Autophagy is the evolutionarily conserved process by which eukaryotic cells engulf their own cytoplasmic contents and deliver them to lysosomes for degradation. Long caricatured as a blunt recycling program switched on during starvation, it is now understood to be a highly selective operation that targets protein aggregates, damaged mitochondria, and invading microbes with remarkable precision. In the intestine, this matters enormously. The gut lining exists in a state of permanent negotiation with trillions of microbes, and the epithelial cells, Paneth cells, goblet cells, and immune populations that maintain the barrier all depend on autophagy to clear cellular debris, secrete antimicrobial peptides, and keep inflammatory signaling in check. When the machinery falters, the result is precisely the pathology seen in inflammatory bowel disease: bacterial persistence, epithelial death, and runaway cytokine production.

The review dissects the canonical pathway in three sequential phases. Initiation begins with the ULK1 kinase complex, composed of ULK1, ATG13, FIP200, and ATG101, which senses cellular energy status through its upstream regulators AMPK and mTOR. In intestinal epithelial cells, this regulatory node behaves in strikingly context-dependent ways. Under glucose deprivation, AMPK activation can suppress ULK1 and dampen autophagy, yet during energy crisis it also protects ULK1 from caspase-mediated degradation, preserving the cell’s capacity to recover. mTOR, frequently activated in inflammatory bowel disease by cytokines such as TNF-alpha and IL-6, does the opposite: it inhibits ULK1, crippling the clearance of intracellular pathogens and damaged organelles. ULK1 is further fine-tuned by ATG8-family proteins, with GABARAP and GABARAPL1 acting as positive regulators while LC3B and LC3C exert negative control, and its activity is modulated by post-translational modifications including ZDHHC13-mediated palmitoylation, which promotes its translocation to autophagosome formation sites.

The clinical consequences of ULK1 dysfunction are vividly illustrated by its relationship with ATG16L1, a Crohn’s disease susceptibility gene. Under nutrient deprivation or infectious stress, ULK1-mediated phosphorylation of ATG16L1 at serine 278 is essential for efficient xenophagy, the selective destruction of intracellular bacteria. But in patients carrying the ATG16L1 T300A variant, that same phosphorylation event triggers caspase-3-mediated cleavage of ATG16L1, destroying the protein and precipitating more severe inflammation. This single molecular interaction explains why T300A carriers are disproportionately susceptible to disease flares during infection. ULK1 signaling also protects the epithelial barrier by promoting the degradation of claudin-2, a pore-forming tight junction protein that is upregulated in active disease and linked to diarrhea, meaning that defective ULK1 activity can directly worsen barrier leakiness in genetically vulnerable individuals.

The elongation phase, during which the phagophore membrane expands and seals into a double-membraned autophagosome, is governed by the Beclin 1-VPS34 complex and the ATG12-ATG5-ATG16L1 conjugation system, which drives lipidation of LC3 into its membrane-bound LC3-II form. Here the review issues an important methodological warning: the widely used LC3-II/I ratio is ambiguous, since an elevated value may reflect either enhanced autophagosome formation or blocked downstream degradation. Interpreting it requires flux assays with lysosomal inhibitors such as bafilomycin A1. With that caveat, the evidence points to a Goldilocks principle. In interleukin-10-deficient mice, a reduced LC3-II/I ratio was restored by xylo-oligosaccharide supplementation, coinciding with decreased bacterial penetration and restored goblet cell function. Conversely, in several colitis models where the ratio was pathologically elevated, traditional formulations such as Huangkui Lianchang Decoction lowered it along with pro-inflammatory cytokines, and excessive autophagic activity damaged the interstitial cells of Cajal that coordinate intestinal motility. Both too little and too much elongation, it seems, sabotage the gut.

Perhaps the most clinically revealing section concerns termination. Counterintuitively, several major IBD risk variants do not impair the final fusion of autophagosomes with lysosomes at all. Cells carrying the T300A variant display normal LC3-II flux and SQSTM1 degradation during starvation, indicating intact fusion machinery. IRGM deficiency instead impairs autolysosomal acidification and cargo degradation during infection with adherent-invasive E. coli, a defect rescued by wild-type IRGM, while the MTMR3 risk variant suppresses early autophagosome formation without affecting degradation of those that do form. The pathophysiology, the authors conclude, resides not in a universal failure of the disposal system but in defective selective autophagy, particularly within specialized secretory cells.

