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Inflammatory bowel disease (IBD) includes patients affected by Crohn’s disease or ulcerative colitis. IBD is thought to be a chronic immune-mediated disease, but its origin remains elusive, and this limits new therapeutic approaches. Human endogenous retroviruses (HERVs) originate from ancestral infections and represent 8% of the human genome. HERVs are no longer infectious, but some retroviral sequences can be activated, and their aberrant expressions have been implicated in inflammatory and autoimmune disorders. HERV transcription is regulated by TRIM28 and SETDB1, which are also directly involved in epigenetic processes and modulation of the immune response. Using a PCR real-time Taqman amplification assay, we assessed, for the first time, the transcription levels of pol genes of HERV-H, -K, and -W families of env genes of syncytin 1 (SYN1), SYN2, and HERV-W, as well as of TRIM28 and SETDB1 in the whole blood of 48 patients with Crohn’s disease (CD), 20 with ulcerative colitis (UC), and in healthy controls (HC) of comparable age. The transcriptional levels of HERV-H-pol (p = 0.0003) and HERV-K-pol (p = 0.001) were significantly higher in IBD patients compared with HC, with no differences between patients with CD and UC. No significant differences were found for the remaining HERVs between IBD patients and HC. The transcript levels of TRIM28 were significantly downregulated in IBD patients (p < 0.001), without differences between CD and UC, while the SETDB1 levels were preserved. The enhanced transcription of HERV-H-pol and HERV-K-pol, as well as the impaired activation of TRIM28, were not influenced by clinical disease activity and type of treatment. The overexpression of HERVs and impaired transcription of TRIM28 in patients affected by CD or UC suggest that they might be the main actors in the pathophysiology of IBD, opening the way to innovative targeted interventions.

BackgroundNicotinamide phosphoribosyltransferase (NAMPT) and nicotinic acid phosphoribosyl transferase (NAPRT) are key intracellular enzymes that participate in the biosynthesis on NAD but have also been shown to be released as proinflammatory cytokines. A number of reports have shown that circulating NAMPT is increased in serum of patients with inflammatory disorders, including inflammatory bowel diseases (IBD), while nothing is known regarding circulating NAPRT and the presence of both cytokines in IBD patient stools. In the present study, we evaluated eNAMPT and eNAPRT levels in a large cohort of IBD patients not on biological therapy and in a subset that then was prescribed biologics.MethodsWe conducted a retro-perspective study on 180 patients, of which 111 underwent subsequent biological treatment (adalimumab, vedolizumab, and ustekinumab). We analyzed eNAMPT and eNAPRT concentrations in serum and faces of IBD patients, correlating them with response to biologics.ResultsWe now report that eNAMPT and eNAPRT are significantly increased in both serum and stools of IBD patients. NAMPT and NAPRT levels correlate with disease severity, with C reactive protein and with serum IL-6 levels. Importantly, levels of NAMPT in patients starting treatment with adalimumab correlate with response failure at three months: patients with levels above 4 ng/ml were significantly less likely to obtain benefit. Serum NAMPT as a biomarker of response yields a sensitivity of 91% and a specificity of 100%.ConclusionThe present work strongly suggests that a prospective trial evaluating eNAMPT and eNAPRT levels in relation to response to biologicals in IBD should be initiated.