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Nutrient Modulation of Autophagy: Implications for Inflammatory Bowel Diseases

Marion-Letellier, Rachel PhD*; Raman, Maitreyi MD; Savoye, Guillaume MD*,‡; Déchelotte, Pierre MD*; Ghosh, Subrata MD

doi: 10.1002/ibd.23001
Basic Science Review

Abstract: During nutrient deprivation, autophagy provides the constituents required to maintain the metabolism essential for survival. Recently, genome-wide association studies have identified genetic determinants for susceptibility to Crohn’s disease (CD) such as ATG16L1 and IRGM that are involved in the autophagy pathway. Both disease-carrying NOD2 mutations and ATG16L1 mutations may result in impairment of autophagy. Impairment in autophagy results in impaired clearance of microbes. Ileal CD is associated with Paneth cell loss of function such as decreased production of α-defensins, which may arise from mutations in NOD2 or autophagy genes. Nutrients are able to modify several cellular pathways and in particular autophagy. We summarize the contribution of a variety of dietary components to activate autophagy. Understanding the crosstalk between nutrients and autophagy in the intestine may provide novel targets that have therapeutics potential in intestinal inflammation. Nutrient activation of autophagy may contribute to restoring the Paneth cell loss of function in ileal CD.

Article first published online 9 May 2012

*INSERM Unit U1073, Rouen University and Rouen University Hospital, Rouen, France

Division of Gastroenterology, University of Calgary, Alberta, Canada

Department of Gastroenterology, Rouen University Hospital, Rouen, France.

Reprints: Dr. Subrata Ghosh, MD, Professor and Chairman, Department of Medicine, Division of Gastroenterology, University of Calgary, Alberta, Canada (e-mail:

Received March 25, 2012

Accepted April 09, 2012

Autophagy is an evolutionarily homeostatic, highly conserved process through which cells self-digest their organelles and cytoplasmic components in order to ensure cellular survival and proper function. Autophagy plays a critical role in a number of physiological functions (Table 1). Some of these functions include: 1) promotion of cell survival by providing an amino acid pool to maintain cell homeostasis under conditions of stress such as starvation or oxidative stress; 2) leading to programmed cell death; 3) elimination of intracellular microbes1; 4) affect B- and T-cell homeostasis2,3; 5) a contribution toward major histo-compatibility complex (MHC II) antigen presentation4,5; and 6) affects Toll-like receptors (TLR) function.6



Upon induction of autophagy, an isolation membrane is developed that sequesters cytosolic content to form double-membrane vesicles called autophagosomes The sequestrated material is degraded in autolysosomes, which are the product of maturation resulting from fusion between autophagosomes and lysosomes. During the step of elongation, a cytosolic form of LC3, (ATG8) called LC3-I, is conjugated to the autophagosomal membrane resulting in a membrane-bound form, LC3-II. LC3 is very commonly used as specific marker of autophagy.

Autophagy (Fig. 1) is regulated by a core signaling pathway such as hVPS34 or target of rapamycin (TOR). Upon TOR inhibition, ATG1 and hVPS34 complexes with ATG6 and results to activation of downstream ATG factors necessary for the next execution steps. The best-characterized inducer of autophagy is nutrient deprivation and starvation. The mammalian TOR (mTOR) acts as a nutrient sensor7 due to its ability to integrate environmental factors to adapt a survival response. mTOR controls cell growth by both activating anabolic processes and by inhibiting autophagy. Other inducers of autophagy include immunological stimuli such as interferon-γ (IFN-γ) and tumor necrosis factor-α 8 and Nod agonists.9



This review focuses on nutrient modulation of autophagy and speculates on potential relevance to modulation of intestinal inflammation such as Crohn’s disease (CD). Key genetic mutations associated with CD such as NOD2 (CARD 15) and ATG16L1 have been associated with defective autophagy and microbial clearance.10 Defective autophagy-dependent microbial clearance determined by genetic mutations in CD is considered a central theme in pathogenesis.11 The mechanism by which NOD genes interact with ATG16L1 has been recently elucidated.12 There is considerable interest in modulating autophagy pathways to enhance microbial clearance in CD, in an attempt to rectify the defect resulting from genetic mutations. Given that autophagy and nutrients are closely related, we focus in this review on potential ways in which nutrient modulation may affect autophagy. We then focus on CD as a target disease for such nutrient modulation approaches to ameliorating intestinal inflammation (Table 2).



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During periods of nutrient shortage, autophagy provides the constituents required to maintain the metabolism essential for survival. In one recent study, hepatic autophagosomes were detected by electron microscopy in 4/12 anorexia nervosa patients presenting with acute liver damage,13 whereas none of the controls displayed autophagosomes. Therefore, when cells lack essential nutrients autophagy is activated to supply the required substances. Recent evidence indicates that autophagy in muscle tissue is quantitatively significant given the large mass involved, and contributes toward producing amino acids in conditions of starvation (Table 2).14 Cell growth is regulated by nutrients via TOR signaling and requires the activation of biosynthetic pathways for the generation of macromolecules, including proteins and lipids. The mTOR pathway is crucial to Nod2-mediated tolerance and antiinflammatory cytokines from human macrophages12 and nutrient modulation of mTOR may have direct relevance in modulating inflammation in CD.



