Introduction

Inflammatory bowel disease (IBD) is a chronic inflammatory process closely linked to diet and nutrition. Diet and nutrition have been proposed to be significantly involved in the pathogenesis of IBD, although their specific propagation and attenuation of gut inflammation remains unclear.

Aims & Methods

Using paired dietary history and serum immunoproteins, we sought to investigate the association of various nutritional components in multi-ethnic Asian IBD patients from a single-center academic hospital in Singapore. Participants completed a self-administered validated 163-item semi-quantitative food frequency questionnaire to determine dietary intake. Adequate micronutrient intake was determined by the recommended dietary allowance (RDA) as stipulated by the Singapore Health Promotion Board. Participants also had 88 paired serum immunoproteins profiled using the Olink Target 96 Inflammation assay. Spearman correlation analysis, with false discovery rate, was used to identify significant diet-immune associations.

Results

Our study cohort included 40 (55.6%) patients with Crohn's disease and 32 (44.4%) patients with ulcerative colitis, with a median age of 40 years (range 30.5 - 57.0). More than two-thirds (n=51, 70.8%) were male. The median body mass index was 23.4kg/m2 (range 20.0 - 26.3). In our study, IBD patients self-reported to be taking insufficient dietary fiber and vitamin A, whereby 86.1% and 58.3% of IBD patients, were taking lower than the RDA for dietary fibre (n=62, median 15.9g/day) and vitamin A (n=42, median 706mcg/day), respectively.
Using spearman correlation, we identified 192 significant (p<0.05) diet-immune associations from only 39 (44%) of the 88 immunoproteins screened. Of note, 8 immunoproteins (4E-BP1, CASP-8, CDCP1, FGF-23, IL-17A, IL-20RA, IL-22 RA1, STAMBP) accounted for almost half (n=92/192) of all the significant diet-inmune associations. Only beta carotene and vitamin A were negatively associated with pro-inflammatory immunoproteins, such as Interleukin-18, Interleukin 10-receptor subunit beta, C-C motif chemokine 19, Vascular endothelial growth factor A, and and Urokinase-type plasminogen activator.
Table 1. List of immunoproteins and their key molecular functions and micronutrient-immunoprotein associations. Eight immunoproteins (4E-BP1, CASP-8, CDCP1, FGF-23, IL-17A, IL-20RA, IL-22 RA1, STAMBP) were identified to have the most diet-immune associations, accounting for almost half (n=92/192) of all significant associations identified.

Protein Name	Function	Count of diet-immune associations	Specific dietary associations
Eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1)	Enables protein binding (GO:0005515) Enables eukaryotic initiation factor 4E binding (GO:0008190) Enables translation repressor activity (GO:0030371)	11	Iron Calcium Riboflavin MUFA Protein Zinc CHO Starch Energy SFA Total fat
Caspase-8 (CASP-8)	Enables cysteine-type endopeptidase activity (GO:0004197) Enables death receptor binding (GO:0005123) Enables tumor necrosis factor receptor binding (GO:0005164) Enables protein binding (GO:0005515) Enables peptidase activity (GO:0008233)	13	Vitamin A Iron Thiamine Potassium Calcium Riboflavin MUFA Protein Zinc CHO Energy PUFA SFA Total fat
CUB domain containing protein 1 (CDCP-1)	Enables protein binding (GO:0005515)	10	BCarotene Vitamin A Vitamin C Potassium Riboflavin MUFA Protein Zinc SFA Total fat
Fibroblast growth factor 23 (FGF-23)	Positive regulation of protein kinase B signalling (GO:0051897) MAPK cascade (GO:0000165) Fibroblast growth factor receptor binding (GO:0005104) Enables type 1 fibroblast growth factor receptor binding (GO:0005105) Enables protein binding (GO:0005515) Enables growth factor activity (GO:0008083)	11	Iron Thiamine Potassium Calcium Riboflavin Zinc Energy PUFA SFA Total fat Dietary fiber
Interleukin-17A (IL-17A)	Positive regulation of antimicrobial peptide production (GO:0002225) Adaptive immune response (GO:0002250) immune system process (GO:0002376) Apoptotic process (GO:0006915) Inflammatory response (GO:0006954)	11	Iron Potassium MUFA Protein Zinc CHO Starch Energy PUFA SFA Total fat
Interleukin-20 receptor subunit alpha (IL-20RA)	Cytokine receptor activity (GO:0004896) Enables protein binding (GO:0005515) Enables interleukin-20 binding (GO:0042015)	11	Thiamine Potassium Calcium Riboflavin MUFA Protein Zinc Energy PUFA SFA Total fat
Interleukin-22 receptor subunit alpha-1 (IL-22RA1)	Cytokine receptor activity (GO:0004896) Enables interferon receptor activity (GO:0004904) Enables protein binding (GO:0005515) Enables interleukin-20 binding (GO:0042015)	13	BCarotene Vitamin C Iron Potassium Calcium Riboflavin MUFA Energy PUFA SFA Total fat Dietary fiber Sugar
STAM-binding protein (STAMBP)	Enables protein binding (GO:0005515) Peptidase activity (GO:0008233) Metallopeptidase activity (GO:0008237) Hydrolase activity (GO:0016787) Enables protein domain specific binding (GO:0019904)	16	Vitamin A Iron Thiamine Potassium Calcium Riboflavin Protein Zinc CHO Starch Energy PUFA SFA Total fat Dietary fiber Sugar

