Colonization with the commensal fungus Candida albicans perturbs the gut-brain axis through dysregulation of endocannabinoid signaling

Abstract

Colonization with the commensal fungus Candida albicans perturbs the gut-brain axis through dysregulation of endocannabinoid signaling

High and Mighty? Cannabinoids and the microbiome in pain

“… Animal Effect Intervention Author/Year Germ-free male mice C57BL/6NTac Gene expression of endocannabinoidome receptors and enzymes and lipid mediators in juvenile and adult ileum, duodenum and colon were altered in germ-free animals FMT from donor age-matched conventional animals partially or completely reversed changes in gene expression and lipid mediator levels after 1 week treatment Manca et al, 2020 5–6 w old Female C57BL/6 Mice The fungus Candida albicans increased serum corticosterone levels, altered lipid metabolism and increased anxiety-like behaviour 1 mg/kg URB597 i.p. attenuated these changes in neuroendocrine, metabolic and behavioural outputs Markey et al, 2020 Adult male C57BL/6 Mice Diet-induced obesity (DIO) model increased gut permeability, increased anandamide levels and CB1R mRNA in adipose tissue, altered glucose and SCFA metabolism, altered tight junction protein expression, and increased inflammatory tone in blood, gut and fat tissues 10 mg/kg daily oral gavage of CB1R antagonist SR141716A for 4 weeks attenuated DIO-mediated changes in physiology and metabolism Mehrpouya-Bahrami et al, 2017 Adult male C57BL/6N mice DIO increased weight gain, had no effect on gut transit time, and altered gut microbiota 2 mg/kg THC i.p. for 3 weeks and 4 mg/kg for 1 additional week attenuated DIO-mediated weight gain and increased Firmicutes:Bacteroidetes ratio with an increase in Akkermansia muciniphila abundance Cluny et al, 2015 Genetic ob/ob, HFD, type 2 diabetic and naïve male C57BL/6 Mice All groups had increased weight gain and adipose tissue weight, increased serum LPS levels and Akkermansia muciniphila was significant lower (>100 fold decrease) in all groups The prebiotic oligofructose (10 g/100 g of diet for ob/ob study or 0.3 g per day HFD study) attenuated weight gain, fat mass accumulation, increase in serum LPS levels and decreases in Akkermansia muciniphila Everard et al, 2013 10w old adult male C57BL/6 Mice HFD increased weight gain and adipose tissue weight, increased serum LPS levels and Akkermansia muciniphila was significantly reduced 2 X 10^8 cfu/0.2 mL daily Akkermansia muciniphila (ATTC BAA-835) oral gavage or heat-killed control for 4 weeks attenuated serum LPS levels, weight gain, fat mass accumulation, and restored gut barrier function and increased intestinal endocannabinoids in DIO mice Everard et al, 2013 Male adult mice with Intestinal epithelial cell-specific deletion of NAPE-PLD NAPE-PLD deletion decreased levels of AEA, OEA, PEA, 2-AG; exacerbated obesity, reduced energy expenditure and altered gut microbiota …”

“…Further evidence that intestinal microbes can influence the endocannabinoid system is provided in another recent study. It was determined that the yeast C andida albicans can manipulate the endocannabinoid system resulting in changes in neuroendocrine levels resulting in changes in anxiety-like behaviour ( Markey et al, 2020 ). Further, increasing AEA levels using the well-characterized FAAH inhibitor URB597 was sufficient to reverse both the neuroendocrine and behavioural phenotypes in these C. albicans -colonized mice, suggesting an interaction between the microbiome and endocannabinoid system in these effects.…”

Endocannabinoids and the Gut-Brain Control of Food Intake and Obesity

“…Collectively, these investigations provide evidence that the eCB system in the gastrointestinal tract is a key component of the gut–brain axis that controls food intake and becomes dysregulated in diet-induced obesity. Exciting new studies suggest important interactions between the eCB system and the gut microbiome [ 35 , 78 , 116 , 117 , 118 , 119 , 120 , 121 ]; however, future investigations will be important to identify molecular and cellular mechanisms in these interactions, and the impact on gut-brain signaling important for food intake and energy metabolism in health and metabolic disease. In addition, studies will be important to elucidate specific intracellular mechanisms that the eCB system recruits to control release of satiation peptides and other signaling molecules from the intestinal epithelium, including those involved in transduction of food-related signals to activation of vagal afferent neurons by “neuropods” [ 9 , 10 ].…”

Evolutionary Significance of the Neuroendocrine Stress Axis on Vertebrate Immunity and the Influence of the Microbiome on Early-Life Stress Regulation and Health Outcomes

“…Commensal fungal species, like Candida albicans , were also shown to perturb the HPA axis in rats by manipulating the endocannabinoid system, which regulates the stress axis and anxiety-like behaviors. Rats colonized with C. albicans had increased basal circulating corticosterone and anxiety, relative to controls ( Markey et al, 2020 ). Behavioral implications of directly communicating with the brain from the gut are significant and intriguing, but require focused studies to determine the mechanistic modalities from these findings.…”