Microbiota–gut–brain axis mechanisms in the complex network of bipolar disorders: potential clinical implications and translational opportunities

Abstract

Bipolar disorders (BD) represent a severe leading disabling mental condition worldwide characterized by episodic and often progressive mood fluctuations with manic and depressive stages. The biological mechanisms underlying the pathophysiology of BD remain incompletely understood, but it seems that there is a complex picture of genetic and environmental factors implicated. Nowadays, gut microbiota is in the spotlight of new research related to this kind of psychiatric disorder, as it can be consistently related to several pathophysiological events observed in BD. In the context of the so-called microbiota–gut–brain (MGB) axis, it is shown to have a strong influence on host neuromodulation and endocrine functions (i.e., controlling the synthesis of neurotransmitters like serotonin or mediating the activation of the hypothalamic–pituitary–adrenal axis), as well as in modulation of host immune responses, critically regulating intestinal, systemic and brain inflammation (neuroinflammation). The present review aims to elucidate pathophysiological mechanisms derived from the MGB axis disruption and possible therapeutic approaches mainly focusing on gut microbiota in the complex network of BD. Understanding the mechanisms of gut microbiota and its bidirectional communication with the immune and other systems can shed light on the discovery of new therapies for improving the clinical management of these patients. Besides, the effect of psychiatric drugs on gut microbiota currently used in BD patients, together with new therapeutical approaches targeting this ecosystem (dietary patterns, probiotics, prebiotics, and other novelties) will also be contemplated.

The commensal protistTritrichomonas musculusexhibits a dynamic life cycle that induces extensive remodeling of the gut microbiota

“…In addition to iron, we also noted a potential for competition over the catabolism of tryptophan, with the expression of a putative tryptophanase by the protist. Recently there has been much interest in the production of neuroactive kynurenines from tryptophan by the gut microbiome, and their potential role in the gut brain access 81, 82 . Through shifting the production of indole at the expense of alternative products, tryptamine and kynurenine, our findings suggest that colonization by the protist may similarly modulate the gut-brain access.…”

“…Production of indole by T. foetus and T. vaginalis was shown to impact host immunity and barrier function, and bacterial signalling 103–105 . Recently there has been much interest in the production of neuroactive kynurenines from tryptophan by the gut microbiome 106,107 . Through promoting production of indole at the expense of alternative products, tryptamine and kynurenine, our findings question whether protists similarly modulate the gut-brain access.…”

What’s gut got to do with it? The role of the microbiota and inflammation in the development of adiposity and obesity

“…The pathway that we describe here represents a common etiology that arises from a changed diet and leads to the metabolic inflammation that is present in most cases of the disease. Changes to the gut microbiota and activation of the immune system are involved in many other diseases as well, including neurological disorders (reviewed in [81][82][83] ). It is important to develop a deeper understanding of the interactions between these important aspects of physiology to develop better treatments for a wide range of diseases in the future.…”

Fecal microbiota transplantation from individual with bipolar disorder and healthy control elicits distinct behaviors and metabolite profiles in mice

“…Individuals with bipolar I (BDI) disorder undergo frequent depressive and manic episodes, and patients with bipolar II (BDII) disorder may experience a depressive or hypomanic episode without fully entering mania. BD is one of the most common psychiatric disorders worldwide [1,2] and is associated with increased mortality due to psychosocial consequences, suicidality, and psychiatric and somatic comorbidities [3,4]. Strengthening our understanding of the biological mechanisms behind BD is crucial for advancing treatment and improving patient outcomes.…”

“…Bipolar disorder (BD) is a chronic mood disorder characterized by recurrent episodes of depression, hypomania, and mania. BD is one of the most common psychiatric disorders worldwide, with an estimated lifetime prevalence of 1.06% for BD1 and 1.57% for BD2 [1,2]. BD can be debilitating and even fatal, with suicide being 10-30% more likely for BD patients than the general population [3].…”