Conclusion

Our study found specific components of the diet, such as carbohydrates, starch, fiber to be positively associated with inflammatory immunoproteins. Only vitamin A and beta-carotene were negatively associated with circulating immunoproteins. We hope our findings assist in the development of specific dietary therapies to provide IBD patients with specific nutrient requirements and yet limit specific dietary substrates that may propagate gastrointestinal inflammation. Further studies are required to investigate the mechanisms of these nutritional factors involved in inflammation and to evaluate the application of specific diets during the course of IBD.

References

1. Mentella, M. C., Scaldaferri, F., Pizzoferrato, M., Gasbarrini, A., &amp; Miggiano, G. A. (2020). Nutrition, IBD and Gut Microbiota: A Review. Nutrients, 12(4), 944. https://doi.org/10.3390/nu12040944

2. Neelakantan, N., Whitton, C., Seah, S., Koh, H., Rebello, S., Lim, J., Chen, S., Chan, M., Chew, L., &amp; van Dam, R. (2016). Development of a semi-quantitative food frequency questionnaire to assess the dietary intake of a multi-ethnic urban Asian population. Nutrients, 8(9), 528. https://doi.org/10.3390/nu8090528

Introduction

Personalizing biologic therapies in inflammatory bowel disease (IBD) remains a critical unmet need. Here, we investigated circulating and stool microRNAs (miRNAs) as prognostic markers for treatment response across three biologics - anti-TNF, vedolizumab (VEDO), and ustekinumab (UST) - and explored their relationship with gut microbiome to uncover potential host-microbe predictors of response.

Aims & Methods

This study included 43 IBD patients (mean age 40.4 years, 25.6% female, 20.1% with ulcerative colitis) enrolled in the ILEITIS cohort at National University Hospital, Singapore. The majority had received anti-TNF (n=35), whilst others were given VEDO (n=9), or UST (n=15) therapies. Clinical non-response was defined as disease flare within 48 weeks post-induction, indicated by C-reactive protein >5 mg/L, fecal calprotectin >150 μg/g, or moderate to severe endoscopic inflammation. Baseline serum and stool samples were collected and isolated for miRNA profiling by the ID3EAL^TM PanoramiR microRNA Knowledge Panel (MiRXES) via the QuantStudio5-384-well qPCR system (Applied Biosystems). Fecal microbial communities were assessed via shotgun metagenomic sequencing. Differential expression analysis and Spearman correlation with false discovery rate (FDR) adjustment were performed to explore miRNA–microbe associations and treatment response patterns.

Results

Among 376 paired serum and stool miRNAs analyzed, only six exhibited significant positive correlations, indicating largely compartment-specific expression patterns. Stool miRNAs demonstrated stronger and more numerous correlations with gut microbial taxa (11 significant pairs, FDR < 0.05), whereas serum miRNAs showed no strong associations. Biologic-specific miRNA signatures were identified. Predictive modelling identified top-ranked miRNA with high discriminative performance for treatment response; serum miR-296 and stool miR-134 perfectly predicted VEDO response (AUROC = 1.0); serum miR-146 predicted UST response (AUROC = 1.0); and stool miR-302 robustly predicted anti-TNF response (AUROC = 0.897). Correlation analysis between biologic-responsive miRNA and microbial taxa revealed 12 significant correlations for stool-derived miRNA and 14 for serum-derived miRNA. Notable microbial species involved in these associations include Bacteroides uniformis, Parabacteroides distasonis, Phocaeicola dorei, Clostridium scindens, Streptococcus sanguinis, Bilophila wadsworthia, Hungatella hathewayi, and Clostridium leptum, all taxa implicated in IBD-associated dysbiosis, showed significant correlations (FDR < 0.05).

