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.

Genetic background is estimated to play >50% in common obesity etiology. FTO single nucleotide polymorphisms (SNPs) are strongly associated with BMI, typically in European cohorts. We investigated the interaction of common FTO SNPs with actionable environmental factors, namely physical activity, sugar-sweetened beverages (SSB) and wine consumption, and verified FTO common SNPs predisposition to obesity in the Israeli population. Adults’ (>18y, n = 1720) FTO common SNPs data and lifestyle and nutrition habits questionnaires were analyzed using binary logistic regression models, adjusted for confounding variables (age, sex) assuming dominant, recessive and additive genetic models. Eighteen FTO SNPs were associated with significant increased obesity risk and interacted with physical activity (p < 0.001), wine consumption (p < 0.014) and SSB consumption (p < 0.01). Inactive rs9939609 risk-allele carriers had significantly higher obesity risk compared to their active counterparts (OR = 2.54, 95% CI 1.91–3.39 and OR = 3.77, 95% CI 2.47–5.75; p < 0.001 with 3.1 and 3.5 BMI increment for heterozygotes and homozygotes, respectively). SSB consumption (≥1 serving/day) significantly raised obesity risk and wine consumption (1–3 drinks/weekly) significantly lowered obesity risk for rs9939609 risk-allele carriers (OR = 1.54, 95% CI 1.05–2.27; p = 0.028 and OR = 0.61, 95% CI 0.47–0.79; p < 0.001, respectively). Our findings demonstrate that actionable lifestyle factors modify the common FTO obesity risk in predisposed carriers, and they have personal and public health implications.

The transmembrane protein 18 (TMEM18) gene plays a central and peripheral role in weight regulation. TMEM18 genetic polymorphisms have been identified as an important risk factor for obesity, depending on ethnic population and age. This research aimed to study the association of common TMEM18 polymorphisms with obesity and their interactions with modifiable factors, namely drinking habits (sugar-sweetened beverages (SSBs), flavored water and wine) and physical activity (PA) in the Israeli population. Adults (n = 3089) were analyzed for common TMEM18 polymorphisms and lifestyle and nutrition habits were obtained from questionnaires using adjusted (age, sex) binary logistic regression models. TMEM18 rs939583 and rs1879523 were significantly associated with increased obesity risk (OR = 1.35, 95% CI (1.17–1.57) and OR = 1.66, 95% CI (1.29–2.15), respectively). TMEM18 rs939583 interacted with consumption of 1–3 weekly glasses of wine and PA to attenuate obesity risk (OR = 0.82 95% CI (0.74–0.9; p < 0.001) and OR = 0.74 95% CI (0.68–0.8), respectively), while physical inactivity, SSBs and flavored water consumption significantly enhanced obesity risk (OR = 1.54 95% CI (1.41–1.67), OR = 1.31 95% CI (1.14–1.51) and OR = 1.35 95% CI (1.13–1.62), respectively). PA duration was significantly associated with a lower BMI for rs939583 risk carriers, with a PA cutoff of >30 min/week (p = 0.005) and >90 min/week (p = 0.01). Common TMEM18 SNPs were significantly linked with adult obesity risk and interacted with modifiable lifestyle factors.

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