Prebiotic inulin ameliorates SARS-CoV-2 infection in hamsters by modulating the gut microbiome

The study addresses the need for safe, accessible interventions to mitigate COVID-19 severity beyond vaccines and advanced therapeutics, particularly as variants and breakthrough infections persist. It builds on evidence linking gut microbiome composition and function to immune health and COVID-19 outcomes, and on reports that prebiotics can enhance beneficial microbial metabolites (e.g., SCFAs) and modulate systemic immunity. The authors hypothesize that dietary inulin can attenuate SARS-CoV-2–induced morbidity and mortality by reshaping the gut microbiome and its metabolites—especially SCFAs and bile acids such as DCA—and test this using a Syrian hamster infection model.

The paper reviews evidence that severe COVID-19 is associated with dysbiosis and loss of immunomodulatory gut bacteria, and that microbiome-targeted approaches (probiotics, prebiotics, synbiotics) may ameliorate disease. Inulin, a soluble fiber from plants (commonly chicory), selectively stimulates beneficial taxa (e.g., bifidobacteria) and promotes SCFA production, with reported benefits including improved gut barrier function, mineral absorption, and immunomodulation. Prior studies show inulin shifts SCFA profiles toward propionate and butyrate and can enhance antiviral immunity in mice via CD8+ T-cell metabolism. Inulin can also alter bile acid circulation, with mixed outcomes; bile acids (via FXR/TGR5) regulate inflammation and can be microbially transformed, influencing host–microbe interactions. Certain bile acids reduce inflammation and have been shown to mitigate COVID-19 severity in animal models. These data support the hypothesis that inulin may reduce SARS-CoV-2 disease via SCFA and bile acid–mediated mechanisms.

Design: Female 4-week-old Syrian hamsters were assigned to control or inulin groups with similar baseline weights. Diets: Control received AIN-93G; inulin group received AIN-93G supplemented with 5% (w/w) native chicory inulin (Frutafit IQ), replacing equal weight of corn starch. After 2 weeks on diets, hamsters were intranasally inoculated with 150 µL PBS containing 10^4 PFU SARS-CoV-2 and monitored for 14 days for body weight and survival; euthanasia occurred if body weight fell below 70% of baseline. Cohorts: Three independent cohorts were used: (1) survival and body weight (control n=9, inulin n=9 per Fig. 1), (2) fecal microbiome and fecal SCFA/bile acid analyses (control n=10, inulin n=9), and (3) serum bile acid analysis (inulin-fed separate cohort vs control; sample sizes not explicitly specified for serum in text). Microbiome analysis: Fecal samples collected after 2 weeks of feeding. DNA extraction used SDS/TE and phenol/chloroform/isoamyl alcohol, bead beating, and automated GENE PREP STAR PI-480. 16S rRNA gene V1–V2 region amplified with primers 27Fmod and 338R; sequenced on Illumina MiSeq. Data processed in QIIME2 (2021.11) with DADA2 (trim lengths: forward 280 bp, reverse 210 bp). Taxonomy assigned with classify-sklearn using SILVA 138 SSU Ref NR 99. Beta diversity assessed by weighted and unweighted UniFrac via core-metrics-phylogenetic; group differences tested by ANOSIM. Metabolite quantification: Fecal and serum samples lyophilized (feces) and homogenized; 10 mg feces or 50 µL serum analyzed. Fecal analytes included SCFAs (formate, acetate, propionate, isobutyrate, butyrate, isovalerate, valerate), lactate, succinate; bile acids in feces and serum. SCFAs, lactate, succinate quantified by GC/MS; bile acids by LC–MS following published protocols. Statistics: Analyses in R 4.1.0. Group comparisons by Wilcoxon rank-sum with FDR correction unless noted. Survival compared by log-rank test (survival package). Correlations by Spearman; linear regression and reporting with ggmisc stat_poly_eq.

