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. 2018 Apr 25;9(3):495-513.
doi: 10.3920/BM2017.0116. Epub 2018 Jan 30.

Variations in diet cause alterations in microbiota and metabolites that follow changes in disease severity in a multiple sclerosis model

J E Libbey  1 , J M Sanchez  1 , D J Doty  1 , J T Sim  1 , M F Cusick  1   2 , J E Cox  3 , K F Fischer  1   4 , J L Round  1 , R S Fujinami  1
Affiliations

Variations in diet cause alterations in microbiota and metabolites that follow changes in disease severity in a multiple sclerosis model

J E Libbey et al. Benef Microbes. .

Abstract

Multiple sclerosis (MS) is a metabolically demanding disease involving immune-mediated destruction of myelin in the central nervous system. We previously demonstrated a significant alteration in disease course in the experimental autoimmune encephalomyelitis (EAE) preclinical model of MS due to diet. Based on the established crosstalk between metabolism and gut microbiota, we took an unbiased sampling of microbiota, in the stool, and metabolites, in the serum and stool, from mice (Mus musculus) on the two different diets, the Teklad global soy protein-free extruded rodent diet (irradiated diet) and the Teklad sterilisable rodent diet (autoclaved diet). Within the microbiota, the genus Lactobacillus was found to be inversely correlated with EAE severity. Therapeutic treatment with Lactobacillus paracasei resulted in a significant reduction in the incidence of disease, clinical scores and the amount of weight loss in EAE mice. Within the metabolites, we identified shifts in glycolysis and the tricarboxylic acid cycle that may explain the differences in disease severity between the different diets in EAE. This work begins to elucidate the relationship between diet, microbiota and metabolism in the EAE preclinical model of MS and identifies targets for further study with the goal to more specifically probe the complex metabolic interaction at play in EAE that may have translational relevance to MS patients.

Keywords: experimental autoimmune encephalomyelitis; metabolomics; microbiome; myelin oligodendrocyte glycoprotein.

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Conflict of interest statement

There are no conflicts of interest to report by any of the authors.

