Introduction

Obesity, characterized by low-grade systemic inflammation, is associated with numerous chronic inflammatory conditions including inflammatory bowel diseases (IBD). While accumulating body fat has direct influence on IBD progression, creeping fat (CF) in Crohn’s disease (CD) manifests independently of body weight. As a response of mesenteric adipose tissue (AT) to intestinal inflammation, preadipocytes migrate towards affected intestinal segments to form a distinct immunophenotypic AT comprising hyperplastic adipocytes, preadipocytes and immune cells which exert complex immunologic and metabolic interactions with the adjacent intestine. However, associations between the cellular architecture of CF and CD progression remain unclear.

Aims & Methods

We aim to study gut-AT interactions in the context of IBD, focusing on the role of preadipocytes in CF as well as relevance of metabolic integrity of mesenteric adipocytes for intestinal homeostasis. Ex vivo co-cultures of wild-type murine intestinal organoids and mesenteric mature adipocytes or preadipocytes using a novel 3D culture system allowed us to study direct effects on transcriptional profiles and growth capacity, distinguishably between adipogenic cells of distinct differentiation states. Furthermore, we generated a mouse model of adipocyte-specific mitochondrial dysfunction by genetic deletion of heat shock protein 60 (Hsp60) to investigate mechanisms of metabolic and inflammatory phenotype transmission between mesenteric AT and intestinal epithelium. In addition, we used human mesenteric and CF explants from CD patients undergoing surgical resection to isolate preadipocytes and perform ex vivo proliferation and differentiation studies.

Results

In intestinal organoids from mice, the presence of both, mature adipocytes and preadipocytes induces downregulation of Hsp60 accompanied by induction of mitochondrial stress markers (Trb3, Chop). However, solely preadipocytes were sufficient to induce intestinal epithelial gene signatures involved in oxidative stress (Ido1, Nos2, Duox2) and reduced stemness (Lgr5) as attributable to metabolic impairment and injury phenotypes. Conversely, in response to presence of intestinal organoids, mesenteric adipocytes show upregulated expression of browning markers (Ucp1, Cidea, Cox7a1) accompanied by reduced inflammatory and mitochondrial stress signaling. In mice, genetically induced mitochondrial dysfunction in adipocytes leads to phenotypic AT remodeling of specifically the mesenteric depot, resulting in extensive immune cell infiltration and crown-like structure formation in anatomic relation to the intestinal epithelium. Human CF-derived preadipocytes in comparison to equivalent cells from healthy mesentery of the same patient exhibit distinct morphological features and diminished lipid incorporation after adipogenic differentiation ex vivo.

Conclusion

We demonstrate that exclusively preadipocytes condition the intestinal epithelium to injury-related phenotypic features, suggesting a novel and crucial relevance for IBD research and management. Vice versa, intestinal epithelial cells can stimulate mesenteric adipocytes to recruit thermogenic capacity, which is associated with anti-inflammatory effects, suggesting a protective role of mesenteric AT browning capacity. Disturbing adipocyte mitochondrial function is sufficient to remodel mesenteric AT architecture and induce propagating inflammation. Consequent effects on the adjacent intestine we address in our ongoing studies considering adipocyte mitochondria as target for therapeutic interventions in CD.

Introduction

Inflammatory bowel disease (IBD), comprising Crohn’s disease (CD) and ulcerative colitis (UC), is part of a broader spectrum of immune-mediated inflammatory diseases (IMIDs). Clinical and epidemiological studies indicate a higher prevalence of IMIDs among patients with IBD and their first-degree relatives, with a significant proportion of patients with IBD also diagnosed with conditions such as asthma, psoriasis, and rheumatoid arthritis^1,2. These patterns suggest shared genetic and/or environmental risk factors. The clinical intersections call for a multidisciplinary management strategy in which decisions account for the broader immune landscape rather than focusing on each diagnosis in isolation^1,3.

Aims & Methods

This study aimed to characterize the relationship between IBD and other IMIDs and disentangle genetic and environmental contributions. This was done by analyzing the tetrachoric correlation⁴ between disease codes registered for 107,651 full sibling pairs born between 1910 and 2010 in the Danish nationwide health registries. We then estimated SNP-based correlations based on summary statistics from genome-wide association studies of each disease using LDSC⁵. Lastly, we downloaded and reanalyzed all V3-V4 16S rDNA fecal microbiota samples available from NCBI⁶ in a unified bioinformatical pipeline. We used this data to generate microbiota disease profiles and estimate their correlations across IBD and IMIDs.

Results

We show that CD and UC have distinct patterns of correlations with other IMIDs. Asthma and celiac disease were correlated with CD (asthma: ρ=0.12, 95% CI=0.10-0.13, celiac disease: ρ=0.12, 95% CI=0.08-0.17), but not UC within full siblings. Oppositely, sarcoidosis (ρ=0.16, 95% CI=0.13-0.19), multiple sclerosis (ρ=0.09, 95% CI=0.06-0.12), systemic lupus erythematosus (SLE) (ρ=0.19, 95% CI=0.13-0.25), and Sjögren’s syndrome (ρ=0.15, 95% CI=0.10-0.20) correlated with UC but not CD. The IMIDs Graves’ disease, type 1 diabetes, iridocyclitis, psoriasis, psoriatic arthritis, rheumatoid arthritis, and ankylosing spondylitis correlated with both CD and UC. Evaluating genetic and gut microbial correlations highlighted that UC exhibits microbiota-linked correlations with multiple sclerosis (ρ=0.11, 95% CI=0.01-0.21) and SLE (ρ=0.15, 95% CI=0.05-0.24) despite an estimated negative genetic overlap (multiple sclerosis: ρ=-0.18, 95% CI=-0.32--0.04, SLE: ρ=-0.21, 95% CI=-0.32--0.09), suggesting a key role for environmental factors, including microbial. In contrast, for both IBD subtypes rheumatoid arthritis showed consistent genetic (CD: ρ=0.12, 95% CI=0.02-0.21, UC: ρ=0.17, 95% CI=0.08-0.27) as well as microbial convergence (CD: ρ=0.30, 95% CI=0.20-0.38, UC: ρ=0.12, 95% CI=0.02-0.22), whereas the correlation with psoriasis appeared to be mainly genetically driven (CD SNP correlation: ρ=0.23, 95% CI=0.14-0.33, CD microbiota correlation: ρ=-0.13, 95% CI=-0.23--0.03, UC SNP correlation: ρ=0.25, 95% CI=0.15-0.35, UC microbiota correlation: ρ=0.06, 95% CI=-0.04-0.16).