- Clinical outcomes: Inulin-fed hamsters had 100% survival over 14 days post-infection, whereas control mortality was 44% (log-rank p=0.027). Inulin attenuated weight loss; five of nine inulin-fed hamsters exceeded 100% of baseline weight at 2 weeks. Body weight was significantly higher in inulin vs control by Day 10; Days 4 and 9 showed trends (p=0.062 and 0.054, respectively; Wilcoxon). - Microbiome composition: Significant beta-diversity separation between groups by UniFrac with ANOSIM: weighted R=0.525, p=0.001; unweighted R=0.728, p=0.001. Fifteen genera differed significantly: nine increased (e.g., Ileibacterium, Mucispirillum, Oscillospiraceae unclassified; log2 fold changes 4.79, 4.72, 4.30) and six decreased (largest decrease Ruminiclostridium, log2 fold change -2.41). - Metabolites: After FDR correction, serum deoxycholic acid (DCA) was significantly increased in inulin-fed hamsters. Pre-FDR trends: fecal DCA increased (p=0.022), fecal succinate decreased (p=0.013), fecal valerate increased (p=0.054). Butyrate increased nominally but was not significant (pre-FDR p=0.2775). - Genus–metabolite correlations (across samples): • Oscillospiraceae (unclassified) positively correlated with fecal LCA (R^2=0.40; Spearman p=0.004) and DCA (R^2=0.30; p=0.014). • Eubacteriaceae (unclassified) positively correlated with fecal DCA (R^2=0.41; p=0.003). • Ileibacterium negatively correlated with fecal succinate (R^2=0.23; p=0.039). • Lachnoclostridium positively correlated with fecal propionate (R^2=0.49; p<0.001) and fecal valerate (R^2=0.29; p=0.018). These correlations aligned with observed group shifts: the associated genera were more abundant with inulin, and their correlated metabolites tended to increase (valerate, DCA) or decrease (succinate) accordingly.

The findings support the hypothesis that dietary inulin ameliorates SARS-CoV-2 disease severity via modulation of the gut microbiome and its metabolic outputs. Improved survival and reduced weight loss in inulin-fed hamsters coincided with significant restructuring of gut communities and changes in metabolites, notably increased circulating DCA. While SCFAs such as butyrate and propionate are established immunomodulators and barrier-supporting metabolites, statistical support for SCFA changes was limited; nevertheless, correlations (e.g., Lachnoclostridium with propionate/valerate; Ileibacterium with succinate) and nominal trends suggest functional shifts consistent with prebiotic fermentation and cross-feeding dynamics. The significant increase in serum DCA suggests a potential mechanistic role for secondary bile acids. DCA can activate FXR and TGR5, pathways implicated in dampening inflammatory responses, and has been reported to reduce neutrophil-driven lung inflammation and directly inactivate enveloped viruses at sufficient concentrations. Thus, elevated DCA could contribute to reduced lung inflammation and viral burden, complementing SCFA-mediated immune support. However, causality remains unproven, and the complexity of host–microbe metabolic networks and interspecies interactions complicates attribution of specific effects to individual taxa or metabolites. Overall, the results highlight prebiotic inulin as an accessible approach to modulate the gut–lung axis and improve outcomes in viral respiratory infections, warranting further mechanistic and translational research.

This study demonstrates that dietary inulin significantly improves survival and mitigates weight loss in SARS-CoV-2–infected hamsters, concomitant with distinct shifts in gut microbiome composition and a significant rise in serum DCA. The data suggest that microbiome-mediated metabolites—particularly secondary bile acids and possibly SCFAs—may contribute to protection against COVID-19. These findings position inulin and related prebiotics as promising, low-cost candidates for preventive or adjunctive strategies against SARS-CoV-2. Future work should include mechanistic dissection of microbial producers and pathways (e.g., SCFA and bile acid biotransformations), causal experiments (e.g., metabolite supplementation, gnotobiotic models), dose–response and timing studies, and well-powered translational/clinical studies to assess efficacy and safety in humans.

- Generalizability: Results are from a hamster model; human relevance requires clinical validation. - Statistical power and corrections: After FDR correction, only serum DCA remained significant among metabolites; several SCFA changes were nominal and underpowered (e.g., butyrate). Multiple testing raises false-positive risk. - Cohort design: Different cohorts were used for survival, fecal omics, and serum bile acids, limiting within-subject integration across endpoints. - Variability: Greater dispersion in body weights within the inulin group indicates heterogeneous responses. - Fecal vs systemic measures: Fecal metabolite levels may not reflect production or systemic exposure due to absorption and utilization (especially for SCFAs like butyrate). - Causality: Correlations between taxa and metabolites do not establish causal relationships; functional attribution is limited by taxonomic resolution (unclassified groups) and the polyphyletic nature of metabolite producers. - Mechanistic ambiguity: Few known gut species perform CA→DCA 7-dehydroxylation; the taxa correlated with DCA may reflect bile acid tolerance rather than production.