Early life diets with prebiotics and bioactive milk fractions attenuate the impact of stress on learned helplessness behaviours and alter gene expression within neural circuits important for stress resistance

Abstract

Manipulating gut microbes may improve mental health. Prebiotics are indigestible compounds that increase the growth and activity of health-promoting microorganisms, yet few studies have examined how prebiotics affect CNS function. Using an acute inescapable stressor known to produce learned helplessness behaviours such as failure to escape and exaggerated fear, we tested whether early life supplementation of a blend of two prebiotics, galactooligosaccharide (GOS) and polydextrose (PDX), and the glycoprotein lactoferrin (LAC) would attenuate behavioural and biological responses to stress later in life. Juvenile, male F344 rats were fed diets containing either GOS and PDX alone, LAC alone, or GOS, PDX and LAC. All diets altered gut bacteria, while diets containing GOS and PDX increased Lactobacillus spp. After 4 weeks, rats were exposed to inescapable stress, and either immediately killed for blood and tissues, or assessed for learned helplessness 24 h later. Diets did not attenuate stress effects on spleen weight, corticosterone and blood glucose; however, all diets differentially attenuated stress-induced learned helplessness. Notably, in situ hybridization revealed that all diets reduced stress-evoked cfos mRNA in the dorsal raphe nucleus (DRN), a structure important for learned helplessness behaviours. In addition, GOS, PDX and LAC diet attenuated stress-evoked decreases in mRNA for the 5-HT autoreceptor in the DRN and increased basal BDNF mRNA within the prefrontal cortex. These data suggest early life diets containing prebiotics and/or LAC promote behavioural stress resistance and uniquely modulate gene expression in corresponding circuits.

Dietary Prebiotics and Bioactive Milk Fractions Improve NREM Sleep, Enhance REM Sleep Rebound and Attenuate the Stress-Induced Decrease in Diurnal Temperature and Gut Microbial Alpha Diversity

“…We chose to start them at such an early age because it has been demonstrated that the gut bacteria can be more easily shaped by exogenous factors such as exercise and a prebiotic diet very early in life, which leads to what is thought to be a stress-protective gut bacteria pheontype (Mika et al, 2015b; Mika and Fleshner, 2016). Additionally, starting the prebiotic diet as early as PND 24 has been shown to alleviate the negative consequences of stress in adulthood (Mika et al, 2016). All of these effects were demonstrated in the F344 rat strain.…”

The enduring effects of early‐life stress on the microbiota–gut–brain axis are buffered by dietary supplementation with milk fat globule membrane and a prebiotic blend

“…More recently, this definition has been updated to include non‐carbohydrate substances, applications to body sites other than the gastrointestinal tract and diverse categories other than food (Gibson et al., ). Recently, we (Burokas et al., ; McVey Neufeld et al., ) and others (Mika et al., ; Tarr et al., ; Thompson et al., ; Williams et al., ) have shown that prebiotics can have a positive effect on physiology and behaviour and can reverse the effects of stress and immune activation in adult animals. Moreover, research now shows that a combination of prebiotics and MFGM improves sleep and attenuates the impact of stress in rats (Mika et al., ; Thompson et al., ); however, the ability of MFGM to counter the enduring effects of early‐life stress remains unexplored.…”

“…maternal separation, neurodevelopment, postnatal, visceral hypersensitivity the effects of stress and immune activation in adult animals. Moreover, research now shows that a combination of prebiotics and MFGM improves sleep and attenuates the impact of stress in rats (Mika et al, 2017;Thompson et al, 2016); however, the ability of MFGM to counter the enduring effects of early-life stress remains unexplored.…”

Gutsy Moves: The Amygdala as a Critical Node in Microbiota to Brain Signaling

“…[89] GF animals also exhibit increased depressive-like behavior. [90] Additional preclinical studies have shown that anxiety-and/or depression-like behaviors are also altered by certain probiotic treatments, [62] prebiotics, [91][92][93] and antibiotics. [94] In humans, alterations in the microbiota have been observed across a variety of amygdala-related clinical disorders, including depression.…”

“…[90,96] Finally, different probiotic strains have been shown to reduce symptoms of anxiety and depression across several studies in clinical and healthy populations. [97,98] While there have also [5,9,10,88,90] Anxiolytic effects, sometimes sex-specific, in mice (light-dark box, elevated-plus maze) [72,113] Anxiolytic effects in mice (open field, defensive marble burying, elevated-plus maze, light-dark box) [91,93] Strain-specific anxiolytic effects in humans (e.g., Beck Anxiety Index, Hospital Anxiety & Depression Scale) and rodents (defensive marble burying, elevated-plus maze, open field) [11,62,133,134] Transplant from humans with depression or comorbid IBS and anxiety increases anxietylike behavior in mice (open field, step-down test, light-dark box) [96,125] Heightened anxiety in rats (open field) [89] Depression Increased depressive-like behavior in mice (forced swim) [90] Increased depressive-like behavior in rats (forced swim) [94] Antidepressant effects in mice and rats (forced swim, tail suspension, learned helplessness after inescapable shock) [91,92] Strain-specific antidepressant effects in humans (e.g. Beck Depression Inventory, Hospital Anxiety & Depression Scale) and rodents (tail suspension test, forced swim, sucrose preference) [11,97,98,133,134] Transplant from depressed human donors induces depressive-like behavior in mice (sucrose preference, forced swim [varied results], tail suspension test) [90,96] Learned fear Impaired fear recall in adult mice [101] Acute administration enhances fear extinction in rodents and exposure therapy in humans, [103,104] reduces fear recall in huma...…”