Targeted 1H NMR metabolomics and immunological phenotyping of human fresh blood and serum samples discriminate between healthy individuals and inflammatory bowel disease patients treated with anti-TNF

Abstract

Inflammatory bowel disease is a multifactorial etiology, associated with environmental factors that can trigger both debut and relapses. A high level of tumor necrosis factor-α in the gut is the main consequence of immune system imbalance. The aim of treatment is to restore gut homeostasis. In this study, fresh blood and serum samples were used to identify biomarkers and to discriminate between Crohn’s disease and ulcerative colitis patients under remission treated with anti-TNF. Metabolomics based on Nuclear Magnetic Resonance spectroscopy (NMR) was used to detect unique biomarkers for each class of patients. Blood T lymphocyte repertories were characterized, as well as cytokine and transcription factor profiling, to complement the metabolomics data. Higher levels of homoserine-methionine and isobutyrate were identified as biomarkers of Crohn’s disease with ileocolic localization. For ulcerative colitis, lower levels of creatine-creatinine, proline, and tryptophan were found that reflect a deficit in the absorption of essential amino acids in the gut. T lymphocyte phenotyping and its functional profiling revealed that the overall inflammation was lower in Crohn’s disease patients than in those with ulcerative colitis. These results demonstrated that NMR metabolomics could be introduced as a high-throughput evaluation method in routine clinical practice to stratify both types of patients related to their pathology. Key messages NMR metabolomics is a non-invasive tool that could be implemented in the normal clinical practice for IBD to assess beneficial effect of the treatment. NMR metabolomics is a useful tool for precision medicine, in order to sew a specific treatment to a specific group of patients. Finding predictors of response to IFX would be desirable to select patients affected by IBD. Immunological status of inflammations correlates with NMR metabolomics biomarkers.

Metabolomics Insights into Inflammatory Bowel Disease: A Comprehensive Review

“…In another study, Scoville et al reported a decrease in essential (leucine, lysine, and valine), semi-essential (arginine and glutamine), and nonessential (serine) amino acids in CD serum samples compared to control subjects, but no differences in serum amino acids in UC compared with controls [25]. Consistently with previous studies, Notararigo et al found lower levels of creatine, proline, and tryptophan in UC patients, reflecting a deficit in the absorption of essential amino acids in the gut [27].…”

“…Recently, Notararigo et al used NMR to detect unique biomarkers for different IBD classes, reporting higher levels of homoserine-methionine and isobutyrate in ileocolonic CD. In addition, among the three CD location types, according to the Montreal classification (ileocolic, ileal, and colonic), only ileocolonic showed significant differences versus control subjects [27].…”

“…Amino-acid malabsorption results in higher levels of amino acids in faeces and lower levels in the urine and blood of IBD patients. Several studies support this hypothesis, reporting increased levels of amino acids in stool samples of IBD patients compared to controls [39,[52][53][54][55], together with decreased levels of amino acids in the serum of IBD patients [25,27,29,33,39,44]. Such results suggest that patients suffering IBD exhibit an impaired absorption of amino acids in the gut, likely due to inflammation and mucosal damage [24].…”

“…Regarding anti-TNF therapy, IBD patients not responding to infliximab were identified as a potentially distinct group according to their metabolic profile, although no applicable response biomarkers could be identified in serum [23]. Interestingly, in a recent study, ileocolic CD patients in remission due to anti-TNF treatment showed an increase in serum SCFA with respect to control subjects [27], pointing to potential serum response biomarkers. Another study conducted in serum, urine, and faeces obtained promising results for the prediction of response to anti-TNF therapy in CD.…”

“…In this sense, longitudinal studies are key for correlating a metabolomic profile with the response to treatment and ongoing disease activity. Few longitudinal studies (excluding interventional studies) have been performed in IBD patients and control subjects, revealing that adequate monitoring is crucial for identifying disease relapse and response to treatments [23,27,36].…”