Conclusion

Stool- and serum-derived miRNAs capture non-overlapping but complementary dimensions of host response to biologic therapy in IBD. There are significant overlaps between host miRNAs and microbiome readouts suggesting plausible links between key microbial responders to therapy and host regulatory miRNAs, especially in the luminal compartment. Our findings highlight the value of integrating compartment-specific miRNA and microbiome profiling to improve precision medicine approaches in IBD.

Introduction

A key feature of IBD pathogenesis is response dysregulation of both the innate and adaptive immune system^1,2. Hence specific inflammatory protein profiles may be a promising biomarker approach for diagnosis and personalized therapy in IBD. Serum proteome of IBD, particularly in multi-ethnic Asian patients, remains less defined.

Aims & Methods

We aim to investigate the systemic inflammatory protein profiles in multi-ethnic Asian patients with IBD and compare them to healthy controls.
The study cohort was made up of 92 patients with IBD (50.0% Ulcerative colitis (UC), 43.5% Crohn's disease (CD), 6.5% Unclassified IBD)), and 42 control subjects, who are asymptomatic patients undergoing screening colonoscopy with no endoscopic pathology. Serum protein profiling was performed using the Olink Target 96 Inflammation assay. A partial-least square discriminant analysis was undertaken to identify additional discriminative inflammatory proteins. Univariate t-test analyses, with false discovery rate correction, were also performed to identify proteins unique to either UC or CD.

Results

Participants with IBD were younger (42.0 (±14.7) in UC, 43.2 (±15.1) in CD, p<0.01), with greater representation of South Asian ethnicity (32.5% amongst UC, 19.6% amongst CD, p<0.01) and males (75.0% amongst UC, 69.6% amongst CD, p=0.03), as compared to controls.
We found 18 proteins were differentially abundant amongst IBD patients (p<0.05). Half (n=9) of these inflammatory proteins (AXIN-1, CD8A, CXCL1, EN-RAGE, FGF-23, HGF, IL17A, OSM, TGF-alpha) were elevated in both UC and CD. The other six proteins were elevated only in patients with UC (4E-BP1, CCL11, IL-18R1, IL-20, MMP-10, TRANCE). Of the remaining three, two were less abundant in patients with CD (DNER, SCF) and TNF was elevated only in patients with CD. Of interest, three immunoproteins were differentially abundant in participants with either UC or CD (i.e. CCL11, MMP10, TRANCE).

Molecular functions	Both UC and CD	UC only	CD only	UC vs CD
Cytokine mediated signaling (GO:0019221)	IL17A CXCL1 OSM HGF	CCL11 TRANCE IL20	TNF	CCL11 TRANCE
Positive regulation of protein kinase B signaling (GO:0051897)	FGF23 HGF OSM TGF-alpha	TRANCE	SCF* TNF	TRANCE
Immune response (GO:0006955)	CD8A CXCL1 IL17A OSM	IL-18R1 TRANCE		TRANCE
Inflammatory response (GO:0006954)	CXCL1 EN-RAGE IL17A	CCL11 IL-18R1	TNF	CCL11
MAPK cascade (GO:0000165)	FGF-23 HGF TGF-alpha		SCF* TNF
Others	AXIN1^	MMP-10# 4E-BP1$	DNER*@	MMP-10#

Table1: List of immunoproteins differentially abundant (p<0.05) in varying IBD subtypes, grouped by their key common molecular functions. *indicates that the immunoprotein of interest to be less abundant compared to controls. ^AXIN1 functions - Activation of protein kinase (GO:0032147), WNT signaling process (GO:0016055). ^#MMP-10 function - extracellular matrix organization (GO:0030198). ^$4E-BP1 function - TOR signaling (GO:0031929). ^@DNER function - Notch receptor processing (GO:0007220).

