A Possible Link between Food and Mood: Dietary Impact on Gut Microbiota and Behavior in BALB/c Mice

<div><p>Major depressive disorder is a debilitating disease in the Western World. A western diet high in saturated fat and refined sugar seems to play an important part in disease development. Therefore, this study is aimed at investigating whether saturated fat or sucrose predisposes mice to develop behavioral symptoms which can be interpreted as depression-like, and the possible influence of the gut microbiota (GM) in this. Fourty-two mice were randomly assigned to one of three experimental diets, a high-fat, a high-sucrose or a control diet for thirteen weeks. Mice on high-fat diet gained more weight (p = 0.00009), displayed significantly less burrowing behavior than the control mice (p = 0.034), and showed decreased memory in the Morris water maze test compared to mice on high-sucrose diet (p = 0.031). Mice on high-sucrose diet burrowed less goal-oriented, showed greater latency to first bout of immobility in the forced swim test when compared to control mice (p = 0.039) and high-fat fed mice (p = 0.013), and displayed less anxiety than mice on high-fat diet in the triple test (p = 0.009). Behavioral changes were accompanied by a significant change in GM composition of mice fed a high-fat diet, while no difference between diet groups was observed for sucrose preferences, LPS, cholesterol, HbA1c, BDNF and the cytokines IL-1α, IL-1β, IL-6, IL-10, IL-12(p70), IL-17 and TNF-α. A series of correlations was found between GM, behavior, BDNF and inflammatory mediators. In conclusion, the study shows that dietary fat and sucrose affect behavior, sometimes in opposite directions, and suggests a possible association between GM and behavior.</p></div

Timeline illustrating the experimental period.

<p>Numbers indicate week number, with mice subjected to the experimental diets from time 0. HbA1c: Glycosylated hemoglobin 1c, WM: Water Maze.</p

The Morris water maze test, distance swum and latency to reach the platform.

<p>A general day to day significant decrease in distance swum and latency to reach platform was seen for all diet groups, indicating that all diet groups learned the task. However, a high-fat diet seemed to influence negatively on coping with the start position sequence on day three. Median with ranges.</p

Dietary-induced differences in cecal microbial composition.

<p>The table shows bacterial OTU's which differs with a significant <i>p</i>-value between diet groups. A high-fat diet impacts the GM composition, significantly increasing the abundance of Firmicutes, primarily within the family Ruminococcaceae, and reducing the abundance of the family S24-7 within the Bacteoidetes phylum. <i>P</i>-values and the FDR-corrected <i>p</i>-values are listed.</p

The Morris water maze test, preference for the previous platform area.

<p>Mice on high-fat diet spent significant less time in the area of the previous situated platform during the first 30 seconds of the retention trial compared to mice on high-sucrose diet. Memory of mice on control diet was similar to mice on high-sucrose diet. This indicate, that consuming a high-fat diet leads to decreased memory. Mean with SE.</p

Multiple linear regression analysis between GM and behavior, cytokines, and BDNF.

<p>Several significant associations are seen between GM and both behavior and systemically circulating inflammatory mediators, indicating a possible influence from the gut on the immune system and the brain. Furthermore a certain GM composition seems to be associated with both improved memory and increased levels of BDNF in mice not subjected to any of the experimental diets. The PCoA analysis denotes whether data was weighted (W) or not (UW) by bacterial abundance and the principal component (PC) listed denotes the significant factor(s) in the multiple linear regression models. Not shown and non-significant are: Risk assessment on OA, Time spent in OF center and PFC BDNF. GM was not correlated to IL-1β, IL-10 and TNF-α, as all samples were at basal concentrations regarding these cytokines. <i>Italic: negative correlation</i>. <b>Bold: Positive correlation</b>.</p

The Burrowing test.

<p>Mice on HF diet removed significantly less bedding material from the tube than mice on C diet (p = 0.035). A tendency of reduced burrow-digging is seen for mice on HS diet (p = 0.064). However, although not quantified, this diet group burrowed less goal-oriented, as observations showed excessive digging in the whole cage. Median with ranges.</p

Cytokine concentrations in plasma, prefrontal cortex and hippocampus.

<p>Median, minimum and maximum levels in each diet group are given, measured in pg/ml plasma or pg/mg brain tissue. No differences in inflammatory state are observed between groups, and levels are in general subclinically, which was also expected. Particular IL-1β, IL-10 and TNF-α are at very low concentrations. Min: Minimum, max: Maximum. <i>: Below detection limit.</i></p

3D plots of the unweighted and weighted PCoA of cecum.

<p>Plots are constructed from the three most primary principal components of the PCoA, with A) showing the unweighted analysis and B) showing the weighted analysis which takes the abundance of the bacteria into account. Both plots visualize that the cecal GM of mice fed a high-fat diet diverge from that of mice fed either a high-sucrose or a control diet.</p