Mapping the Baseline Gut Microbiome Landscape in People at Risk for Multiple Sclerosis
Zongqi Xia1, Charles White3, Wei Zong2, Chris Gaiteri4, Wei Jia5, Yian Gu6, Aleksandar Kostic7, George Tseng2, Philip De Jager6
1Department of Neurology, 2Department of Biostatistics, University of Pittsburgh, 3Broad Institute, 4Rush University, 5University of Hawaii, 6Columbia University, 7Harvard Medical School
We examined the gut microbiome in asymptomatic individuals with first-degree family history of MS.
Gut microbiome may contribute to multiple sclerosis (MS) onset. The gut microbiome landscape in at-risk population such as family members needs detailed examination.
In a cross-sectional study of asymptomatic participants across the MS genetic susceptibility distribution, each participant completed the food frequency questionnaire (FFQ), and donated stool and blood samples. From FFQ, we calculated a diet quality score (DQS). From stool, we generated the gut metagenome profiles using shotgun sequencing. From serum, we measured the concentration of molecules produced by gut bacteria on a metabolome platform. We normalized the microbiome features (relative abundance of community and functions) by arcsine square root, filtered by feature frequency, clustered co-abundant groups (CAG) using a Bayesian community-detection method, and calculated the mean abundance of component gut microbiome features as a meta-feature of each CAG. We performed multivariate modeling with host factors and microbiome CAG meta-features, adjusting for age, sex, smoking, and body mass index.
The cohort included 80 self-reported Europeans (100%), 57 women (73%), with 37.7 years (SD 8.6) as mean age at sampling. Species CAG 1 is the most significantly associated CAG with host genetic risk score for MS susceptibility (beta=-0.0067+/-0.0026, p=0.013, FDR=0.079).  Importantly, species CAG 1 includes a community of the gut bacteria reportedly associated with MS, some of which also play key roles in short-chain fatty acid (SCFA) production and metabolism (*): Akkermansia muciniphila, Faecalibacterium prausnitzii*, Lachnospiraceae*, Methanobrevibacter, Parabacteroides, Prevotella and Ruminococcus* members. When assessing the gut bacterial functions, CAG 111 is the most significantly associated CAG with DQS (beta=0.0028+/-0.0008, p=0.00068, FDR=0.082).

Human MS-susceptibility genetic factors are associated with a network of gut bacteria species. Our study begins to uncover the complexity of the gut microbiome in MS at-risk populations and highlights the importance of longitudinal examination.