Conclusion

Our pilot study in a multi-ethnic Asian population found distinctive serum protein profile in IBD patients. While some protein changes were shared in both UC and CD, other changes were specific for either UC or CD, suggesting different disease pathways in these two IBD subtypes. We reaffirmed that inflammatory proteins, such as EN-RAGE³, MMP-10⁴ and OSM⁵, were differentially abundant in IBD, consistent with previous reports in predominantly Caucasian cohorts. Further studies with large sample sizes would be required to validate these biomarkers for IBD activity, and prognosis for biologic therapy response.

References

1. Neurath MF. Cytokines in inflammatory bowel disease. Nat Rev Immunol. 2014 May;14(5):329-42.
2. Mahida YR. The key role of macrophages in the immunopathogenesis of inflammatory bowel disease. Inflamm Bowel Dis. 2000;6:21–33.
3. Foell D, Kucharzik T, Kraft M, et al. Neutrophil derived human S100A12 (EN-RAGE) is strongly expressed during chronic active inflammatory bowel disease. Gut 2003;52:847-853.
4. Fonseca-Camarillo G, Furuzawa-Carballeda J, Martínez-Benitez B, et al. Increased expression of extracellular matrix metalloproteinase inducer (EMMPRIN) and MMP10, MMP23 in inflammatory bowel disease: Cross-sectional study. Scand J Immunol. 2021 Jan;93(1):e12962.
5. Sare Verstockt, Bram Verstockt, Kathleen Machiels, et al. Oncostatin M Is a Biomarker of Diagnosis, Worse Disease Prognosis, and Therapeutic Nonresponse in Inflammatory Bowel Disease. Inflamm Bowel Dis. 2021 Oct 18;27(10):1564-1575.

Introduction

Inflammatory bowel disease (IBD) is strongly associated with joint inflammation, as is highlighted by the high prevalence of spondyloarthritis (SpA) in patients with IBD (up to 13%) compared to the general population (0.2-1.6%) [1, 2]. IBD and SpA have many overlapping features, including genetic risk factors, changes in the gut microbiota, and therapies targeting TNF-α , IL-23, or JAK [3]. However, current therapies for both diseases are unable to break the cycle of chronic inflammation, and still a significant proportion of patients fail to respond. Disease heterogeneity likely plays a role in this [4, 5], underscoring the necessity to improve management and refine classification.

Aims & Methods

In this study, 92 inflammation-related proteins were quantified in serum of patients from one IBD and one SpA cohort using the novel Olink proteomics proximity extension assay. Fold changes (FC) in expression with |log₂FC| > 0.5 were considered meaningful, and false discovery rates (FDR) <0.05 were considered significant. The IBD cohort existed of 255 IBD patients with (n=155) and without (n=100) self-reported joint complaints [8]. From the patients with joint complaints, 58 fulfilled any of the SpA criteria. The SpA cohort, or SPACE cohort, consisted of 169 patients with chronic back pain (≥3 months, ≤2 years) of unknown origin [9]. After 2 years of follow-up, 85 patients had proven axSpA. Serum samples were taken at baseline, and 167/169 samples from the SPACE cohort and 241/255 samples from the IBD cohort passed quality control and were included in the analysis.

Results

Thirty-four proteins were differentially expressed between 95 IBD patients without joint complaints and 85 proven axial SpA (axSpA) patients from the SPACE cohort, of which 14 were higher in IBD patients (including 4E‑BP1, IFN‑γ, TNF, FGF‑21, CD8A, and CCL9), and 20 were higher in axSpA patients (including CASP‑8, SIRT2, STAMBP, FGF‑19, ST1A1, and EN‑RAGE). In addition, the immune profile of IBD patients with joint complaints differed from IBD patients without joint complaints: 4E‑BP1, CASP-8, STAMBP, SIRT2, AXIN1, and TNFSF14, were significantly upregulated in patients with joint complaints. Of note, if IBD patients without joint complaints were compared to the subgroup of 58 patients with joint complaints who met criteria for SpA, the same proteins showed significant upregulation, suggesting minimal difference between IBD patients with joint complaints who meet or who do not meet SpA criteria. Direct comparison of patients who met and who did not meet SpA criteria within the group of IBD patients with joint complaints indeed showed no noteworthy difference in serum immune profile. Within the SPACE cohort, comparison of patients with chronic back pain with and without axSpA diagnosis also showed no significant difference in serum protein expression.

