Lack of gastric acidification reduces postprandial energy expenditure and protein digestion but not growth in <i>Astyanax mexicanus</i>

The vertebrate stomach is responsible for the secretion of hydrochloric acid (HCl) and is the first site of protein digestion in the gut. The secretion of HCl occurs through the gastric proton pump, a hydrogen-potassium ATPase (HKA) composed of α and β subunits encoded by the ATP4A and ATP4B genes, respectively. In the past, the evidence for the role of the gastric acid secretion in nutrient digestion and absorption, growth, and postprandial energy metabolism has been gathered using indirect methods such as diet modulation experiments, or the use of proton-pump inhibitors. These methods may introduce confounding factors and lead to erroneous conclusions. With the aim of directly observing the role of the gastric proton pump, we have generated a knockout (KO) model using targeted gene editing. Using atp4a-null Astyanax mexicanus, we examined the growth rate, nitrogen and energy metabolism, and nutrient assimilation in the presence and absence of gastric acidification. Our results show no effect of KO on growth or appetite, but a significant reduction in post-prandial nitrogen excretion and oxygen consumption (specific dynamic action). Furthermore, atp4a-/- animals had significantly less body magnesium, calcium, phosphorus and protein, while having more lipid in their carcasses. Importantly, administration of proton-pump inhibitors suppressed growth in both experimental groups indicating possible off-target effects of these drugs. This study is the first to directly examine the impact of gastric acidification on body composition, growth and metabolism and offers new and targeted evidence on the importance of stomach acidification for gut and digestion homeostasis.