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

Glucagon-like peptide 2 (GLP-2) is a gut secreted hormone in response to dietary nutrients. GLP-2 derivatives demonstrated therapeutic efficacy for Short Bowel Syndrome (SBS), a malabsorptive disease due to physical or functional loss of parts of the small intestine. However, injection administration may decrease patient compliance. The objective of this study is to discover an oral, long-acting and best-in-class GLP-2.

Aims & Methods

The objective of this study is to discover an oral, long-acting and best-in-class GLP-2. Following methods were applied in the discovery. Fatty acid conjugated peptides were designed and tested in CHO-K1 CRE reporter cells overexpressing human or rat GLP-2 receptor. 1037331 was selected, evaluated for small intestine growth (intestine weight and thickness coefficient as readout) by once daily injection for 5 days in SD rats, and tested in pharmacokinetic (PK) study in SD rats, minipigs and beagle dogs by subcutaneous injection. Finally 1037331 was formulated into pills (7 mg 1037331/pill) and assessed for oral absorption in beagle dogs by once daily dosage for 5 days. Apraglutide (VectiveBio), a GLP-2 analog in Phase 3 studies, was used as a comparator.

Results

Among the peptide tested, 1037331 activated both human and rat GLP-2 receptor more potently than apraglutide (EC₅₀ for 1037331 and apraglutide, respectively, human receptor: 0.68 nM vs 2.11 nM; rat receptor: 0.17 nM vs 1.07 nM). In SD rats, 10 nmol/kg 1037331 increased small intestine weight and thickness comparable to 250 nmol/kg apraglutide. In PK study, 1037331 showed longer half-lives resulting higher exposure by injection in all animal models (T_1/2 for 1037331 and apraglutide, respectively, SD rat: 10.3 h vs 7.3 h; minipig: 22.4 vs 16.6 h; beagle dog: 54.8 h vs 17.7 h). In oral PK study, daily dosing leads to accumulation of 1037331 in circulation and Cmax at 62.4 nM was achieved.

Conclusion

Overall, 1037331 demonstrated better in vitro and in vivo potencies, and better PK profiles than apraglutide. Most importantly, 1037331 with fatty acid conjugation showed oral bioavailability, which may improve patient compliance and convenience.