Conclusion

This study shows that patients with axSpA versus patients with IBD without joint complaints have differing serum immune profiles. Within IBD patients with self-reported joint complaints and within patients with self-reported chronic back pain (from the SPACE cohort), no distinct difference in immune profile is observed, regardless of SpA diagnosis. The inflammation signatures of patients with chronic inflammatory diseases should be further investigated to provide insights for enhancing disease management in the future.

References

1. Karreman, M.C., et al., The Prevalence and Incidence of Axial and Peripheral Spondyloarthritis in Inflammatory Bowel Disease: A Systematic Review and Meta-analysis. J Crohns Colitis, 2017. 11(5): p. 631-642.
2. Stolwijk, C., et al., Global Prevalence of Spondyloarthritis: A Systematic Review and Meta-Regression Analysis. Arthritis Care Res (Hoboken), 2016. 68(9): p. 1320-31.
3. Gracey, E., et al., Revisiting the gut-joint axis: links between gut inflammation and spondyloarthritis. Nat Rev Rheumatol, 2020. 16(8): p. 415-433.
4. van Unen, V., et al., Mass Cytometry of the Human Mucosal Immune System Identifies Tissue- and Disease-Associated Immune Subsets. Immunity, 2016. 44(5): p. 1227-39.
5. Gulino, G.R., M. Van Mechelen, and R. Lories, Cellular and molecular diversity in spondyloarthritis. Semin Immunol, 2021. 58: p. 101521.
6. van Erp, S.J., et al., Classifying Back Pain and Peripheral Joint Complaints in Inflammatory Bowel Disease Patients: A Prospective Longitudinal Follow-up Study. J Crohns Colitis, 2016. 10(2): p. 166-75.
7. Marques, M.L., et al., Can rheumatologists unequivocally diagnose axial spondyloarthritis in patients with chronic back pain of less than 2 years duration? Primary outcome of the 2-year SPondyloArthritis Caught Early (SPACE) cohort. Ann Rheum Dis, 2024. 83(5): p. 589-598.

Disclosure

FAG: grants from Stichting vrienden van Sole Mio and Stichting ASAS, grants and/or consulting fees from Abbvie, ASAS, BMS, Galapagos, Janssen, Lilly, Novartis, Pfizer, and UCB.
AEM: grants from Nestle, Norgine, Cablon, Galapagos, and ZonMW, ad boards/speaker fees from Tramedico, Janssen, Takeda, Galapagos, Vedanta, Ferring, AbbVie, and Dear Health.
PV: speaker fees from Takeda and Galapagos, advisory board: Takeda, Galapagos, Lilly, BMS, Janssen, and Abbvie

Introduction

Both patients and clinicians would benefit from less invasive means than endoscopy for detection of gut inflammation in inflammatory bowel disease (IBD), such as faecal or serological biomarkers.

Aims & Methods

The aim of this study was to investigate the presence of the neutrophilic proteins: calprotectin (CP), myeloperoxidase (MPO), neutrophil gelatinase-associated lipocalin (NGAL) and the eosinophilic protein: eosinophil-derived neurotoxin (EDN) in faecal and serum samples from IBD patients with ulcerative colitis (UC) and Crohn’s disease (CD) in relation to disease activity and intestinal inflammation localization. Their diagnostic potential in IBD was studied using irritable bowel syndrome (IBS) patients as controls.
Faecal (f) and serum (s) samples from 97 IBD (median: 38y, range 18-79y) and 100 IBS (median: 36y, range 18-75y) patients from the outpatient Gastroenterology Clinic, Uppsala University Hospital were included in the study. Active disease was defined as having a Partial Mayo score ≥ 2 (UC) or Harvey-Bradshaw score ≥5 (CD). Disease localization was obtained from patient journals.
CP and EDN were measured by commercial EliA and ImmunoCAP assays, respectively. MPO and NGAL were measured with in-house research assays based on the ImmunoCAP technology. All analyses were done using the automated Phadia 250 instrument.

