Bipolar disorder is marked by recurrent changes in mood, activity, sleep, and cognition, yet the biological events that precede short-term mood destabilisation remain insufficiently resolved. Cross-sectional microbiome studies have associated bipolar disorder with altered bacterial diversity and relative abundance, but they cannot distinguish stable inter-individual variation from biological changes that occur before worsening symptoms. This prospective cohort study will examine whether within-person variation in gut microbial functional capacity and circulating microbial-host metabolites tracks with disturbed sleep timing and subsequently with mood instability. Seventy-two adults with bipolar I or bipolar II disorder in clinical remission and 36 age- and sex-balanced community comparators will be followed for 24 weeks. Participants will complete daily mood and sleep records, wear a wrist actigraphy device continuously, and provide stool, fasting blood, and saliva at four visits. Stool will undergo shotgun metagenomic sequencing and targeted quantification of short-chain fatty acids and bile acids. Blood will be analysed for lipopolysaccharide-binding protein, soluble CD14, high-sensitivity C-reactive protein, interleukin-6, tumour necrosis factor-alpha, tryptophan, kynurenine, and cortisol. Medication exposure, dietary intake, tobacco use, body mass index, menstrual phase, and recent antimicrobial exposure will be recorded at every visit. The primary analysis will estimate whether departures from each participant’s usual sleep midpoint, sleep regularity, and microbial functional profile precede a rise in the following week’s composite mood-instability score. Repeated-measures mixed models, dynamic Bayesian networks, and prespecified negative-control analyses will separate temporal association from medication-related and seasonal influences. The study is designed to identify reproducible temporal signatures rather than a diagnostic microbial label. Its results will determine whether future interventional work should target microbial metabolism, circadian regularity, or their joint regulation in bipolar disorder.
Bipolar disorder is marked by recurrent changes in mood, activity, sleep, and cognition, yet the biological events that precede short-term mood destabilisation remain insufficiently resolved. Cross-sectional microbiome studies have associated bipolar disorder with altered bacterial diversity and relative abundance, but they cannot distinguish stable inter-individual variation from biological changes that occur before worsening symptoms. This prospective cohort study will examine whether within-person variation in gut microbial functional capacity and circulating microbial-host metabolites tracks with disturbed sleep timing and subsequently with mood instability. Seventy-two adults with bipolar I or bipolar II disorder in clinical remission and 36 age- and sex-balanced community comparators will be followed for 24 weeks. Participants will complete daily mood and sleep records, wear a wrist actigraphy device continuously, and provide stool, fasting blood, and saliva at four visits. Stool will undergo shotgun metagenomic sequencing and targeted quantification of short-chain fatty acids and bile acids. Blood will be analysed for lipopolysaccharide-binding protein, soluble CD14, high-sensitivity C-reactive protein, interleukin-6, tumour necrosis factor-alpha, tryptophan, kynurenine, and cortisol. Medication exposure, dietary intake, tobacco use, body mass index, menstrual phase, and recent antimicrobial exposure will be recorded at every visit. The primary analysis will estimate whether departures from each participant’s usual sleep midpoint, sleep regularity, and microbial functional profile precede a rise in the following week’s composite mood-instability score. Repeated-measures mixed models, dynamic Bayesian networks, and prespecified negative-control analyses will separate temporal association from medication-related and seasonal influences. The study is designed to identify reproducible temporal signatures rather than a diagnostic microbial label. Its results will determine whether future interventional work should target microbial metabolism, circadian regularity, or their joint regulation in bipolar disorder.