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Amino Acids

Changes in the availability of amino acids result in modifications of cell function such as cell signaling or gene expression.15 Arginine, glutamine, and leucine play crucial roles in intestinal growth, integrity, and function through cellular signaling mechanisms. It is increasingly clear that mTOR signaling plays an important role in modulating amino acid-induced intestinal homeostasis.16 An amino acidrich environment enhances mTOR activity, regulates protein translation, and inhibits autophagy. However, deprivation of amino acids leads to recycling of intracellular contents in an attempt to provide an alternate source of amino acids. These events have been described in the intestine. Amino acids deprivation resulting in upregulated autophagy has been identified, as assessed by an increase of LC3 expression in several colon cancer cell lines.17 Activation of S6K by arginine in the intestine has been well described.18,19 Arginine upregulates phosphorylation of S6K in vitro in a model of rat intestinal epithelial cell migration19 and also in vivo in a model of rotavirus-infected piglets.18 In rat intestinal epithelial cells, incubation with the amino acids arginine or leucine results in a regulation of mTOR pathway through S6K and 4E-BP.20

The crucial need of a high concentration of glutamine in cell culture medium established its role in cell proliferation. Glutamine exerts protective effects in intestinal epithelial cells (IECs)21–23 and may possibly involve autophagy. First, we have previously shown by a proteomic approach that a 12-hour incubation with glutamine (from 2–10 mM) led to a downregulation of autophagy protein 5 expression in enterocyte-like HCT-8 cell line under apoptotic conditions.24 Second, Sakiyama et al25 performed a well-designed study to better understand the mechanisms underlying the role of glutamine on autophagy in IECs. Twenty-four-hour incubation of both intestinal epithelial cell lines Caco-2BBE and IEC-18 with increasing concentrations of glutamine (from 0–2.8 mM) results in an upregulation of LC3-II and a number of autophagosomes. The range of glutamine concentrations used in cell culture experiments is often a subject of debate. Indeed, IECs including HCT-8, Caco-2BBE, and IEC-18 are routinely grown in a culture medium containing 2 mM of glutamine. Should we consider a range of glutamine from 0–2.8 mM as increasing concentrations of glutamine or as a deprivation of glutamine compared to standard cell culture conditions? By contrast, the authors of the study used 0.8 mM of leucine as a basal concentration because it is the concentration contained in Dulbecco's modified Eagle's medium (DMEM). They reported that leucine incubation (0.8–6.4 mM) has an opposing effect on glutamine-induced autophagy.25 Autophagy may exert a protective response under stress and the authors therefore investigated the effect of glutamine in IECs in response to heat stress (42°C for 30 min)25 and have shown that glutamine regulates autophagy under stress conditions. They have shown that glutamine inactivates both signaling pathways involved in the negative control of autophagy, mTOR, and p38 MAP kinase.25 Recently, we studied the effect of essential amino acids or glutamine deprivation on GCN2 and mTOR pathways in IECs.26 We have shown that 6 hours deprivation of essential amino acids decreased phosphorylated 4E-BP, whereas it increased phosphorylated-eiF2α. In contrast, glutamine deprivation decreased phosphorylated 4E-BP.26 In conclusion, glutamine may induce autophagy to maintain cell survival under stress conditions. Clinical studies with glutamine in CD have been disappointing but new formulations and targeting to mucosal lesions have the potential of enhancing its efficacy.

Amino acids also modulate mTOR signaling at a central level.27 In rats, intracerebroventricular administration of leucine results in an increase of hypothalamic mTOR signaling, whereas food intake and body weight are decreased.28 Moreover, high-protein diets also activate hypothalamic mTOR.29

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Fatty Acids

Cell growth is not only dependent on the availability of amino acids, but also on the presence of various lipid-containing molecules such as cellular membranes. Lipid biosynthesis is under control of transcription factors called sterol-responsive binding proteins (SREBP). Recently, it has been demonstrated that mTOR signaling is also involved in fatty acid synthesis.30 Indeed, rapamycin treatment is able to block the expression of SREBP target genes.31

Nutrient deprivation upregulates triglyceride hydrolysis to supply free fatty acids for oxidation to meet energy demands. Furthermore, autophagy is induced to use proteins and organelles as a cellular fuel. It has been recently demonstrated that both these steps are interrelated.32 Singh et al32 demonstrated that inhibition of autophagy by 3-methyl adenine in a rat hepatocyte cell line leads to storage of triglycerides in lipids droplets. They subsequently confirmed these findings in vivo by a silencing approach of ATG genes in mouse liver.32

