Mol Psychiatry. 2016 Jun; 21(6): 738–748.
Published online 2016 Apr 19. doi: 10.1038/mp.2016.50
PMCID: PMC4879184


From gut dysbiosis to altered brain function and mental illness: mechanisms and pathways


G B Rogers,1,* D J Keating,2 R L Young,3 M-L Wong,4 J Licinio,4 and S Wesselingh1
Author information ► Article notes ► Copyright and License information ► This article has been cited by other articles in PMC.
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Abstract
The human body hosts an enormous abundance and diversity of microbes, which perform a range of essential and beneficial functions. Our appreciation of the importance of these microbial communities to many aspects of human physiology has grown
dramatically in recent years. We know, for example, that animals raised in a germ-free environment exhibit substantially altered immune and metabolic function, while the disruption of commensal microbiota in humans is associated with the development of a
growing number of diseases. Evidence is now emerging that, through interactions with the gut–brain axis, the bidirectional communication system between the central nervous system and the gastrointestinal tract, the gut microbiome can also influence
neural development, cognition and behaviour, with recent evidence that changes in behaviour alter gut microbiota composition, while modifications of the microbiome can induce depressive-like behaviours. Although an association between enteropathy and
certain psychiatric conditions has long been recognized, it now appears that gut microbes represent direct mediators of psychopathology. Here, we examine roles of gut microbiome in shaping brain development and neurological function, and the mechanisms
by which it can contribute to mental illness. Further, we discuss how the insight provided by this new and exciting field of research can inform care and provide a basis for the design of novel, microbiota-targeted, therapies.

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Introduction
The disruption of the microbes that are resident in our gastrointestinal tract has long been implicated in the development or exacerbation of mental disorders. There is, for example, a long history of anecdotal reports of psychiatric side-effects of
antibiotics, even in those without a premorbid psychiatric history.1 There have also been attempts to influence the composition of the gut microbiota to achieve clinical benefit. For example, in the first decades of the twentieth century, probiotic
preparations containing Lactobacillus strains were marketed widely as a means to improve mental health or treat psychiatric disorders.2 These approaches fell from favour in the 1920s because of a lack of mechanistic understanding and their link to the
increasingly unfashionable ‘autointoxication' model. However, the interest in the role of gut microbes in mental health, and our ability to improve psychiatric wellbeing through their manipulation, is resurgent.2, 3

In this review, we consider the potential of dysbiosis to contribute to psychopathology and the evidence linking disruption of gut microbiota with specific psychiatric disorders. We examine the role of the microbiome in neurological development and
regulation, and consider its contribution to aging-related morbidity. Finally, we discuss the potential for modification of the gut microbiome to provide clinical benefit in the context of altered brain function.

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Regulation of neurological function by the gut microbiome
The potential contribution of bidirectional communication between the gut and central nervous system (CNS) is suggested by high rates of comorbidity between gastrointestinal and psychiatric illnesses.4, 5 For example, mood disorders affect more than half
of all patients with irritable bowel syndrome,6 with antidepressants being one of the most common pharmaceutical interventions for irritable bowel syndrome.4 The gut–brain axis consists of a bidirectional communication network that monitors and
integrates gut functions and link them to cognitive and emotional centres of the brain. It encompasses the central, autonomic and enteric nervous systems, as well as the neuroendocrine, enteroendocrine and neuroimmune systems.7, 8 It mediates the effects
of both genetic and environmental factors on brain development and function, and has been implicated in the aetiology of a number of psychiatric disorders.9, 10, 11, 12

In recent years, we have increasingly understood the contribution made by the gut microbiome not only in the regulation of host physiology, particularly metabolism and immunity,13, 14, 15, 16, 17 but also the CNS and brain function.11, 18, 19 Given
mounting evidence that the microbiome has a key role in influencing the development and function of the nervous system through its interaction with the gut–brain axis, it has been suggested that a ‘microbiome–gut–brain axis' may be a more
appropriate model.19, 20, 21, 22

The delicate balance between the human microbiome and the development of psychopathologies is particularly interesting given the ease with which the microbiome can be altered by external factors, such as diet,23 exposure to antimicrobials24, 25 or
disrupted sleep patterns.26 For example, a link between antibiotic exposure and altered brain function is well evidenced by the psychiatric side-effects of antibiotics, which range from anxiety and panic to major depression, psychosis and delirium.1 A
recent large population study reported that treatment with a single antibiotic course was associated with an increased risk for depression and anxiety, rising with multiple exposures.27 Bercik et al.28 showed that oral administration of non-absorbable
antimicrobials transiently altered the composition of the gut microbiota in adult mice and increased exploratory behaviour and hippocampal expression of brain-derived neurotrophic factor (BDNF), while intraperitoneal administration had no effect on
behaviour. Alteration of brain function may therefore add to the many reasons that inappropriate antibiotic use should be avoided. It should be noted though that unchecked bacterial infection also represents an acute stressor, and has been shown to be
associated with memory dysfunction in mice.29

