Alcohol, clinical & experimental research · 2025
Early upregulation of alpha-7 nicotinic acetylcholine receptor in limbic system correlates with gut dysbiosis in mice exposed to binge ethanol.
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Khan Mohammed A S, Bishir Muhammed, Huang Wenfei, Chidambaram Saravana Babu, Chang Sulie L
Аннотация
BACKGROUND: Alcohol use disorder (AUD) causes neuroinflammation and disrupts the gut microbiome through bidirectional communication between the brain and gut. However, it remains unclear whether the brain or gut responds first to alcohol exposure. We hypothesized that brain regions respond to alcohol first, preceding changes in the gut microbiome.
METHODS: B6 mice were given ethanol (EtOH; 5 g/kg/day, 42%v/v, i.g.) at various time points. Fecal samples were collected prior to the first EtOH injection (Day 0), at 24 h following the first, second, and third injections (Day 1, Day 2, and Day 3, respectively), and at 96 h after the third injection (Day 6). Brain regions, central amygdala (CeA), hypothalamus (Hyp), and nucleus accumbens (NAc) were isolated at 2 min, 12 h, 24 h, and 192 h following the first and third doses of binge EtOH, respectively. mRNA or protein expression levels of TNF-α, IL-1β, P2Y12, ITGβ2, and α7nAChR were analyzed by qRT-PCR and western blot, respectively. Fecal microbial composition and abundance were assessed using 16S rRNA metagenomic sequencing.
RESULTS: Data revealed increased TNF-α expression in the Amg, Hyp, and NAc and increased IL-1β expression in the Amg and NAc, 12 h after the first EtOH injection. α7nAChR expression in the CeA, Hyp, and NAc was also upregulated at 24 h after the third EtOH dose, compared to the control group. α7nAChR expression in the Hyp was observed at 2 min after the first EtOH dose. CHRNA7 mRNA levels were upregulated 24 h after the third EtOH dose. ITGβ2 showed an increasing trend in the Amg at 12 h after the first dose, followed by a significant reduction at 24 h, and 192 h after the third dose. 16S rRNA sequencing revealed a significant difference in β-diversity on Day 6. The relative abundance of the Prevotellaceae family was higher in EtOH-treated mice compared to controls at Day 3 and Day 6.
CONCLUSION: This study showed that brain inflammation, indicated by α7nAChR upregulation, occurred before EtOH-induced gut dysbiosis, supporting an anterograde sequence of events.
METHODS: B6 mice were given ethanol (EtOH; 5 g/kg/day, 42%v/v, i.g.) at various time points. Fecal samples were collected prior to the first EtOH injection (Day 0), at 24 h following the first, second, and third injections (Day 1, Day 2, and Day 3, respectively), and at 96 h after the third injection (Day 6). Brain regions, central amygdala (CeA), hypothalamus (Hyp), and nucleus accumbens (NAc) were isolated at 2 min, 12 h, 24 h, and 192 h following the first and third doses of binge EtOH, respectively. mRNA or protein expression levels of TNF-α, IL-1β, P2Y12, ITGβ2, and α7nAChR were analyzed by qRT-PCR and western blot, respectively. Fecal microbial composition and abundance were assessed using 16S rRNA metagenomic sequencing.
RESULTS: Data revealed increased TNF-α expression in the Amg, Hyp, and NAc and increased IL-1β expression in the Amg and NAc, 12 h after the first EtOH injection. α7nAChR expression in the CeA, Hyp, and NAc was also upregulated at 24 h after the third EtOH dose, compared to the control group. α7nAChR expression in the Hyp was observed at 2 min after the first EtOH dose. CHRNA7 mRNA levels were upregulated 24 h after the third EtOH dose. ITGβ2 showed an increasing trend in the Amg at 12 h after the first dose, followed by a significant reduction at 24 h, and 192 h after the third dose. 16S rRNA sequencing revealed a significant difference in β-diversity on Day 6. The relative abundance of the Prevotellaceae family was higher in EtOH-treated mice compared to controls at Day 3 and Day 6.
CONCLUSION: This study showed that brain inflammation, indicated by α7nAChR upregulation, occurred before EtOH-induced gut dysbiosis, supporting an anterograde sequence of events.