Hypothesis

During intermittent fasting or caloric restriction (CR), the brain actively shapes the gut microbiome through efferent vagal pathways and neuropeptide release, rather than merely responding to microbial metabolites. This bottom‑up control selects for longevity‑promoting taxa (e.g., Bifidobacterium pseudolongum) and suppresses pro‑aging species (e.g., Parasutterella goldsteinii), and is necessary for the lifespan‑extending effects of CR.

Mechanistic Rationale

1. Fasting‑induced hypothalamic activation – Nutrient deficit raises activity in arcuate nucleus neuropeptide Y (NPY) and oxytocin (OT) neurons, which project to the dorsal motor nucleus of the vagus (DMV)【https://doi.org/10.1101/2025.05.04.652093】.
2. Vagal efferent neurotransmission – DMV neurons release acetylcholine (ACh) and vasoactive intestinal peptide (VIP) onto the intestinal epithelium and enteric nervous system. ACh stimulates α7‑nicotinic receptors on epithelial cells, increasing secretion of antimicrobial peptides (RegIIIγ) and mucus, while VIP modulates IEC barrier function and immune tone.
3. Microbiota selection pressure – Enhanced antimicrobial peptide milieu preferentially suppresses mucus‑degrading, pro‑inflammatory taxa such as P. goldsteinii (whose metabolites impair hippocampal neurogenesis)【https://www.news-medical.net/news/20260312/Gut-microbes-may-drive-memory-decline-during-aging-by-disrupting-vagal-brain-signaling.aspx】, while fostering symbionts that thrive in a well‑mucus environment like B. pseudolongum (linked to improved cognition when transferred to young mice)【https://pmc.ncbi.nlm.nih.gov/articles/PMC12266779/】.
4. Feedback to brain – The reshaped microbiome produces short‑chain fatty acids and tryptophan metabolites that further bolster central BDNF and oxytocin signaling, creating a reinforcing loop that sustains the pro‑longevity state.

Testable Predictions

• Prediction 1: Chemogenetic inhibition of DMV vagal efferent neurons in mice undergoing 24‑h intermittent fasting will block the CR‑induced rise in fecal B. pseudolongum and the fall in P. goldsteinii relative to fasted controls.
• Prediction 2: Optogenetic stimulation of the same vagal efferent pathway in ad libitum‑fed mice will recapitulate the microbiome shifts seen with fasting, even without nutrient restriction.
• Prediction 3: Fecal microbiota transplantation (FMT) from vagal‑inhibited fasted mice into germ‑free recipients will fail to transfer the lifespan extension observed with FMT from untreated fasted mice.
• Prediction 4: Pharmacological blockade of α7‑nicotinic receptors in the gut will abolish the antimicrobial peptide surge and microbial remodeling during CR, despite intact central fasting signals.

Falsifiability

If any of the above interventions—vagal efferent silencing, vagal stimulation, α7‑nicotinic blockade, or FMT transfer—do not produce the predicted microbiome or longevity outcomes, the hypothesis that brain‑derived efferent signals are the primary drivers of CR‑mediated microbiome remodeling would be falsified. Conversely, consistent support across these tests would establish a bidirectional, brain‑centric model of the gut‑brain axis in aging, redirecting longevity research toward neuro‑gastrointestinal therapeutics.