Colonization with the commensal fungusCandida albicansperturbs the gut-brain axis through dysregulation of endocannabinoid signaling

Abstract

19Anxiety disorders are the most prevalent mental health disorder worldwide, with a 20 lifetime prevalence of 5-7% of the human population. Although the etiology of anxiety 21 disorders is incompletely understood, one aspect of host health that affects anxiety 22 disorders is the gut-brain axis. We used a mouse model of gastrointestinal (GI) 23 colonization to demonstrate that the commensal fungus Candida albicans affects host 24 health via the gut-brain axis. In mice, bacterial members of the gut microbiota can 25 influence the host gut-brain axis, affecting anxiety-like behavior and the hypothalamus-26 pituitary-adrenal (HPA) axis which produces the stress hormone corticosterone (CORT). 27Here we showed that mice colonized with C. albicans demonstrated increased anxiety-28 like behavior and increased basal production of CORT as well as dysregulation of CORT 29 production following acute stress. The HPA axis and anxiety-like behavior are 30 negatively regulated by the endocannabinoid anandamide (AEA). C. albicans-colonized 31 mice exhibited changes in endocannabinoid levels within the GI tract and a negative 32 correlation between brain AEA levels and serum CORT. Further, increasing AEA levels 33 using the well-characterized fatty acid amide hydrolase (FAAH) inhibitor URB597 was 34 sufficient to reverse both neuroendocrine phenotypes in C. albicans-colonized mice. 35Thus, a commensal fungus that is a common colonizer of humans had widespread effects 36 on the physiology of its host. To our knowledge, this is the first report of microbial 37 manipulation of the endocannabinoid (eCB) system that resulted in neuroendocrine 38 changes contributing to anxiety-like behavior. 39 Keywords 40Endocannabinoid, microbiota, Candida albicans, anxiety, corticosterone 41 3 42 Significance Statement 43Anxiety disorders are the most prevalent mental health disorder worldwide yet 44 their etiology is incompletely understood and treatment options are limited. The gut-45 brain axis has been shown to influence the development of anxiety disorders. Recent 46 work has established that the bacterial gut microbiota can influence the gut-brain axis and 47 result in changes to neuroendocrine health including anxiety-like behavior in mice. We 48 describe a novel role for a fungal member of the gut microbiota, Candida albicans, that 49 influences the neuroendocrine system through manipulation of the endocannabinoid 50 system. Additionally, this work demonstrates that acute, limited manipulation of 51 endocannabinoids can have a significant impact on host health, emphasizing the potential 52 of this system as a target for the treatment of anxiety disorders. 53Introduction 54Anxiety disorders are the most prevalent mental health disorder worldwide, with a 55 lifetime prevalence of 5-7% of the human population 1 . The etiology of anxiety disorders 56 is complex and incompletely understood, although many different genetic and 57 environmental factors have been identified 2 . The gut-brain axis, the bi-directional 58 communication between the gut...

Targeted and untargeted nanopore sequencing approaches to profile the gut microbiota of mice infants exposed to ethanolin utero

“…Usually, nanopore sequencing achieves a higher number of taxa at the species level than Illumina sequencing (2), most likely explained by the capacity of nanopore sequencing reads to span multiple 16S rRNA variable regions (2). Indeed, nanopore sequencing approaches rely on longer reads and reference databases are mostly composed of standard and shorter gene markers, such as fragments of the 16S rRNA gene or the ITS region (3,4). Therefore, nanopore sequencing may have limited reliability in profiling unknown microbial communities, decreasing the confidence on the taxonomical composition obtained (5).…”