Figures

Figure 1
Figure 1
Effects of diet on disease course and pathology in C57BL/6J mice sensitised with MOG35-55 and maintained on irradiated or autoclaved diet. (A) Clinical scores given as the mean ± standard error of the mean (SEM) for groups of 18 mice (autoclaved) and 16 mice (irradiated). * P<0.05, t-test. (B) Weight changes represented as percent of daily weight in comparison to weight at day-1, given as mean ± SEM for groups of 18 mice (autoclaved) and 16 mice (irradiated). (C) Mortality represented as percent daily survival of animals in comparison to day 0 (20 mice per group). (D) Demyelination (Demyl.), perivascular cuffing (PVC), meningitis (Menin.) and overall spinal cord pathology scores for mice sacrificed on day 16 post sensitisation. Data is given as the mean + SEM for groups of 18 mice (autoclaved) and 16 mice (irradiated). * P<0.05, Mann-Whitney U test.
Figure 2
Figure 2
Effects of Lactobacillus paracasei or PBS treatment on disease course in C57BL/6J mice on autoclaved diet and sensitised with MOG35-55. (A) Clinical score is given as the mean ± standard error of the mean (SEM) for groups of 15 mice (PBS) and 13 mice (L. paracasei). (B) Weight change represented as percent of daily weight in comparison to weight at day 6 post sensitisation, given as mean ± SEM for groups of 15 mice (PBS) and 13 mice (L. paracasei). * P<0.05, ** P<0.01, § P<O.001, † P<0.0001, t-test.
Figure 3
Figure 3
Several serum metabolites, altered with significance on day 16 with disease in targeted analysis, share the common glycolysis/tricarboxylic acid (TCA) pathway. Grey arrows indicate multi-step reactions. The data presented in table format are discussed in the Metabolomics portion of the Results section; metabolites that were altered In 2 or more of the comparisons are similarly shaded in Table 5. * P<0.05. Abbreviations: 2-DG = 2-deoxyglucose; Glucose/Fructose-6-P = glucose/fructose-6-phosphate; Fru-1,6-diP = fructose-1,6-diphosphate; 3/2-PGA = 3/2-phosphoglycerate; PEP = phosphoenolpyruvate; 3-HPP Acid = 3-(3-hydroxyphenyl)propanoic acid; 3-HA Acid = 3-hydroxyanthranilic acid; Hyp = 4-hydroxyproline; 2-KG Acid = 2-ketoglutaric acid; Succ-CoA = succinyl-CoA; Auto = autoclaved; Irrad = irradiated.
Figure 4
Figure 4
Several faeces metabolites, altered with significance on day 16 with disease in targeted analysis, share the common glycolysis/tricarboxylic acid (TCA) pathway. Grey arrows indicate multi-step reactions. The data presented in table format are discussed in the Metabolomics portion of the Results section; metabolites that were altered In 2 or more of the comparisons are similarly shaded in Table 5. * P<0.05. Abbreviations: AMP = adenosine monophosphate; ADP = adenosine diphosphate; ATP = adenosine triphosphate; Pi = phosphate; Glucose/Fructose-6-P = glucose/fructose-6-phosphate; Glucose/Fructose-1-P = glucose/fructose-1-phosphate; Fru-1,6-diP = fructose-1,6-diphosphate; SH-7-P = sedoheptulose-7-phosphate; SH = sedoheptulose; 3/2-PGA = 3/2-phosphoglycerate; PEP = phosphoenolpyruvate; 12:0 FA = lauric acid; 16:1 FA = palmitelaidic acid; 5-HIAA = 5-hydroxyindoleacetic acid; 1-MPG = 1-monopalmitoylglycerol; 1-MSG = 1-monostearylglycerol; 2/3-HB Acid = 2/3-hydroxybutyric acid; Free FA = free fatty acids; 2-KG Acid = 2-ketoglutaric acid; Succ-CoA= succinyl-CoA; a-KB Acid = α-ketobutyric acid; GDP = guanosine diphosphate; GTP = guanosine triphosphate; Auto = autoclaved; Irrad = irradiated.
Figure 4
Figure 4
Several faeces metabolites, altered with significance on day 16 with disease in targeted analysis, share the common glycolysis/tricarboxylic acid (TCA) pathway. Grey arrows indicate multi-step reactions. The data presented in table format are discussed in the Metabolomics portion of the Results section; metabolites that were altered In 2 or more of the comparisons are similarly shaded in Table 5. * P<0.05. Abbreviations: AMP = adenosine monophosphate; ADP = adenosine diphosphate; ATP = adenosine triphosphate; Pi = phosphate; Glucose/Fructose-6-P = glucose/fructose-6-phosphate; Glucose/Fructose-1-P = glucose/fructose-1-phosphate; Fru-1,6-diP = fructose-1,6-diphosphate; SH-7-P = sedoheptulose-7-phosphate; SH = sedoheptulose; 3/2-PGA = 3/2-phosphoglycerate; PEP = phosphoenolpyruvate; 12:0 FA = lauric acid; 16:1 FA = palmitelaidic acid; 5-HIAA = 5-hydroxyindoleacetic acid; 1-MPG = 1-monopalmitoylglycerol; 1-MSG = 1-monostearylglycerol; 2/3-HB Acid = 2/3-hydroxybutyric acid; Free FA = free fatty acids; 2-KG Acid = 2-ketoglutaric acid; Succ-CoA= succinyl-CoA; a-KB Acid = α-ketobutyric acid; GDP = guanosine diphosphate; GTP = guanosine triphosphate; Auto = autoclaved; Irrad = irradiated.
Figure 5
Figure 5
Metabolic flux assay. (A) Ratio of oxygen consumption rate (OCR) to extracellular acidification rate (ECAR) in enriched T cell populations stimulated with anti-CD3/CD28 beads for 24 h. T cells were enriched from the spleens of C57BL/6J mice receiving either the irradiated (Irrad) or autoclaved (Auto) diet and exhibiting either high (Hi) or low (Lo) clinical disease, as indicated. Data is given as the mean + standard error of the mean for samples run in triplicate. * P<0.05, ** P<0.01, t-test. (B) Correlation graph plotting the ratio of OCR to ECAR against disease (clinical score), Spearman’s rank correlation.
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