Results

All four biomarkers were elevated in IBD compared to IBS in faecal samples (p<0.001) and serum (p<0.01), and most biomarkers were also elevated in the separate UC and CD groups (Table 1). Faecal EDN were higher in CD compared to both UC (p=0.016) and IBS.
Table 1. Biomarker levels in UC and CD patients in comparison to IBS patients

	UC N=59	CD N=38	IBS N=100	p-value (UC vs. IBS)	p-value (CD vs. IBS)
fCP	305.8 mg/kg	165.8 mg/kg	16.51 mg/kg	<0.0001	<0.0001
fMPO	3.74 mg/kg	2.42 mg/kg	0.10 mg/kg	<0.0001	<0.0001
fNGAL	7.30 mg/kg	6.78 mg/kg	2.36 mg/kg	<0.0001	<0.0001
fEDN	0.50 mg/kg	1.79 mg/kg	0.29 mg/kg	0.049	<0.0001
sCP	4186 µg/L	4124 µg/L	3037 µg/L	0.0145	ns
sMPO	291.6 µg/L	291.2 µg/L	151.3 µg/L	0.0006	0.0038
sNGAL	240.2 µg/L	239.5 µg/L	162.2 µg/L	<0.0001	0.0004
sEDN	29.07 µg/L	24.54 µg/L	19.4 µ/L	0.0020	ns

Four biomarkers were elevated in active UC vs remission: fCP (610.9 mg/kg vs 45.5 mg/kg, p=0.0180), fMPO (6.84 mg/kg vs 1.30 mg/kg, p=0.0479), sCP (4599 µg/L vs 3128 µg/L, p=0.0194) and sNGAL (298.3 µg/L vs 189.3 µg/L p=0.0012). No association was observed between the biomarkers and disease activity in CD.
Patients with extensive UC had significantly higher levels, compared to patients with left-sided UC, of fCP (851.6 mg/kg vs 148.3 mg/kg, p=0.0135), fMPO (17.67mg/kg vs 2.84 mg/kg, p=0.0493) and fEDN (1.34 mg/kg vs 0.36 mg/kg, p=0.0146). None of the biomarkers were associated with disease localization in CD.

Conclusion

Faecal and serum CP, MPO, NGAL and EDN may be used as diagnostic biomarkers to differentiate patients with IBD from IBS. Our study indicates that fMPO may be used as an alternative to fCP as disease activity marker in UC, and that sCP and sNGAL are promising novel serum markers for disease activity. In addition to the neutrophil markers, fEDN could be of value for characterization of extensive disease in UC patients. The higher fEDN levels in CD compared to UC observed in the present study indicates an important role of activated eosinophils in the clinical manifestation of CD.
The biomarkers MPO, NGAL and EDN measured both in faecal and serum could, in addition to CP, potentially aid in the clinical decision-making in IBD.

Disclosure

H Ekoff, N Rydell and R Movérare are employed by Thermo Fisher Scientific.

Introduction

Apelin, an adipokine secreted from visceral fat, has been associated with endothelial cells dysfunction‐related chronic inflammatory diseases. Decreased serum apelin levels have been found in patients with cardiovascular disease (CVD). Higher apelin levels have been measured in mesenteric adipose tissue and inflamed colonic epithelium of patients with Inflammatory Bowel Disease (IBD), but data on the role of serum apelin levels in IBD patients are lacking.

Aims & Methods

We aimed to a) compare serum apelin levels between 104 consecutive IBD patients and 104 age and sex matched healthy controls (blood donors), b) to evaluate the correlation between serum apelin levels with demographics, disease characteristics, treatment and disease course.
Serum apelin-13 levels were measured using ELISA (Wuhan Fine Biological Technology Co., Ltd). Statistical analysis was performed with SPSS 24 (SPSSInc. Chicago, IL, USA).

Results

Mean apelin levels were significantly higher in IBD patients compared to their matched healthy controls (1996.29 ± 1592.96pg/ml vs 1552.99 ± 809.64, p=0.012). Among the examined parameters only smoking was found independently associated with serum apelin levels in IBD patients (p<0.001).
IBD patients with CVD (25) had lower but not significant different serum apelin levels compared to patients without CVD (79) (1743.01 ± 1116.26pg/dl vs 2465.09 ± 2006.51pg/ml, p=0.122). In a subgroup analysis of patients without CVD (79 IBD patients) significantly elevated serum apelin levels were found in patients with extended UC, history of immunomodulator use and absence of musculoskeletal EIMs (2539,69 ± 1969.29pg/ml vs 1164.45 ± 818.89pg/ml, p=0.044, 2317.69 ± 1867.99pg/ml vs 1451.40 ± 1024.20pg/ml, p=0.043 and 2340.58 ± 1850.16pg/ml vs 1392.09 ± 1054.99pg/ml, p=0.027, respectively).
Finally, a moderate positive correlation was found among UC extent and serum apelin levels in patients without CVD (r=0.525, p=0.004). Νegative correlations were found among age at study entry and serum apelin levels in both IBD patients without CVD and all IBD patients (r=-0.263, p=0.001 and r=-0.214, p=0.002, respectively) and between immunomodulator use, history of musculoskeletal EIMs and serum apelin levels in patients without CVD (r=-0.26, p=0.021 and r=-0.336, p=0.005, respectively).

