# Melatonin alleviates airway inflammation and anxiety-depression in asthma via gut microbiota–SCFA axis-mediated inhibition of microglial activation

## TL;DR

Melatonin helps reduce asthma symptoms and related anxiety and depression by improving gut bacteria and brain signaling.

## Contribution

Melatonin's therapeutic effects are shown to be mediated via the gut microbiota-SCFA axis and microglial inhibition.

## Key findings

- Melatonin and sodium butyrate reduced airway inflammation and improved lung function in asthmatic mice.
- Melatonin increased butyrate levels and restored gut microbiota balance, effects replicated by fecal microbiota transplantation.
- Both treatments inhibited the MAPK/P65/NLRP3 pathway in hippocampal microglia and BV2 cells.

## Abstract

Asthma frequently co-occurs with anxiety and depression, yet the mechanisms underlying this lung-brain comorbidity remain elusive. The gut-lung-brain axis has emerged as a potential key mediator.

Using an ovalbumin (OVA)-induced murine asthma model, we administered melatonin or sodium butyrate via drinking water. We assessed airway inflammation, lung function, anxiety- and depression-like behaviors, gut microbiota composition, short-chain fatty acid (SCFA) levels, and the MAPK/P65/NLRP3 signaling pathway in the hippocampus and BV2 microglial cells. Fecal microbiota transplantation (FMT) and antibiotic depletion experiments were conducted to establish causality.

Both melatonin and sodium butyrate significantly alleviated airway inflammation, improved lung function, and ameliorated anxiety- and depression-like behaviors in asthmatic mice. Melatonin increased gut-derived butyrate levels and restored gut microbiota balance. FMT from melatonin-treated donors replicated the therapeutic benefits, whereas antibiotic-mediated microbiota depletion abrogated the effects of melatonin. Mechanistically, both treatments inhibited the activation of the MAPK/P65/NLRP3 pathway in hippocampal microglia and LPS-stimulated BV2 cells.

Our findings demonstrate that melatonin mitigates asthma-related airway inflammation and neuropsychiatric comorbidity by modulating the gut microbiota-SCFA axis and suppressing microglial activation via the MAPK/P65/NLRP3 pathway. This study highlights a novel systemic mechanism and potential therapeutic strategy for asthma and its comorbidities.