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Effect of a Fructose-Rich Diet on Gut Microbiota and Immunomodulation: Potential Factors for Multiple Sclerosis - PubMed

  • ️Sun Jan 01 2023

Effect of a Fructose-Rich Diet on Gut Microbiota and Immunomodulation: Potential Factors for Multiple Sclerosis

Stephanie R Peterson et al. Immunohorizons. 2023.

Abstract

Multiple sclerosis (MS) is an autoimmune demyelinating disease of the CNS that is linked with both genetic and environmental factors. A Western-style diet rich in fat and simple sugars is hypothesized as a potential factor contributing to the increased incidence of inflammatory autoimmune diseases, such as MS, in developed countries. Although the adverse effects of a high-fat diet in MS have been studied extensively, the effect of a fructose-rich diet (FRD) on MS etiology is unknown. We hypothesized that an FRD will alter the gut microbiome, influence immune populations, and negatively impact disease in experimental autoimmune encephalomyelitis (EAE), an animal model of MS. To test this, we fed C57BL/6 mice either an FRD or normal feed for 4 or 12 wk and analyzed the effect of an FRD on gut microbiota, immune populations, and EAE. An FRD significantly influenced the gut microbiota, with reduced abundance of beneficial bacteria and enrichment of potentially proinflammatory bacteria. We also observed immune modulation in the gut and periphery. Of particular interest was a population of Helios-RORγt+Foxp3+CD4+ T cells that was enriched in the small intestine lamina propria of FRD-fed mice. However, despite gut microbiota and immune modulations, we observed only a subtle effect of an FRD on EAE severity. Overall, our data suggest that in C57Bl6/J mice, an FRD modulates the gut microbiota and immune system without significantly impacting myelin oligodendrocyte glycoprotein 35-55/CFA-induced EAE.

Copyright © 2023 The Authors.

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Conflict of interest statement

A.K.M. is one of the inventors of a technology claiming the use of Prevotella histicola to treat autoimmune diseases. A.K.M. received royalties from the Mayo Clinic (paid by Evelo Biosciences). However, no funds or products from the patent were used in the current study. The other authors have no financial conflicts of interest.

Figures

FIGURE 1.
FIGURE 1.

An FRD can modulate the composition of the gut microbiome. Four- to 6-wk-old B6 mice were fed an FRD or ND for 6 wk before fecal pellets were collected, microbial DNA was isolated, and shotgun metagenomic analysis was performed. (A) Schematic of the experimental procedure. (B) Chao1 α diversity of the mice in each group. (C) Bray–Curtis dissimilarity measure of β diversity within each diet group displayed using a principal coordinate analysis plot. Each dot represents a single mouse. (D) Stacked bar plots visualizing alterations in relative abundance of the top 20 bacterial genera in each diet group. Genera depicted represent 79.9% of bacterial genera in each group. (E) Heatmap depicting the relative abundance of bacterial species at α = 0.01 in both dietary groups. Each column represents a single mouse. n = 8 per group, two cages per diet. Values are representative of one independent experiment.

FIGURE 2.
FIGURE 2.

An FRD can modulate specific bacterial genera in the microbiome. Four- to 6-wk-old B6 mice were fed an FRD or ND for 6 wk before fecal pellets were collected, microbial DNA was isolated, and shotgun metagenomic analysis was performed. (A and B) Univariate analysis of bacterial genera (A) and species (B) abundance in ND- and FRD-fed mice. n = 8 per group, two cages per diet. **p < 0.01.

FIGURE 3.
FIGURE 3.

Algorithm-based method reveals unique microbial identifiers in microbiomes shaped by an FRD or ND. Four- to 6-wk-old B6 mice were fed an FRD or ND for 6 wk before fecal pellets were collected, microbial DNA was isolated, and shotgun metagenomic analysis was performed. (A and B) Random forest analysis at (A) genus and (B) species levels. Green indicates higher confidence in utilizing the indicated bacteria to blindly differentiate between diets. n = 8 per group, two cages per diet.

FIGURE 4.
FIGURE 4.

An FRD modulates immune populations in the ileal lamina propria. Mice were fed an FRD or ND for 4 or 12 wk before ileal lamina propria cells were isolated and analyzed by flow cytometry. tSNE analysis was performed on CD45+ cells previously gated on lymphocytes and single cells. (A) Schematic of the experimental procedure. (B) tSNE and FlowSOM analysis of flow cytometry data. (C) Table of selected markers expressed by the indicated populations taken from the tSNE analysis. (D) The number of cells in the indicated populations in each diet group. (E) Two-dimensional plot of Helios and RORγt in populations 3 and 4 from mice fed an FRD. n = 5 per group, two-way ANOVA for bar graphs. *p < 0.05.

FIGURE 5.
FIGURE 5.

An FRD may modulate some immune populations in the colonic lamina propria. Mice were fed an FRD or ND for 4 or 12 wk before colonic lamina propria cells were isolated and analyzed by flow cytometry. tSNE analysis was performed on CD45+ cells previously gated on lymphocytes and single cells. (A) Schematic of the experimental procedure. (B) tSNE and FlowSOM analysis of flow cytometry data and (C) the number of cells in the indicated populations in each diet group. (D) Histograms from flow cytometry data depicting expression of selected identifying markers by the selected populations. n = 5 per group, two-way ANOVA for bar graphs. *p < 0.05.

FIGURE 6.
FIGURE 6.

An FRD can moderately modulate immune populations in the spleen over time. Four- to 6-wk-old mice were fed an FRD for 4 or 12 wk before splenic immune cells were isolated and analyzed by flow cytometry. (A) Schematic of the experiment. tSNE analysis was performed on CD45+ cells previously gated on lymphocytes and single cells. (B) tSNE and FlowSOM analysis of splenic immune populations in each diet group. (C) Number of cells in selected populations in each diet group. (D) Histograms from flow cytometry depicting prominent identifying markers of the selected populations. n = 5 per group, two-way ANOVA for bar graphs.

FIGURE 7.
FIGURE 7.

An FRD only moderately modulates EAE disease severity, regardless of the route of ingestion or length of time on the diet. (A) Schematic of the experimental procedure. (B) Mice were fed an FRD or ND for 4 or 12 wk before EAE was induced and disease severity monitored via scoring, survival, and area under the curve. n = 5 mice per group, Mantel–Cox log-rank test for survival. (C) Mice were fed an FRD, ND, or fructose-supplemented water (30% w/v fructose) for 6 wk before EAE was induced and disease severity was monitored via scoring, survival, and area under the curve. n = 10 mice per group, two-way ANOVA for EAE, Mantel–Cox log-rank test for survival.

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