Tobacco smoking disrupts bile acid and tryptophan metabolism in multiple sclerosis.

BACKGROUND

Smokers with multiple sclerosis (MS) experience worse disease, yet underlying mechanisms remain unknown. Smoking disrupts bile acid and tryptophan metabolism in non-MS populations; both pathways involve host-microbiome co-metabolism and have been linked to MS.

OBJECTIVE

Determine whether smoking perturbs these metabolic pathways in MS and whether such alterations statistically mediate smoking's effect on MS severity.

METHODS

We analyzed serum bile acid, tryptophan, and tobacco-related metabolites across four independent MS cohorts (N = 266) using discovery-replication analyses. Mixed-effects regression assessed replicating associations with current smoking and nicotine exposure. Mediation analyses tested if replicating metabolites were potential mediators between smoking and MS severity. Hypothesis-generating metagenomic analyses explored smoking-associated gut-microbial shifts and metabolite correlations.

RESULTS

Current smokers and nicotine-exposed MS subjects had reductions in bile acids and tryptophan metabolites, notably indolepropionate, a neuroprotective, anti-inflammatory gut-microbial metabolite. Lower indolepropionate statistically mediated ~20% of smoking's adverse effect on MS severity. Metagenomic analyses identified potential smoking-enriched MS-linked taxa, and that indolepropionate broadly co-occurs with microbial networks (e.g. Lachnoclostridium appeared inversely associated with indolepropionate in smokers with MS).

CONCLUSION

Tobacco exposure disrupts host-microbiome tryptophan and bile acid metabolism in persons with multiple sclerosis, with indolepropionate depletion partially mediating disease severity, highlighting a potential mechanistic pathway warranting further investigation in MS smokers.