Adult-Onset Vitamin-A Deficiency Reshapes the Gut Microbiome and is associated with Sex-Specific and shared Systemic Effects in Adult Wistar Rats.

BACKGROUND

Vitamin A deficiency (VAD) remains a major global health concern. Vitamin A promotes immunity, neurogenesis, energy balance, and gut integrity. However, most studies have focused on early developmental stages and adult-onset VAD remain poorly understood.

OBJECTIVE

To determine whether physiological, behavioural, and gut microbial responses to adult-onset VAD differ between male and female rats.

METHODS

Adult male and female Wistar rats (9-10 weeks) were fed a vitamin A-sufficient (VAS, n = 6) or VAD (n = 6) diet for 20 weeks. Vitamin A levels were monitored every 4 weeks. Behavioural function was assessed at 12th and 18th weeks. After 20 weeks, rats were euthanised, and serum, cecal contents, liver, duodenum, hippocampus, and visceral white adipose tissue (vWAT) were collected for assessment of vitamin A metabolites, physiological and morphological changes, gut microbiome, and serum metabolome. Data were analysed using Student's t-test or the Mann-Whitney U test, as appropriate, with Benjamini-Hochberg correction.

RESULTS

Females and males reach the deficiency threshold (<0.7 μmol/L) at 12 and 16 weeks, respectively. At week 12, females showed a 2-fold reduction in serum vitamin A levels (VAS, 1.1 vs VAD, 0.5 μmol/L;p = 0.012), despite unchanged body weight and feed intake. Microbial responses were sex-divergent; the Bacillota/Bacteroidota ratio increased only in females (4.18 in VAS vs 7.0 in VAD; p = 0.008). The virome shifted in both sexes, with distinct signatures. Anxiety-like behaviour appears by 12 weeks in females but not in males. Systemic responses (reduced gut barrier, increased immune gene expression, and adipocyte hypertrophy) were largely shared.

CONCLUSIONS

This study provides evidence that adult-onset VAD in rats may be associated with sex-specific alterations in the microbiome, but with more generalised systemic outcomes.