Susceptibility to
Crohn's disease, a complex
inflammatory disease involving the
small intestine, is controlled by over 30 loci. One
Crohn's disease risk
allele is in
ATG16L1, a gene homologous to the essential
yeast autophagy gene ATG16 (ref. 2). It is not known how
ATG16L1 or autophagy contributes to
intestinal biology or
Crohn's disease pathogenesis. To address these questions, we generated and characterized
mice that are
hypomorphic for
ATG16L1 protein expression, and validated conclusions on the basis of studies in these
mice by analysing
intestinal tissues that we collected from
Crohn's disease patients carrying the
Crohn's disease risk
allele of
ATG16L1. Here we show that
ATG16L1 is a bona fide autophagy protein. Within the ileal
epithelium, both
ATG16L1 and a second essential autophagy protein
ATG5 are selectively important for the biology of the
Paneth cell, a specialized
epithelial cell that functions in part by
secretion of granule contents containing
antimicrobial peptides and other proteins that alter the
intestinal environment. ATG16L1- and ATG5-deficient
Paneth cells exhibited notable abnormalities in the granule
exocytosis pathway. In addition,
transcriptional analysis revealed an unexpected
gain of function specific to ATG16L1-deficient
Paneth cells including increased
expression of genes involved in
peroxisome proliferator-activated receptor (
PPAR) signalling and
lipid metabolism, of
acute phase reactants and of two
adipocytokines,
leptin and
adiponectin, known to directly influence
intestinal injury responses. Importantly,
Crohn's disease patients
homozygous for the
ATG16L1 Crohn's disease risk
allele displayed
Paneth cell granule abnormalities similar to those observed in autophagy-protein-deficient
mice and expressed increased levels of
leptin protein. Thus,
ATG16L1, and probably the process of autophagy, have a role within the
intestinal epithelium of
mice and
Crohn's disease patients by
selective effects on the
cell biology and specialized regulatory properties of
Paneth cells.
