Potential role of indolelactate and butyrate in multiple sclerosis revealed by integrated microbiome-metabolome analysis

Abstract

Summary Multiple sclerosis (MS) is an immune-mediated disease whose precise etiology is unknown. Several studies found alterations in the microbiome of individuals with MS, but the mechanism by which it may affect MS is poorly understood. Here we analyze the microbiome of 129 individuals with MS and find that they harbor distinct microbial patterns compared with controls. To study the functional consequences of these differences, we measure levels of 1,251 serum metabolites in a subgroup of subjects and unravel a distinct metabolite signature that separates affected individuals from controls nearly perfectly (AUC = 0.97). Individuals with MS are found to be depleted in butyrate-producing bacteria and in bacteria that produce indolelactate, an intermediate in generation of the potent neuroprotective antioxidant indolepropionate, which we found to be lower in their serum. We identify microbial and metabolite candidates that may contribute to MS and should be explored further for their causal role and therapeutic potential.

Multi-omic evaluation of metabolic alterations in multiple sclerosis identifies shifts in aromatic amino acid metabolism

“…Prior studies in PwMS note divergent metabolomic profiles, which is consistent with our findings, 8 , 31 , 32 , 33 , 34 , 35 , 36 and several studies note alterations in AAA-related metabolites. 8 , 37 Intriguingly, one study also found reduced levels of ILA, which was linked with lower levels of ILA-producing bacteria in the gut microbiome in PwMS.…”

“… 8 , 37 Intriguingly, one study also found reduced levels of ILA, which was linked with lower levels of ILA-producing bacteria in the gut microbiome in PwMS. 36 Distinct from our findings, other metabolomics studies have noted differences in various lipid subspecies (phosphatidylcholine, short-chain fatty acids). 31 , 36 Differences between results from these studies and the results presented here may be related to differences in the analytical platform used to assess metabolomic profiles or differences in the underlying study populations.…”

“… 36 Distinct from our findings, other metabolomics studies have noted differences in various lipid subspecies (phosphatidylcholine, short-chain fatty acids). 31 , 36 Differences between results from these studies and the results presented here may be related to differences in the analytical platform used to assess metabolomic profiles or differences in the underlying study populations. We also only included metabolites that were consistently measured across populations in our study.…”

Convergent pathways of the gut microbiota–brain axis and neurodegenerative disorders

“…Several Trp-derived metabolites have been shown to regulate inflammation, with implications for autoimmune and neurodegenerative disorders [ 41 ]. One of the largest integrated metabolomics-metagenomic studies revealed that plasma indolelactate, indolepropionate, and its producing bacteria are lower in patients with MS compared with controls [ 80 ]. In the EAE mouse model, dietary Trp is required for induction of autoimmune neuroinflammation as mice fed a free-Trp diet have decreased numbers of circulating myelin oligodendrocyte glycoprotein (MOG) 35–55 reactive CD4 + T-cells—a finding that was dependent on the presence of an intact gut microbiota as antibiotics-treated mice do not exhibit the phenotype [ 89 ].…”

“…In line with this, the levels of circulating SCFAs are also lower [ 79 ]. A recent study demonstrated that individuals with MS have fewer species and lower levels of genes involved in butyrate production [ 80 ]. However, compared with healthy controls, MS patients have increased acetate levels, which correlated with greater disability and increased T helper 17 (T H 17) cells [ 81 ].…”