Diet is another important determinant of gut microbiota composition and function that is strongly linked with psychopathological outcomes. For example, consumption of high fat diet (HFD) is associated with altered microbial diversity and reduced synaptic
plasticity,30, 31 with increased vulnerability to anxiety-like behaviour in mice,32 while altered microbial diversity upon consumption of a diet high in sucrose results in significantly impaired development of a spatial bias for long-term memory, short-
term memory and reversal training.33 In contrast, adolescent rats fed a low-calorie diet show augmented neurogenesis and BDNF levels, and improved cognition in adulthood,34 and a diet that increases microbiota diversity is associated with improved
cognitive ability.35 Although human data have shown reduced microbial diversity in individuals is linked with increased adiposity, insulin resistance, dyslipidaemia and more pronounced inflammatory phenotype,36, 37 strong evidence of a direct microbiome
effect comes from studies using conventionally housed mice subjected to a microbiome depletion and/or transplantation paradigm using microbiota isolated from donors on either an HFD or control diet. Following re-colonization, mice given the HFD exposed
microbiota showed significant and selective disruptions in exploratory, cognitive, and stereotypical behaviour.38 Although it is not possible to exclude the direct effect of host metabolism on brain function, such findings do suggest that diet-induced
changes in the intestinal microbiome substantially influence brain function.

Diet and antibiotic exposure are only two factors that potentially influence brain function through shaping the gut microbiome (Figure 1). An array of common variables may be equally important. For example, alcohol consumption,39, 40 smoking habits41 and
disruption of diurnal rhythm,26 have all been shown to substantially affect microbiota composition. As such, how wider influences on the microbiome contribute to dysregulation of brain function is an area of growing interest.

Figure 1
Figure 1
Communication pathways linking the gut microbiome with brain function.
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The microbiome in specific psychiatric conditions
While the links between the microbiome and specific psychiatric conditions have been reviewed elsewhere,18, 42, 43, 44, 45 a brief examination of the contribution of inter-kingdom interactions to two particularly distressing neuropsychiatric disorders
provides a useful illustration.

Major depressive disorder (MDD) is typified by markers known to be influenced by the microbiome. For example, depression-associated changes seen in the hypothalamic-pituitary-adrenal (HPA) stress response,46 and altered levels of depression-associated
monoamines (or their receptors) in corticolimbic regions of the brain, have both been demonstrated in germ-free (GF) mice.28, 47, 48, 49, 50 The increased concentrations of pro-inflammatory cytokines seen in MDD46 may also result from interactions with
gut microbes. Levels of serum antibodies against lipopolysaccharide from gram-negative enterobacteria are higher in patients with MDD than in controls,51 and cause stress-associated with increased gut permeability and bacterial translocation in animal
models.22, 52 Evidence also exists that depression alters the gut microbiota, as demonstrated in mice in which chronic depression- and anxiety-like behaviours has been induced by olfactory bulbectomy,53 suggesting a feedback loop between depressive
states and dysbiosis. A reflection of the importance of this circular relationship may be the existence of host mechanisms that regulate microbiota composition.54, 55

Similar parallels between dysbiosis and psychopathogenesis exist in schizophrenia (reviewed by Dinan et al.56 and Nemani et al.44). Many of the strongest associations identified between genetic risk and schizophrenia relate to genes involved in immunity,
57, 58 paralleling clinical studies that report an upregulated immune and inflammatory status in schizophrenia patients.59, 60, 61, 62, 63, 64, 65, 66, 67, 68 Serological markers of bacterial translocation are also substantially elevated in schizophrenia
subjects and significantly correlated with systemic inflammatory markers.69 In turn, cytokine levels are correlated with the severity of clinical symptoms,59, 70, 71 and it has been suggested that the resulting neuroinflammation is involved directly in
schizophrenia pathogenesis.72, 73, 74

As described later, the microbiota also modulate a range of neurotrophins and proteins involved in brain development and plasticity.48, 49, 75 There is evidence that such alterations are central to the pathophysiology of schizophrenia. For example, BDNF
expression is believed to have a role in the molecular mechanism underlying altered cognition,76 and through its influence on brain plasticity, may contribute to the N-methyl-d-aspartate receptor dysfunction seen in schizophrenia.77

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Treatment interactions with the microbiome in mental illness
In addition to influencing psychopathogenesis directly, the gut microbiome makes an important contribution to drug metabolism, and potentially explains much of the inter-individual variability in treatment efficacy and side-effects.78, 79 For example,
the gut microbiota has been implicated in the reductive metabolism of psychotropic medications, including benzodiazepine clonazepam,80 risperidone81 and levodopa.82 In addition, the gut microbiome is also able to influence the gene expression of hepatic
enzymes that aid in the metabolism and detoxification of drugs outside of the gut.83, 84

A reciprocal interaction also exists, with drugs used to target psychiatric or neurological disorders having the potential to affect the composition and function of the gut microbiome. For example, the atypical antipsychotic olazapine has been shown to
affect microbiota composition in rats, as well as triggering inflammatory effects and weight gain,85, 86 with the co-administration of antibiotics shown to attenuate these physiological effects.87 The impact of atypical antipsychotics on the gut
microbiota may therefore explain to some extent the increased levels of cardiac and metabolic disease in patients receiving these medications.88, 89, 90

The clinical implications of these pathways remain poorly understood, but suggest the utility of a precision approach to therapy, as has been advocated in psychiatry91, 92 and other disease contexts.93

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The role of the microbiome in brain development

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https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4879184/?report=classic

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