Although H2S is generated by the host and is increasingly recognized to have a multitude of important beneficial physiologic functions [33], it becomes a potent toxin once its concentration exceeds the detoxifying capacity in the tissue. Specifically, higher amounts of H2S generated in the intestine have the potential to disrupt the gut barrier function, which may be an early and critical initiating event in triggering the onset of UC and the perpetuation of its activity [34]. Traditionally, the H2S toxin hypothesis has focused on the potential injurious effects of sulfide gas on the cellular metabolism of colonocytes, mainly the inhibition of cytochrome c oxidase activity in mitochondria, which induces oxidative stress in a fashion similar to cyanide [35]. Roediger and colleagues demonstrated that H2S inhibits β-oxidation of butyrate by colonocytes, their preferred energy source [36]. Notably, UC mucosa has lower rates of butyrate uptake and oxidation relative to healthy controls [37]. In summary, oxidative stress and energy starvation caused by excessive H2S concentrations may lead to colonocyte death, penetration of the epithelial barrier by the intestinal microbes and their direct interaction with the mucosal immune system. Resulting inflammation leads to further disruption of the gut barrier, decreased butyrate oxidation [37], and decreased mucosal sulfide detoxification and the subsequent perpetuation of inflammation [38].
