Transferring the blues: Depression-associated gut microbiota induces neurobehavioural changes in the rat

Abstract

The gut microbiota interacts with the host via neuroimmune, neuroendocrine and neural pathways. These pathways are components of the brain-gut-microbiota axis and preclinical evidence suggests that the microbiota can recruit this bidirectional communication system to modulate brain development, function and behaviour. The pathophysiology of depression involves neuroimmune-neuroendocrine dysregulation. However, the extent to which changes in gut microbiota composition and function mediate the dysregulation of these pathways is unknown. Thirty four patients with major depression and 33 matched healthy controls were recruited. Cytokines, CRP, Salivary Cortisol and plasma Lipopolysaccharide binding protein were determined by ELISA. Plasma tryptophan and kynurenine were determined by HPLC. Fecal samples were collected for 16s rRNA sequencing. A Fecal Microbiota transplantation was prepared from a sub group of depressed patients and controls and transferred by oral gavage to a microbiota-deficient rat model. We demonstrate that depression is associated with decreased gut microbiota richness and diversity. Fecal microbiota transplantation from depressed patients to microbiota-depleted rats can induce behavioural and physiological features characteristic of depression in the recipient animals, including anhedonia and anxiety-like behaviours, as well as alterations in tryptophan metabolism. This suggests that the gut microbiota may play a causal role in the development of features of depression and may provide a tractable target in the treatment and prevention of this disorder.

Behavioural and neurochemical consequences of chronic gut microbiota depletion during adulthood in the rat

“…The antibiotic cocktail was administered in drinking water to avoid any adverse effects from chronic stress induced by alternative administration methods such as oral gavage. The antibiotic cocktail consisted of ampicillin (1g/L), vancomycin (500mg/L), and ciprofloxacin HCL (20mg/L), imipenem (250mg/L) and metronidazole (1g/L) and was chosen based on published protocols from our group (Kelly et al, 2016) and others (Heimesaat et al, 2013) and was made up in autoclaved 5 water and changed every 3 days. Control animals received autoclaved water without any antibiotics which was also changed every 3 days.…”

Gut microbiota, metabolism and psychopathology: A critical review and novel perspectives

“…They demonstrated that a fecal transfer of microbiota from patients diagnosed with major depressive disorder (MDD) to germ-free mice, resulted in more depression-like behaviors for these mice as compared to germ-free mice that were colonized with healthy individuals' microbiota. Kelly et al [32] found the same effect of a fecal transfer from MDD patients to an antibiotics-induced microbiotadepleted rat model. While they failed to observe any significant differences in hippocampal BDNF expression associated with the depression, rats who received the depressive gut microbiota had an increased kynurenine/tryptophan ratio in blood.…”

Lost in translation? The potential psychobiotic Lactobacillus rhamnosus (JB-1) fails to modulate stress or cognitive performance in healthy male subjects

“…Recently, several studies have demonstrated altered gut microbiota composition in depression (Jiang et al, 2015;Kelly et al, 2016a;Naseribafrouei et al, 2014) and suggest that this altered gut microbiota composition may play a causal role in the development of certain features of depression (Kelly et al, 2016a;Zheng et al, 2016), though the precise mechanisms have yet to be elucidated. To date, only one small study has investigated a probiotic intervention in depressed patients (Akkasheh et al, 2016).…”