A non-pharmacological intervention for insomnia: tryptophan-fructooligosaccharides combination improves sleep in mice <i>via</i> anti-inflammation and gut microbiota modulation

Insomnia, a widespread condition affecting approximately 30% of the global population, is characterized by persistent sleep disturbances and leads to significant impairments in physical and psychological health. While current treatments can provide beneficial outcomes, limitations including accessibility, efficacy, side effects, and short-term usage hinder their use. Tryptophan, an essential amino acid, serves as the precursor for serotonin synthesis, a neurotransmitter critical for sleep regulation, and its dietary supplementation has been linked to improved sleep quality. Fructooligosaccharides (FOS) are a prebiotic able to promote the growth of beneficial bacteria such as <i>Lactobacillus</i> and <i>Bifidobacterium</i>, which are involved in serotonin production and anti-inflammatory processes. This study explores the potential of a novel combination of tryptophan and FOS (TF) as a non-pharmacological intervention for insomnia. C57BL/6J mice were treated with TF at low (10 mg kg^-1 tryptophan, 500 mg kg^-1 FOS; LD) or high (20 mg kg^-1 tryptophan, 1000 mg kg^-1 FOS; HD) doses in caffeine-induced sleep disturbance and <i>p</i>-chlorophenylalanine (PCPA)-induced insomnia mouse models for 14 and 7 days respectively. The efficacy of TF treatment on sleep duration, inflammation, and gut microbiota composition was evaluated. Sleep duration was improved by high dose TF in both caffeine-induced (81.0%, <i>p</i> < 0.001) and PCPA-induced (50.8%, <i>p</i> < 0.01) models. In the PCPA-induced model, TF-HD treatment significantly reduced plasma levels of TNFα in mice by 38% (<i>p</i> < 0.05). Furthermore, TF-LD and -HD-treated mice exhibited a 26% (<i>p</i> < 0.001) and 28% (<i>p</i> < 0.001) respective reduction in plasma IL-6 levels. In PCPA-induced mice, TF-LD and -HD treatments increased the abundance of <i>Lactobacillus</i> by 5.04 (<i>p</i> < 0.05) and 9.75 (<i>p</i> < 0.05) -fold respectively and <i>Bifidobacterium</i> by 610-fold (<i>p</i> < 0.05) and 979-fold (<i>p</i> < 0.05) respectively. Our findings suggest that the sleep-promoting effects of TF are mediated through anti-inflammatory mechanisms and gut microbiota modulation. This study highlights the potential of TF as an effective non-pharmacological intervention for insomnia.