Oral selective serotonin reuptake inhibitors activate vagus nerve dependent gut-brain signalling

Abstract

The vagus nerve can transmit signals to the brain resulting in a reduction in depressive behavior as evidenced by the long-term beneficial effects of electrical stimulation of the vagus in patients with intractable depression. The vagus is the major neural connection between gut and brain, and we have previously shown that ingestion of beneficial bacteria modulates behaviour and brain neurochemistry via this pathway. Given the high levels of serotonin in the gut, we considered if gut-brain signaling, and specifically the vagal pathway, might contribute to the therapeutic effect of oral selective serotonin reuptake inhibitors (SSRI). Mesenteric nerve recordings were conducted in mice after treatment with SSRI to ascertain if this class of drugs resulted in increased vagal excitability. Patch clamp recordings of enteric neurons were carried out to measure activity of primary afferent neurons in the gut in response to SSRI and to assess the importance of gut epithelium in transducing signal. The tail suspension test (TST) was used following 14d feeding of SSRI in vagotomised and surgical sham mice to measure depressive-like behaviour. Brain mRNA expression was examined via PCR and the intestinal microbiome was assessed. Mesenteric nerve recordings in BALB/c mice demonstrated that oral treatment with SSRI leads to a significant increase in vagal activity. This effect was not observed in mice treated with a representative noradrenaline-dopamine reuptake inhibitor. It is known that signals from the gut can be transmitted to the vagus via the enteric nervous system. Exposure of the gut to SSRI increased the excitability of intrinsic primary afferent neurons in the myenteric plexus, through an intestinal epithelium dependent mechanism, and alpha-diversity of gut microbiota was altered. Critically, blocking vagal signaling from gut to brain, via subdiaphragmatic vagotomy, abolished the antidepressive effects of oral SSRI treatment as determined by the tail suspension test. This work suggests that vagus nerve dependent gut-brain signaling contributes to the effects of oral SSRI and further, highlights the potential for pharmacological approaches to treatment of mood disorders that focus on vagal stimulation and may not even require therapeutic agents to enter the circulation.

Vagus nerve stimulation boosts the drive to work for rewards

“…Moreover, as suggested by preclinical research, stimulation at the left ear exerts stronger effects on invigoration when food rewards are at stake. We conclude that taVNS may provide a promising brain stimulation technique to acutely improve motivational syndromes characterized by a lack of vigor to pursue rewards such as apathy 55,59 or anhedonia 60 as these symptoms might be partly caused by aberrant vagal signaling 61,62 . Notwithstanding, it is unknown to date whether acute improvements can predict sustained therapeutic effects of potential taVNS-based treatments, which remains as a vital question for the translation to clinical settings.…”

Neurovisceral regulatory circuits of affective resilience in youth

“…Beyond the heart, research should address the consequences of decreased vagal activity including the systematic investigation of different organs. Preliminary research in animals has shown, that subdiaphragmatic vagotomy abolishes the antidepressive effects of pharmacological treatment with selective serotonin reuptake inhibitors (Neufeld et al, 2019). It is research like this that questions our current understanding and conceptualization of psychiatric disorders.…”

The Brain-Gut Team

“…Some of these metabolites participate in the gutbrain axis activity with potential to modulate central physiological and pathologic processes. Mechanisms potentially include binding to host receptors in the brain, stimulation of vagus nerve in the gut, alteration of central neurotransmission, and modulation of neuroinflammation [8,9]. Microbiota-gut-brain axis signaling can occur via several pathways including the immune system, recruitment of host neurochemical signaling, direct enteric nervous system routes and the vagus nerve, and the production of bacterial metabolite such as short-chain fatty acids, branchedchain amino acids, and peptide glycans [10,11].…”

“…This vagal activity appears to have protective properties on the intestinal barrier, inflammatory mechanisms, and the microbiome. This potentially useful pathway deserves to be explored therapeutically [8,13].…”