The gut and mitochondria have emerged as two important hubs at the cutting edge of research
across a diverse array of medical conditions, including most psychiatric conditions. This article highlights
the interaction of the gut and mitochondria over the course of development, with an emphasis on
the consequences for transdiagnostic processes across psychiatry, but with relevance to wider medical
conditions. As well as raised levels of circulating lipopolysaccharide (LPS) arising from increased gut
permeability, the loss of the short-chain fatty acid, butyrate, is an important mediator of how gut dysbiosis
modulates mitochondrial function. Reactive cells, central glia and systemic immune cells are also
modulated by the gut, in part via impacts on mitochondrial function in these cells. Gut-driven alterations
in the activity of reactive cells over the course of development are proposed to be an important determinant
of the transdiagnostic influence of glia and the immune system. Stress, including prenatal stress,
also acts via the gut. The suppression of butyrate, coupled to raised LPS, drives oxidative and nitrosative
stress signalling that culminates in the activation of acidic sphingomyelinase-induced ceramide. Raised
ceramide levels negatively regulate mitochondrial function, both directly and via its negative impact on
daytime, arousal-promoting orexin and night-time sleep-promoting pineal gland-derived melatonin.
Both orexin and melatonin positively regulate mitochondria oxidative phosphorylation. Consequently,
gut-mediated increases in ceramide have impacts on the circadian rhythm and the circadian regulation of
mitochondrial function. Butyrate, orexin and melatonin can positively regulate mitochondria via the disinhibition
of the pyruvate dehydrogenase complex, leading to increased conversion of pyruvate to acetyl-
CoA. Acetyl-CoA is a necessary co-substrate for the initiation of the melatonergic pathway in mitochondria
and therefore the beneficial effects of mitochondria melatonin synthesis on mitochondrial function.
This has a number of treatment implications across psychiatric and wider medical conditions, including
the utilization of sodium butyrate and melatonin.
Overall, gut dysbiosis and increased gut permeability have significant impacts on central and systemic
homeostasis via the regulation of mitochondrial function, especially in central glia and systemic immune