirectional effects of these factors. Some of the important studies, summarized in Table1. conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). Int. J. Mol. Sci. 2021, 22, 9747. https://doi.org/10.3390/ijms22189747 https://www.mdpi.com/journal/ijms Int.Int. J.J. Mol.Mol. Sci.Sci. 20212021,,22 22,, 9747x FOR PEER REVIEW 22 ofof 1313 Figure 1. Stress and dysregulation of the gut microbiome can rarely be effective alone. Stressful life Figure 1. Stress and dysregulation of the gut microbiome can rarely be effective alone. Stressful life eventsevents inin combination combination with with the the effects effects of theof the gut–brain gut–brain axis axis may may induce induce bidirectional bidirectional effects effects and lead and tolead schizophrenia. to schizophrenia. 2. Schizophrenia 2. Schizophrenia Schizophrenia is a severe neuropsychiatric disorder that affects 20 million people Schizophrenia is a severe neuropsychiatric disorder that affects 20 million people worldwide [13]. Schizophrenia causes a significant burden on wellbeing and global health. worldwide [13]. Schizophrenia causes a significant burden on wellbeing and global The interactions of different factors that play roles in the disease’s etiology are not fully health. The interactions of different factors that play roles in the disease’s etiology are not understood. There are possible reasons for the onset of schizophrenia, such as the possible increasedfully understood. activation There of components are possible of reasons the immune for the system onset of [14 schizophrenia,], including alterations such as the in intestinalpossible increased permeability activation and the of gut components microbiome of [the15], immune and stressful system life [14], events including [8–11]. altera- There aretions three in intestinal major groups permeability of symptoms and the recognized gut microbiome in schizophrenia, [15], and stressful which life are events classified [8– as11]. positive, There are negative, three major and cognitivegroups of [ 16symptoms]. The etiology recognized of schizophrenia in schizophrenia, remains which largely are unknown,classified as although positive, the negative, roles of theand genes cognitive in combination [16]. The etiology with environmental of schizophrenia factors remains have beenlargely reported unknown, [17, 18although]. The onset the roles of schizophrenia of the genes in is combination typically in earlywith environmental adulthood, and fac- it istors associated have been with reported life time [17,18]. disability The onset [19–21 of]. schizophrenia Dysfunctions is in typically dopaminergic in early neurotrans- adulthood, mittersand it is may associated contribute with to life psychotic time disability symptoms, [19–21]. although Dysfunctions there is evidence in dopaminergic that shows neuro- the involvementtransmitters ofmay other contribute areas and to circuits psychotic of the symptoms, brain [22]. although there is evidence that showsThe the terminology involvement for of positive other areas and and negative circuits symptoms of the brain has [22]. been evolved for around 150 yearsThe [terminology23]. for positive and negative symptoms has been evolved for around 150 yearsClinically, [23]. schizophrenia is characterized by its diverse psychopathology; the core featuresClinically, are positive schizophrenia symptoms is (thoughtcharacterized disorders, by its delusionsdiverse psychopathology; and hallucinations, the andcore psychoticfeatures are symptoms positive symptoms in which the (thought person disorders, loses contact delusions with reality), and hallucinations, negative symptoms and psy- (restrictedchotic symptoms affect, poverty in which of the speech, person impaired loses co motivation,ntact with andreality), social negative withdrawal), symptoms and cog- (re- nitivestricted impairments affect, poverty (impairments of speech, in impaired cognitive motivation, processes, such and associal memory withdrawal), dysfunction, and poor cog- performancenitive impairments in a wide (impairments range of cognitive in cognitive functions, processes, working such memory as memory deficits, dysfunction, executive dysfunction,poor performance and attentional in a wide impairments)range of cognitive [3,24 –functions,27]. Importantly, working a memory patient with deficits, cognitive exec- symptomsutive dysfunction, may show and a cognitiveattentional disability; impairments) however, [3,24–27]. a patient Importantly, with negative a patient symptoms with maycognitive just show symptoms either anhedoniamay show or a unsociabilitycognitive disability; without however, other signs. a patient Furthermore, with negative each of thosesymptoms symptoms may just can beshow individually either anhedonia scaled [27 or]. unsociability The heterogeneity without of theother symptoms signs. Further- of the diseasemore, each makes of those it very symptoms difficult to can diagnose be individu and cureally scaled patients. [27]. As The a result, heterogeneity the etiology of the of schizophreniasymptoms of the is notdisease yet fullymakes understood. it very difficul Thet disorder’sto diagnose etiology and cure is patients. multifactorial; As a result, as a Int. J. Mol. Sci. 2021, 22, 9747 3 of 13 result, investigation of the different risk factors (e.g., gut microbiome dysregulation and stress) alone or in combination can be very helpful. 3. Stress Psychological stress can lead to several neuropsychiatric disorders, such as depression and schizophrenia [28]. Nowadays, it is suggested that environmental factors may play a major role in the pathogenesis of
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