Fucoidan alleviated colitis aggravated by fiber deficiency through protecting the gut barrier, suppressing the MAPK/NF-κB pathway, and modulating gut microbiota and metabolites

Abstract

Insufficient dietary fiber intake has become a global public health issue, affecting the development and management of various diseases, including intestinal diseases and obesity. This study showed that dietary fiber deficiency enhanced the susceptibility of mice to colitis, which could be attributed to the disruption of the gut barrier integrity, activation of the NF-κB pathway, and oxidative stress. Undaria pinnatifida fucoidan (UPF) alleviated colitis symptoms in mice that fed with a fiber deficient diet (FD), characterized by increased weight gain and reduced disease activity index, liver and spleen indexes, and histological score. The protective effect of UPF against FD-exacerbated colitis can be attributed to the alleviation of oxidative stress, the preservation of the gut barrier integrity, and inhibition of the MAPK/NF-κB pathway. UPF ameliorated the gut microbiota composition, leading to increased microbiota richness, as well as increased levels of Muribaculaceae, Lactobacillaceae, and Bifidobacterium and reduced levels of Proteobacteria, Bacteroidetes, and Bacteroides. Metabolomics analysis revealed that UPF improved the profile of microbiota metabolites, with increased levels of carnitine and taurine and decreased levels of tyrosine and deoxycholic acid. This study suggests that UPF has the potential to be developed as a novel prebiotic agent to enhance human health.

Keywords: IBD susceptibility; gut microbiota; intestinal diseases; metabolites; polysaccharide.

Figure 1

Effect of FD on symptoms of colitis induced by DSS (n = 7/group). Procedure of mice experiment (A). Body weight (B). DAI (C). ^*p < 0.05 and ^***p < 0.001 vs. the NC group; ^#p < 0.05, ^##p < 0.01, and ^###p < 0.001 vs. the DSS group. Liver index (D). Spleen index (E). Cecum weight (F). Colon length (G). Macroscopic examination of the colon (H).

Figure 2

Effect of UPF on symptoms of FD-aggravated colitis (n = 7/group). Schematic diagram of mice experiment (A). Body weight (B). DAI (C). ^***p < 0.001 vs. the NC group; ^#p < 0.05 vs. the model group. Liver index (D). Spleen index (E). Cecum weight (F). Colon length (G). Macroscopic examination of the colon (H). Histological analysis based on HE staining (I), scale bar = 500 μm (up), scale bar = 500 μm (down). The red arrows indicate the presence of crypts, the black arrows indicate the infiltration of inflammatory cells. Histological score, n = 3/group (J).

Figure 3

FD aggravated colonic inflammation in mice. Representative images of the colon stained with HE, AB, and PAS (A–C). Scale bar = 100 μm. Black arrows indicate inflammatory infiltration, blue arrows denote colonic mucus, and red arrows indicate crypt damage. Histological score, n = 3/group (D). The amount of goblet cells per crypt, n = 3/group (E). Representative images of p-p65, p65, and MyD88 in the colon tissues and their relative content, n = 3/group (F–H). The contents of LPS, CAT, T-SOD, iNOS, and MPO in the colon, n = 5/group (I–M). TNF-α (N), IL-1β (O), and IL-10 (P), n = 5/group.

Figure 4

Inhibition effect of UPF on colonic inflammation. The contents of TNF-α, IL-1β, and IL-10, n = 5/group (A). Representative images of TLR4, p-p65, p65, p-IκBα, IκBα, and MyD88 in the colon and their relative levels, n = 3/group (B). The levels of MPO, T-SOD, CAT, and LPS in the colon, n = 5/group (C).

Figure 5

Inhibition effect of UPF on MAPK pathway. Representative images of p-JNKs, JNKs, p-p38, p38, p-ERKs, and ERKs in the colon and their relative levels, n = 3/group.

Figure 6

Protective effect of UPF on the gut barrier integrity. AB/PAS staining (A), number of goblet cells per crypt (B), and mucin area (C), scale bar = 100 μm, n = 3/group. Immunohistochemistry staining and analysis, including MUC2, ZO-1, occludin, and claudin-1 (D–H), scale bar = 60 μm, n = 3/group. Representative images of ZO-1, occludin, and claudin-1 in the colon and their relative levels, n = 3/group (I).

Figure 7

Modulation effect of UPF on the gut microbiota (n = 5/group). Chao1 and Shannon indexes (A). PCoA (B). UPGMA (C). Relative abundances of Bacteroidetes, Firmicutes, Proteobacteria, and Actinobacteria at the phylum level (D).

Figure 8

Effect of UPF on gut microbes at the different taxonomic levels (n = 5/group). LDA (A). Statistical analysis of key bacteria at the family (B) and genus (C) level.

Figure 9

Effect of UPF on microbiota metabolites (n = 5/group). PCA based on ESI⁺ and ESI⁻ modes (A). Heatmap constructed by the metabolites that most affected in the different groups (B). Metabolic pathways analysis based on the KEGG database (C). Spearman analysis between key metabolites and biochemical parameters (D).