This review will focus on how differing developmental processes in the intestinal epithelium affect the macromolecular passage in different species and the possible impact of such passage on the establishment of immunity during the critical perinatal period in young mammals.

Studies have highlighted the existence of two intra-pancreatic axes of communication: one involved in the regulation of enzyme production by insulin—the insular–acinar axis; and another involved in the regulation of insulin release by pancreatic enzymes—the acini–insular axis. Previous studies by our laboratory show that pancreatic enzymes can affect blood glucose homeostasis and insulin secretion independently of their digestive functions, both from the gut lumen and probably from the blood. As a result we would like to introduce here the concept of acini–islet–acinar (AIA) axis communication (feedback), which could play an important role in the development of obesity and diabetes type 2. The AIA feedback links the endocrine and exocrine parts of the pancreas and emphasizes the essential role that the pancreas plays, as a single organ, in the regulation of glucose homeostasis by amylase most probably in gut epithelium and by insulin and glucagon in peripheral blood.

Limitations in efficacy and/or tolerance of currently available urate-lowering therapies (ULTs), such as oral xanthine oxidase inhibitors, uricosurics, and intravenous uricase agents contribute to the development of refractory gout. Renal excretion is the major route of uric acid elimination, but the intestinal tract plays an increasingly recognized role in urate homeostasis, particularly in chronic kidney disease (CKD) in which the renal elimination of urate is impaired. We targeted intestinal degradation of urate in vivo with ALLN-346, an orally administered, engineered urate oxidase, optimized for proteolytic stability, and activity in the gut. We tested ALLN-346 in uricase/urate oxidase deficient mice (URKO mice) with severe hyperuricemia, hyperuricosuria, and uric acid crystalline obstructive nephropathy. A total of 55 male and female URKO mice were used in the two consecutive studies. These seminal, proof-of-concept studies aimed to explore both short- (7-day) and long-term (19-day) effects of ALLN-346 on the reduction of plasma and urine urate. In both the 7- and 19-day studies, ALLN-346 oral therapy resulted in the normalization of urine uric acid excretion and a significant reduction of hyperuricemia by 44 and 28% when therapy was given with food over 24 h or was limited for up to 6 h, respectively. Fractional excretion of uric acid (FEUA) was normalized with ALLN-346 therapy. Oral enzyme therapy with engineered urate oxidase (ALLN-346) designed to degrade urate in the intestinal tract has the potential to reduce hyperuricemia and the renal burden of filtered urate in patients with hyperuricemia and gout with and without CKD.