That selective layer comprises three specialist pathways. Mitophagy, mediated by the PINK1-Parkin axis or receptors such as Nix/BNIP3L, clears depolarized mitochondria before they spill reactive oxygen species and mitochondrial DNA that activate the NLRP3 inflammasome. Its importance is cell-type specific: CD8-positive T cells and memory lymphocytes depend critically on mitophagy to sustain mitochondrial quality and fatty acid oxidation, whereas CD4-positive T cells tolerate its loss far better. In ulcerative colitis patients, the transcription factor ATF7, which directly activates PINK1 expression, is reduced in colonic mucosa and correlates negatively with disease severity. Yet mitophagy is a double-edged sword: Parkin can paradoxically worsen colitis by degrading the vitamin D receptor, and abnormally activated Piezo1 channels can drive mitochondrial calcium overload and ferroptosis through excessive mitophagy. ER-phagy, the second pathway, manages endoplasmic reticulum stress in protein-secreting Paneth and goblet cells, where the IRE1-alpha-XBP1 arm of the unfolded protein response supports mucin production under moderate stress but collapses into apoptosis and mucus layer disruption when chronically engaged. Xenophagy, the third, directly destroys intracellular bacteria, and its genetic disruption, whether through ATG16L1 T300A or a 20-kilobase IRGM deletion that impairs phagosome maturation in a dose-dependent manner, allows persistent bacterial survival, prolonged antigen exposure, and heightened risk of colitis-associated cancer.

Adding a further layer of complexity, the review catalogues the non-autophagic functions of autophagy-related genes. ATG16L1 influences epithelial sensitivity to interferon-gamma-induced apoptosis, secretory granule architecture, and NOD1/2-driven cytokine release through mechanisms that may operate independently of autophagosome formation, though the extent of that independence remains debated. ATG5 modulates Toll-like receptor signaling in B cells and antigen presentation in the thymus, while TRIM31-mediated surrogate autophagy can clear Shigella even without ATG5, and TRIM31 is downregulated by 45 percent in Crohn’s disease epithelium despite unchanged ATG5 mRNA. IRGM, meanwhile, binds the NLRP3 inflammasome and scaffolds the NOD2-ATG16L1 complex at bacterial entry sites through ubiquitin-dependent mechanisms that do not require full autophagic flux. These findings complicate any simple equation of autophagy gene variants with autophagy defects alone.

The therapeutic implications are already tangible. Infliximab and other TNF-alpha inhibitors restore xenophagic clearance of adherent-invasive E. coli and enhance autophagic flux in macrophages, yet patients carrying NOD2 or ATG16L1 risk alleles show accelerated drug clearance and higher relapse rates within six months. Ustekinumab, by contrast, appears to work through the STAT3-p62 axis of selective autophagy and retains effectiveness in T300A carriers, while the JAK1 inhibitor upadacitinib activates AMPK-driven protective autophagy and alleviates ER stress. The overarching message of the review is that autophagy in inflammatory bowel disease is neither hero nor villain but a context-dependent force: protective during acute inflammation, potentially pathogenic when chronically hyperactivated or suppressed, and exquisitely sensitive to cell type, genetic background, and microbial environment. Mapping that context, the authors argue, is the prerequisite for the next generation of autophagy-targeted precision therapies.

Subject of Research: The role of canonical and selective autophagy pathways in the pathogenesis of inflammatory bowel disease

Article Title: Canonical pathways and selective mechanisms of autophagy in inflammatory bowel disease

Article References: Lin, R., Xu, Z., & Zhi, M. (2026). Canonical pathways and selective mechanisms of autophagy in inflammatory bowel disease. Advanced Biotechnology, 4(1), Article 4. https://doi.org/10.1007/s44307-026-00094-y

Image Credits: AI Generated

DOI: 10.1007/s44307-026-00094-y

Keywords: autophagy, inflammatory bowel disease, Crohn's disease, ulcerative colitis, ATG16L1, ULK1, mitophagy, xenophagy, ER-phagy, IRGM, intestinal barrier, biologics