There is emerging evidence that an unhealthy dietary pattern may increase the risk of developing depression or anxiety, whereas a healthy dietary pattern may decrease it. This nascent research suggests that dietary interventions could help prevent, or be an alternative or adjunct therapy for, depression and anxiety. The relation, however, is complex, affected by many confounding variables, and is also likely to be bidirectional, with dietary choices being affected by stress and depression. This complexity is reflected in the data, with sometimes conflicting results among studies. As the research evolves, all characteristics of the relation need to be considered to ensure that we obtain a full understanding, which can potentially be translated into clinical practice. A parallel and fast-growing body of research shows that the gut microbiota is linked with the brain in a bidirectional relation, commonly termed the microbiome-gut-brain axis. Preclinical evidence suggests that this axis plays a key role in the regulation of brain function and behavior. In this review we discuss possible reasons for the conflicting results in diet-mood research, and present examples of areas of the diet-mood relation in which the gut microbiota is likely to be involved, potentially explaining some of the conflicting results from diet and depression studies. We argue that because diet is one of the most significant factors that affects human gut microbiota structure and function, nutritional intervention studies need to consider the gut microbiota as an essential piece of the puzzle.

Episodes of depression and anxiety commonly follow the experience of stress, however not everyone who experiences stress develops a mood disorder. Individuals who are able to experience stress without a negative emotional effect are considered stress resilient. Stress-resilience (and its counterpart stress-susceptibility) are influenced by several psychological and biological factors, including the microbiome-gut-brain axis. Emerging research shows that the gut microbiota can influence mood, and that stress is an important variable in this relationship. Stress alters the gut microbiota and plausibly this could contribute to stress-related changes in mood. Most of the reported research has been conducted using animal models and demonstrates a relationship between gut microbiome and mood. The translational evidence from human clinical studies however is rather limited. In this review we examine the microbiome-gut-brain axis research in relation to stress resilience.

“Ryegrass staggers” is a neurological condition of unknown mechanism that impairs motor function in livestock. It is caused by infection of perennial ryegrass pastures by an endophytic fungus that produces neurotoxins, predominantly the indole-diterpenoid compound lolitrem B. Animals grazing on such pastures develop uncontrollable tremors and become uncoordinated in their movement. Lolitrem B and the structurally related tremor inducer paxilline both act as potent large conductance calcium-activated potassium (BK) channel inhibitors. Using patch clamping, we show that their different apparent affinities correlate with their toxicity in vivo. To investigate whether the motor function deficits produced by lolitrem B and paxilline are due to inhibition of BK ion channels, their ability to induce tremor and ataxia in mice deficient in this ion channel (Kcnma1^-/-) was examined. Our results show that mice lacking Kcnma1 are unaffected by these neurotoxins. Furthermore, doses of these substances known to be lethal to wild-type mice had no effect on Kcnma1^-/- mice. These studies reveal the BK channel as the molecular target for the major components of the motor impairments induced by ryegrass neurotoxins. Unexpectedly, when the response to lolitrem B was examined in mice lacking the β4 BK channel accessory subunit (Kcnmb4^-/-), only low-level ataxia was observed. Our study therefore reveals a new role for the accessory BK β4 subunit in motor control. The β4 subunit could be considered as a potential target for treatment of ataxic conditions in animals and in humans.

Large-conductance Ca²⁺- and voltage-activated K⁺ (BK) channels play prominent roles in shaping muscle and neuronal excitability. In the cardiovascular system, BK channels promote vascular relaxation and protect against ischemic injury. Recently, inhibition of BK channels has been shown to lower heart rate in intact rodents and isolated hearts, suggesting a novel role in heart function. However, the underlying mechanism is unclear. In the present study, we recorded ECGs from mice injected with paxilline (PAX), a membrane-permeable BK channel antagonist, and examined changes in cardiac conduction. ECGs revealed a 19 ± 4% PAX-induced reduction in heart rate in wild-type but not BK channel knockout ( Kcnma1^−/−) mice. The heart rate decrease was associated with slowed cardiac pacing due to elongation of the sinus interval. Action potential firing recorded from isolated sinoatrial node cells (SANCs) was reduced by 55 ± 15% and 28 ± 9% by application of PAX (3 μM) and iberiotoxin (230 nM), respectively. Furthermore, baseline firing rates from Kcnma1^−/− SANCs were 33% lower than wild-type SANCs. The slowed firing upon BK current inhibition or genetic deletion was due to lengthening of the diastolic depolarization phase of the SANC action potential. Finally, BK channel immunoreactivity and PAX-sensitive currents were identified in SANCs with HCN4 expression and pacemaker current, respectively, and BK channels cloned from SANCs recapitulated similar activation as the PAX-sensitive current. Together, these data localize BK channels to SANCs and demonstrate that loss of BK current decreases SANC automaticity, consistent with slowed sinus pacing after PAX injection in vivo. Furthermore, these findings suggest BK channels are potential therapeutic targets for disorders of heart rate.