Conclusion

The circulating serum apelin levels are significantly increased in IBD patients compared to matched healthy controls. Increased apelin levels are independently associated with smoking status and disease extend (in UC). IBD patients with musculoskeletal manifestations have decreased serum apelin levels compared to IBD patients without musculoskeletal manifestations. Further investigation with larger studies on the role of serum apelin in IBD is needed.

Disclosure

None

Introduction

The therapeutic goal in inflammatory bowel disease (IBD), which includes Crohn´s disease (CD) and ulcerative colitis (UC), is the control of the inflammatory process through drugs (biologic and JAK-inhibitor therapies) that generally have a high cost and may have side effects. Unfortunately, only one-third of patients respond to these treatments and there are no markers that accurately predict this response.

Aims & Methods

The aim of this study was to identify potential serum metabolic biomarkers predictive of response to different drugs for IBD at baseline (before treatment), which could facilitate the selection of the most appropriate therapy for each patient. For this purpose, a prospective and multicenter study was conducted including CD and UC patients who initiate biologic (anti-TNF, ustekinumab or vedolizumab) or JAK-inhibitor (tofacitinib) therapies. Patients were assessed at 14 weeks to determine if they had achieved endoscopic response, based on the SES-CD and on the endoscopic sub score of the Partial Mayo Score. The analysis of the serum metabolome and deconvolution of the serum lipoprotein profile into 110 fractions were conducted using nuclear magnetic resonance for quantitative differential analysis comparing baseline serum samples of responders compared with non-responders.

Results

A total of 150 patients were included (30 CD anti-TNF, 30 UC anti-TNF, 30 CD ustekinumab, 30 UC vedolizumab, and 30 UC tofacitinib). Table 1 shows a summary of the most relevant results obtained during the metabolomic analysis, which revealed metabolites and lipoproteins (common or drug-specific) with significantly altered levels (p<0.05) in the baseline serum samples of subsequent responders compared to non-responders. Moreover, based on ROC curves, potential biomarkers with good sensitivity and specificity for distinguishing between responders and non-responders before treatment were identified. Finally, our analysis identified alanine, aspartate, glutamate, arginine and butanoate metabolism, and the citrate cycle, as the main baseline altered metabolic pathways that could be associated with the response to IBD treatment.

Table 1. Summary of identified potential metabolic biomarkers predictive of endoscopic response to IBD treatment.

Study group	Number of Biomarkers*		Best AUC values**
	Metabolites	Lipoproteins
CD anti-TNF	2	3	0.83; 0.81; 0.78; 0.75; 0.74
UC anti-TNF	1	7	0.88; 0.84; 0.83; 0.77; 0.76; 0.73
CD ustekinumab	4	24	0.96; 0.95; 0.94; 0.91; 0.90; 0.89; 0.87; 0.80
UC vedolizumab	5	8	0.90; 0.79; 0.78
UC tofacitinib	3	8	0.98; 0.96; 0.91; 0.88; 0.87; 0.85

​*Biomarkers with significantly altered levels (p<0.05) in the baseline serum of responders vs non-responders patients. **AUC corresponding to the biomarkers with the best sensitivity and specificity for distinguishing between responders and non-responders patients before treatment. AUC: Area Under the Curve calculated using the Metabolanalyst software in univariate analysis; CD: Crohn's disease; IBD: Inflammatory bowel disease; UC: Ulcerative colitis.

Conclusion

The present study represents an effort towards personalized medicine in targeted therapy selection in IBD patients, which is an important unmet need. Although it needs further validation, we were able to identify a number of serum metabolites and lipoproteins with the potential of predicting response to biologic and JAK-inhibitor therapies.