Living with IBD: Dietary wheat fiber alters macrophage function to mitigate experimental colitis.

Background & Rationale

Inflammatory bowel disease (IBD) encompasses chronic inflammation of the gastrointestinal tract, with significant morbidity and increasing global incidence. Current therapeutic strategies often exhibit limited efficacy or are associated with considerable adverse effects. Dietary interventions represent a potentially valuable adjunct or alternative approach for IBD management. Wheat fiber, a complex carbohydrate, is poorly digested in the upper gastrointestinal tract, reaching the colon where it undergoes microbial fermentation. Previous studies have demonstrated the potential of dietary fiber to influence gut microbiota composition and function, but the precise mechanisms by which it impacts intestinal inflammation remain incompletely elucidated. This study investigated the role of wheat fiber in modulating intestinal macrophages and its effect on colitis development.

Study Design

This research employed a murine model of chemically induced colitis, specifically the dextran sulfate sodium (DSS) colitis model. Male C57BL/6 mice were subjected to a 3% DSS solution in their drinking water for 7 days, with wheat fiber added to their diet at a concentration of 10% w/w. Researchers used a combination of 16S rRNA gene sequencing to analyse gut microbiota composition and single-cell RNA sequencing to characterise macrophage phenotypes. Intestinal macrophages were isolated from both the intestinal lamina propria and mesenteric lymph nodes to examine changes in gene expression. Metabolomic analysis was conducted on cecal contents. Specific metabolic pathways were examined using isotope tracing experiments.

Patient Population

The study population comprised male C57BL/6 mice, aged 8–12 weeks and weighing approximately 20–25 g. Mice were randomly assigned to either a control diet or a diet supplemented with 10% wheat fiber. Inclusion criteria included being healthy at the study outset. Exclusion criteria included pre-existing signs of illness or abnormal behaviour. Sample sizes varied across analyses, ranging from n=6 to n=12 mice per group, determined by power calculations based on expected effect sizes from pilot studies.

Key Findings

Administration of 10% wheat fiber significantly attenuated DSS-induced colitis, demonstrated by reduced disease activity index scores. Mortality was reduced from 60% in the DSS-only group to 20% in the wheat fiber + DSS group. Histopathological assessment revealed that wheat fiber supplementation decreased colonic shortening and reduced epithelial damage compared to DSS-only mice. 16S rRNA gene sequencing showed that wheat fiber induced minor alterations in gut microbiota composition, but these shifts did not fully explain the observed protective effects.

Single-cell RNA sequencing identified distinct macrophage populations within the intestinal lamina propria. Wheat fiber treatment induced a population of macrophages with an altered transcriptional profile, characterised by upregulation of genes involved in metabolic reprogramming and decreased expression of pro-inflammatory genes. These macrophages exhibited increased phagocytic capacity in vitro, but did not depend on short-chain fatty acid (SCFA) production. Metabolomic analyses identified upregulated levels of specific microbial metabolites – namely, 3-(3-hydroxyphenyl)propionic acid – which were sufficient, when administered directly to macrophages, to induce the observed transcriptional and functional changes.

Discussion

This study demonstrates that dietary wheat fiber can ameliorate experimental colitis, independent of canonical SCFA-mediated mechanisms. The observed protective effect is mediated by modulation of intestinal macrophage function, driven by specific non-SCFA microbial metabolites. Modulating intestinal macrophages through dietary means presents a novel therapeutic avenue for IBD. The identification of 3-(3-hydroxyphenyl)propionic acid as a key mediator offers a potential target for the development of novel therapeutic interventions. The study reports that wheat fiber was well-tolerated by the mice, with no observed signs of systemic toxicity. Further research is needed to determine the generalisability of these findings to human populations.

Authors’ Conclusions

The authors conclude that wheat fiber mitigates colitis by inducing a specific population of intestinal macrophages exhibiting enhanced metabolic reprogramming and phagocytic function via microbial metabolites distinct from SCFAs. This work highlights the therapeutic potential of dietary interventions that harness host-microbe interactions without relying solely on modulation of SCFA production, and identifies 3-(3-hydroxyphenyl)propionic acid as a key metabolite mediating these effects.

Reference

Kim SG, Ott R, Bretin A, Abo H, Wang Y, Wang Y, Winer S, Winer DA, Reddivari L, Heaver SL, Ley RE, Pellizzon M, Ngo VL, Gewirtz AT. Wheat fiber mitigates colitis via non-SCFA microbial metabolite-trained intestinal macrophages. Science advances. 2026;2(2):eabc5757. DOI: 10.1126/sciadv.aec5757.