Although it seems clear that an abnormal function of the colonic epithelium is the central problem causing inflammation and the unusual immunological response to the normal gut flora in inflammatory bowel disease (IBD), the actual causes of these dysfunctions are still unknown. Short Chain Fatty Acids (SCFA) are the main fuel of the colonic epithelium, and are normally produced by the bacterial flora by fermentation of the complex carbohydrates forming non soluble fibers usually introduced with everyday diet. Butyrate alone contributes 70% of the normal colonocyte energy. Studies done using animal models and colonic mucosa biopsies from patients suffering form ulcerative colitis (UC) have consistently shown that a metabolic change occurs in diseased colonic mucosa, with an impairment of butyrate oxidation (and of beta-oxidation) and an energy shortage that is only incompletely compensated by oxidation of glucose and other substrates such as glutamine. It is also well known that matrix metalloproteases production is highly increased in IBD and that serum transglutaminase activity is significantly reduced in patients with IBD. Transglutaminases are enzymes contributing to the crosslinking of matrix proteins and the reduction seen in patients affected by IBD correlates well with the endoscopic and histopathologic grading in UC, meaning that part of the circulating enzyme is sequestered in the injured colonic tissue in the effort to re-build the extracellular matrix during the healing process. Propionyl-L-carnitine Hydrochloride (PLC) is a molecule that has already been shown to reduce membrane lipid peroxidation in endothelial cells from bovine aorta and coronary vessels, to reduce the effects of hypoxia in coronary endothelial cells, and to play a role in the cardiac metabolic abnormalities that contribute to the mechanical dysfunctions leading to heart failure. Given these properties of Propionyl-L-carnitine Hydrochloride (ST 261) and given the peroxidative damage suffered by colonocytes in UC together with their metabolic impairment, the use of this molecule for the treatment of UC seemed to be appropriate and sound, in particular as a carrier of a propionate moiety that, once transformed into succinate, enters the Kreb cycle, acting as an extra burst fuel improving the balance of energy production inside tissues. Previous clinical experience has shown that PLC promoted complete or nearly complete regression of cutaneous trophic ulcers in a large number of vasculopathic patients refractory to all other therapies. As far as the UC pathology is concerned, the effects of ST 261, given orally or intrarectally, were investigated at different dosages, in preclinical experimentation, either after a single trinitrobenzene sulphonic acid (TNBS) administration (acute colitis) or after repeated TNBS administrations (reactivated colitis). The results showed a reduction in the damaged colon area both in acute model and reactivated colitis, even if the beneficial effect of restoration of TNBS-induced alterations of tissue morphology is more evident in the reactivated colitis model, particularly after oral administration. Based on the above-described results a development plan in humans started to investigate the activity of PLC in the treatment of ulcerative colitis.