Accumulation of cellular damage, inflammation and loss of regenerative capacity are major challenges that tissues have to overcome to keep their functionality. In superior eukaryotes, cell replacement is a key process for tissue maintenance, particularly relevant when damages surpass the protection and repair mechanisms in cells. The intestinal epithelium is in constant replacement throughout life (every 3–5 days in mouse and 5–7 days in humans), being one of the tissues with the highest renewal rate, possibly due to the high cellular activity and damage during nutrient absorption and to the continuous exposure to the lumen adverse environment [1,2]. Intestinal epithelium renewal is driven by a small population of adult stem cells (intestinal stem cells; ISCs) that reside in specialized niches called crypts [3]. The ISCs are the source of the different cell types that compose the intestinal epithelium, each with a specific role that give the functional characteristics to the intestine. The Paneth cells (PCs) are interspersed between each ISCs and, in addition to their intestine protecting functions, have a determinant role in the stemness maintenance of ISCs by providing signals such as EGF, Notch ligands and Wnt [4,5] or, in extreme circumstances, by acquiring stem-like features [6]. The loss of intestine regenerative capacity with aging has been linked to the exhaustion of ISCs, whereas the development of epithelial barrier leakiness, reduced antimicrobial protection and microbial dysbiosis, all alterations associated with intestinal diseases, can directly relate to the loss of PC functions [1,7,8]. In agreement with the relevant role of PCs in the establishment of a fully functional intestine, the necrotizing enterocolitis syndrome, a common pathology of premature infants or newborns with low body weight, and the Crohn's disease, a chronic inflammatory bowel pathology that affects young and old patients, are both associated with a loss in PC functions [9,10].

Fatty acid (FA) oxidation plays a role in the maintenance and function of many stem cell populations including ISCs [11]. Accordingly, intestinal crypt cells have a large capacity to import FA [12], and metabolic interventions where FA metabolism is altered, such as fasting and high fat or ketogenic diets, have a significant impact on ISCs behavior [[13], [14], [15], [16]]. In addition, Cpt1-mediated FA oxidation in mitochondria of ISCs is a key requirement for their maintenance and induced intestinal epithelium renewal [15], a mechanism that appears to be conserved in ISCs of Drosophila melanogaster [17]. Downstream, HMGCS2, the limiting enzyme in the conversion of acetyl-CoA into ketone bodies, is also relevant for ISC maintenance. Ketone bodies in ISC contribute to Notch signaling by inhibiting histone deacetylases [13]. Interestingly, the reduced number of ISCs in the intestine of aged mice correlates with a low FA oxidation activity [15].

Very long chain fatty acids (VLCFA) are mainly catabolized in peroxisomes [18]. As a by-product of the peroxisomal β-oxidation of these VLCFAs, hydrogen peroxide (H2O2) is produced. Thus, several β-oxidation cycles from the starting VLCFA increase the levels of H2O2 and of several FA-derived metabolites in peroxisomes, including acyl-CoA derivatives that incorporate into mitochondria and contribute to establish the levels of acetyl-CoA and, under certain circumstances, also of ketone bodies. On the other hand, in mitochondria, through the trichloroacetic acid cycle, acetyl-CoA fuels the oxidative phosphorylation chain, a major source of reactive oxygen species (ROS [19]). Therefore, it is possible that, directly or indirectly, ROS produced in peroxisomes and mitochondria through lipid metabolism, influence intestinal epithelium homeostasis. The increase in peroxisomes in ISC after injury with the consequent promotion of intestine regeneration, observed in flies and mammals [20], and the influence of oxidative phosphorylation and mitochondria-derived ROS in stem cell function in intestinal crypts [21] support this possibility.

In tissues, the levels of ROS are determined by their production, frequently in association with metabolic activities such as those mentioned above, and also by the antioxidant capacity. In aging, the increase in ROS is estimated from the accumulation of oxidative damage [22,23], which in some instances has been correlated with an increase in antioxidant activities [[24], [25], [26]]. Several antioxidant enzymes are compartmentalized in certain organelles where it is expected that they displayed a specific role. For instance, in peroxisomes, catalase (CAT) is the main antioxidant enzyme that prevents from H2O2 accumulation during FA β-oxidation [18]; thus, the impaired capacity of peroxisomes of aged cells to import catalase [27,28], as well as other peroxisomal defects, could have significant pathological consequences [29,30]. Acatalasemia (i.e., very low CAT activity) in humans generally does not cause health problems but increased incidence of several age-related diseases, particularly diabetes, has been observed [31,32]. In mitochondria, nicotinamide nucleotide transhydrogenase (NNT), an enzyme powered by the proton gradient generated by the respiratory chain, produces NADPH that, through its essential role in glutathione regeneration, provides an important antioxidant activity against the elevated production of ROS in active mitochondria [33,34]. Mitochondrial failure has been proposed at the bottom of many degenerative disease [35] and, in particular, the lack of NNT causes glucocorticoid deficiency in mice and humans [36] and, at least in mice, is associated with increased body weight gain under control and high-fat diets [36].

Presently, although increased levels of ROS are expected, there is no evidence that the lack of CAT or NNT in mice causes an early in life general oxidative damage [37,38], suggesting a mild and/or a restricted elevation in ROS in these conditions. Interestingly, however, a deficiency in either Cat or Nnt genes causes significant metabolic alterations of fatty acids [[37], [38], [39]]. In addition, the interaction between these two enzymes is revealed from the increased accumulation of fat in the liver and adipose tissue when both CAT and NNT are lacking [40,41]. Because this latter interaction and the fact that mice of the C57BL/6J strain lacking NNT are commonly used for gene function characterization, we consider particularly relevant to determine the role of NNT in intestinal epithelium renewal in the presence or absence of CAT. Here we report that the loss of CAT and/or NNT cause intestinal abnormalities, likely by a mechanism involving alterations in fatty acid metabolism, that parallel those found in the aged intestine and are causal of specific intestinal diseases.