Abstract One million Americans live with Ulcerative Colitis (UC), and 30% of that population is over 60. Thirty-eight thousand new cases are diagnosed yearly, with 15% over 65. More than a quarter of UC patients are aged, and prevalence in the over 65 is increasing at an annual rate of 2.8%. Surgery treatment is risky in geriatric patients, and better therapy is needed. UC is an immune-mediated disorder of the colon that is debilitating and not medically curable. Extensive studies have shown a pathogenesis due to aberrant immune responses to the intestinal microbiota, resulting in acute and chronic inflammations characterized by infiltrates of activated macrophages (MΦ), neutrophils (Ns), and lymphocytes, indicating a deregulated activation of the intestine- innate immunity responder cells (MΦ and Ns). In UC, correlating with this deregulation is the unusual expression of the Triggering Receptor Expressed on Myeloid cells-1 (TREM1) on the intestinal MΦ and the presence of activated platelets expressing a ligand for TREM1. TREM1 is a potent activation receptor of MΦ and Ns, and its excess triggering leads to the overproduction of inflammatory mediators and excess inflammation. Two-thirds of patients obtain only partial or no benefit from current therapies, specifically those with MΦ high-TREM1 expression sustained inflammation. Over 1400 scientific articles document the role of the TREM1-activation pathway (TAP) in inflammation. We have identified TREM1-sv, a natural splice variant and competitive inhibitor of TREM1, which can downregulate TAP. TREM1-sv was very efficient at downregulating excess inflammation in preclinical sepsis trials, a disease driven by a deregulated TAP. In UC, deregulation of TAP might occur from depletion of TREM1-sv, ensuing persistent activation of myeloid cells from activated platelets. We anticipate that administering TREM1-sv intravenously or subcutaneously will stop the excess inflammation. The rationale is that TREM1-sv downregulates TAP by competing for the TREM1 ligands, thereby reducing the number of TREM1-ligand complexes and avoiding an excess triggering activation of MΦ and Ns. Hence, the intestine can recover a healthy immunity and heal. We aim to show therapeutic efficacy by conducting experiments in which different regimens of TREM1-sv are administered to well-established mouse models of chronic ulcerative colitis with altered innate immunity. We use a custom-made strain of P. pastoris to produce a batch of purified biologically active human recombinant (hu r) TREM1-sv for animal treatments. After induction of UC, inflammation will be assessed before and after hu rTREM1-sv treatment with an established four-parameter UC scoring system and correlated with measurements in the blood of the inflammatory cytokine levels and TREM1-sv concentration. Neutralization experiments with an anti-TREM1-sv antibody and comparative anti-TNF therapy will be conducted. We aim to produce innovative data demonstrating the bene...