Gut Microbiota and Pediatric MS: New Insights Into Potential Disease Drivers

A new multicenter, matched case-control study investigates the association between gut microbiota composition and pediatric-onset multiple sclerosis (POMS). Recognizing the complexity and variability of gut microbiome studies in adult MS cohorts, this study provides a window into early disease pathogenesis, relatively free from decades of accumulated confounders like comorbidities and environmental exposures.

35 POMS cases (within five years of symptom onset) were matched 1:1 to healthy controls on age, sex, race, ethnicity, and recruiting site. Stool samples underwent 16S ribosomal RNA sequencing to assess microbial diversity, composition, and co-occurrence networks. Metagenomic functional prediction (PICRUSt2) and dietary assessments were included to address potential confounders.

Key Findings

Reduced Phylogenetic Diversity

While α-diversity, measured by Shannon and Chao1 indices, showed no significant difference between groups, phylogenetic diversity, measured by Faith’s PD index, was significantly lower in POMS patients (p=0.02), suggesting a reduced evolutionary breadth of microbial species. This nuance matters: decreased phylogenetic diversity can translate to diminished functional redundancy and resilience in microbial ecosystems.

 β-diversity, on the other hand, revealed no significant overall compositional differences between cases and controls (p = 0.25), reinforcing the need to dig deeper into microbial networks and functional pathways

Altered Microbial Composition

Several taxa, particularly within the Ruminococcaceae and Lachnospiraceae families, were less abundant in POMS. Notably, Subdoligranulum and Faecalibacterium prausnitzii—known short-chain fatty acid (SCFA) producers—were depleted. Conversely, Blautia and Prevotella species were enriched in POMS.

Co-occurrence Networks and Functional Predictions

Rather than spotlighting a single bacterial hero or villain, the study identified networks—microbial co-abundance modules—that may be biologically more meaningful. Using weighted correlation network analysis (WGCNA), two co-abundance clusters stood out, with one maintaining significance after correction for multiple testing. These networks were largely populated by known SCFA-producing taxa, such as Subdoligranulum, Faecalibacterium prausnitzii, and several members of the Ruminococcaceae and Lachnospiraceae families. POMS patients consistently exhibited lower abundances of these bacteria.

Additionally and conversely, Blautia and Prevotella were enriched in POMS cases, while SCFA producers like Subdoligranulum and F. prausnitzii were depleted—especially among treatment-naive patients, adding credence to the findings.

The SCFA Connection

The study’s most compelling narrative emerged from the predicted functional analyses. Key microbial pathways related to SCFA production—specifically, butanoate and acetone fermentation from pyruvate—were identified as significantly more abundant in controls. These pathways are classic signatures of microbial fermentation, particularly of nondigestible dietary fibers into beneficial SCFAs such as butyrate and propionate, which have well-established anti-inflammatory effects. The presence of these pathways in controls raises intriguing possibilities about their protective role in MS pathogenesis.

Dietary Considerations

Dietary intake—often a confounder in microbiome studies—was similar between cases and controls. While some microbial abundances correlated with nutrient intake (e.g., higher Subdoligranulum levels with greater fat/protein intake), these patterns were not sufficient to explain the group-level microbial differences.

The data positions SCFA-producing gut bacteria as potential contributors to MS pathogenesis—at least in its pediatric form. Next steps include incorporating metabolomic data, expanding cohort sizes, and investigating how modifying SCFA levels—perhaps through diet or supplementation—could influence disease onset or progression.

References
Schoeps VA, Zhou X, Horton MK, Zhu F, McCauley KE, Nasr Z, Virupakshaiah A, Gorman MP, Benson LA, Weinstock-Guttman B, Waldman A, Banwell BL, Bar-Or A, Marrie RA, van Domselaar G, O'Mahony J, Mirza AI, Bernstein CN, Yeh EA, Casper TC, Lynch SV, Tremlett H, Baranzini S, Waubant E; US Network of Pediatric MS Centers. Short-chain fatty acid producers in the gut are associated with pediatric multiple sclerosis onset. Ann Clin Transl Neurol. 2024 Jan;11(1):169-184. doi: 10.1002/acn3.51944.