Conclusion

These findings uncover heterogeneity in shared etiological pathways across immune diseases, underscoring the need for stratified approaches to diagnosis and therapeutic intervention in IBD. Importantly, our findings demonstrate that CD and UC—though often co-studied—harbor distinct immunogenetic and microbial associations, reinforcing the need for subtype-specific approaches in clinical management and research design. Further, the correlation between IBD and other IMIDs appears to be driven by different genetic and environmental mechanisms, which must be further explored.

References

1. Bezzio C, Corte C Della, Vernero M, et al. Inflammatory bowel disease and immune-mediated inflammatory diseases: looking at the less frequent associations. Therap Adv Gastroenterol 2022;15. Available at: https://journals.sagepub.com/doi/full/10.1177/17562848221115312 [Accessed March 14, 2025].
2. García MJ, Pascual M, Pozo C Del, et al. Impact of immune-mediated diseases in inflammatory bowel disease and implications in therapeutic approach. Sci Rep 2020;10:10731. Available at: https://pmc.ncbi.nlm.nih.gov/articles/PMC7330038/ [Accessed March 14, 2025].
3. Park SW, Kim TJ, Lee JY, et al. Comorbid immune-mediated diseases in inflammatory bowel disease: a nation-wide population-based study. Aliment Pharmacol Ther 2019;49:165–172. Available at: https://pubmed.ncbi.nlm.nih.gov/30506945/ [Accessed March 14, 2025].
4. Falconer DS, Mackay TFC. Introduction to Quantitative Genetics. Third Ddit. Longman Scientific & Technical; 1989.
5. Bulik-Sullivan B, Finucane HK, Anttila V, et al. An atlas of genetic correlations across human diseases and traits. Nature Genetics 2015 47:11 2015;47:1236–1241. Available at: https://www.nature.com/articles/ng.3406 [Accessed March 14, 2025].
6. Sayers EW, Bolton EE, Brister JR, et al. Database resources of the national center for biotechnology information. Nucleic Acids Res 2022;50:D20–D26. Available at: https://pubmed.ncbi.nlm.nih.gov/34850941/ [Accessed March 14, 2025].

Disclosure

TJ reports consultancy for Ferring and Pfizer. The remaining authors have no disclosures.

Introduction

The cause of Crohn’s Disease (CD) remains unclear; however evidence suggests that dietary factors play a key role. With a rising incidence and no definitive cure, identifying modifiable risk factors is critical in preventing CD development. We aimed to study the association between fermentable dietary fibre intake and the future development of CD in an at-risk population.

Aims & Methods

Participants were recruited as part of the Crohn’s and Colitis Canada GEM study, a prospective cohort study of healthy first-degree relatives of patients with CD. At enrolment, a validated food frequency questionnaire was administered. Pectin, β-glucan, inulin, fructooligosaccharides (FOS), and arabinoxylan intake were quantified, and values energy-adjusted. Survival analysis was used to test the association between intake of fibre subtypes and risk of CD development. Generalized estimating equation tested the association between fibre intake and baseline impaired intestinal permeability (fractional urinary excretion of lactulose to mannitol ratio (LMR) >0.025); subclinical gut inflammation (faecal calprotectin (FCP) >250 μg/g); and faecal microbiome composition via 16s rRNA sequencing.

Results

76 of the 2,659 participants developed CD with a median follow-up of 8.9 years (IQR=5.7-12.3). Median age at recruitment was 17 years (IQR=12-25). 47% were male. Higher intake of inulin (HR = 0.78; 95% CI=0.61–0.99; p=0.04) and β-glucan (HR = 0.78; 95% CI=0.61–0.99; p=0.04) were associated with a reduced risk of CD development. No fibre subtype was associated with a higher risk of CD development. Lower intake of pectin, inulin, FOS and β-glucan was associated with impaired intestinal permeability (0.005<p<0.04). Lower inulin intake was associated with high FCP levels (p = 0.046). Higher pectin intake was associated with increased alpha diversity of faecal microbiome (p = 0.028). Higher inulin, FOS and pectin intake was associated with a shift in microbial taxa previously shown to be protective against CD onset in the GEM cohort; a reduction in Ruminococcus torques and an increase in NK4A214 group (phylum Firmicutes) presence (3.25×10⁻¹⁰<q<0.04).

Conclusion

This study demonstrates that dietary intake of fermentable fibre subtypes is associated with a reduced risk of CD development as well as with pleiotropic changes in CD risk biomarkers including microbiome, intestinal permeability, and subclinical inflammation. This suggests that the potential benefit of fermentable fibres on CD risk may involve changes in barrier function, and microbiome composition and function. Targeted interventions based on these findings could prove effective in preventing the onset of CD.