To our knowledge, no group has yet investigated the effect of polyunsaturated fatty acid (PUFA) supplementation on autophagy in the intestine. Interestingly, a recent study has shown that docosahexaenoic acid (DHA), an n-3 PUFA, is involved in the degradation of apolipoprotein-B, a protein implicated in atherosclerosis through a mechanism of hepatic autophagy.33 We consider DHA as a potentially good candidate to induce autophagy in the intestine through Akt,34 a kinase upstream of mTOR or through peroxisome proliferator-activated receptor-γ (PPAR-γ) signaling. Whether fatty acid modulation of autophagy may influence inflammation requires further studies.

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Natural PPAR-γ Ligand

Fatty acids such as DHA are powerful regulators of inflammation35,36 and their effect may be mediated through PPAR-γ.35,36 PPAR-γ is a nuclear receptor involved in lipid metabolism37 and in the regulation of intestinal inflammation.38 It can be activated by dietary factors such as PUFAs, curcumin, and resveratrol.36 PPAR-γ is highly expressed in the colon. PPAR-γ activation may be linked to an increased autophagy through different mechanisms. PPAR-γ activation leads to a downregulation of the nuclear factor kappaB (NF-κB) pathway39 that plays a key role in intestinal inflammation and in autophagy repression.40 ATG16L1-deficient Paneth cells present an increased expression of genes involved in PPAR signaling.41 In a mice model of hepatic ischemia-reperfusion, pretreatment with rosiglitazone (10 mg/kg), a specific ligand of PPAR-γ, activates PPAR-γ and increased autophagy as assessed by increased expression of LC3II.42 More recently, Jiang et al43 documented the link between PPAR-γ and autophagy. They generated a model of PPAR-γ-deficient mice in the prostatic epithelium by a Cre-Lox system that exhibits an increase in autophagy.43 PPAR-γ may be the target of dietary compounds to induce autophagy in the intestine. Indeed, curcumin, a dietary inducer of PPAR-γ, has been demonstrated to be involved in autophagy induction.44,45 In vitro, curcumin at 40 μM induces LC3-II expression in glioma cells through the AkT/mTOR pathway.44 Incubation with 15-deoxy-Delta-12,14-prostaglandin J2 (15dPGJ2) at 5 μM, an inducer of PPAR-γ, results in an increase of autophagic vesicles compared to vehicle control (14.7 ± 0.9 vs. 0.7 ± 0.2 autophagic vesicles per cell) in neuroblastoma cell line IMR-32.46 Capsaicin is a component of cayenne pepper and is able to activate PPAR-γ in the human intestinal epithelial cell line HT-29.47 The effect of one of its analogs, dihydrocapsaicin (DHC), has been investigated on autophagy in HCT-116 colon cancer cells.48 Incubation of HCT-116 with DHC at a concentration of 200 μM results in an upregulation of autophagy-related protein expression such as atg4, atg5, atg7, and LC3.48 These open the avenue of novel diet or natural product-induced modulation of autophagy and inflammation.

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Flavonoids are a class of chemicals found in food and beverages derived from plants. These phytochemicals exhibit antiinflammatory properties as well antioxidant activities.49 Impaired autophagy results in the nondegradation of damaged mitochondria that provide a source of reactive oxygen species (ROS). As ROS have been reported to induce autophagy in several models,50–52 protection against oxidative stress by administration of flavonoids may be mediated by induction of autophagy as one of the mechanisms.

Quercetin is a ubiquitous polyphenol and seems to exert anticancer properties by inhibiting cell survival. Its effect has been evaluated in human colon cells.53 In the intestinal epithelial cell line Caco-H2 with a low expression of oncogenic Ha-Ras, quercetin treatment at 20 μM for 24 hours induced a marked vacuolization of the cytoplasm.53 In addition, activation of autophagy by fluorescence microscopy was established. Caco-H2 cells were transiently transfected by a plasmid that expresses the EGFP-LC3 protein fusion before quercetin addition and then stained by MDC (monodansylcadaverine), a marker for autophagosome.53 The authors observed a punctuate pattern of EGFP-LC3 in quercetin-treated cells with an overlap of MDC-positive autophagosomes.53

Resveratrol is a polyphenolic compound derived from grapes, nuts, or red wine. Whereas its effect has not yet been established on autophagy in the intestine, it has been demonstrated in ovarian54 and breast cancer cells.55

Saponins derived from soy bean also exhibit autophagic properties in human colon cells HCT-15.56 Indeed, treatment with soyasaponins (25–100 ppm) results in a 4.5-fold increase of MDC incorporation, marker of autophagic vacuoles, and an upregulation of LC3 expression.56

MK615 is an extract from Japanese apricot and its effect has been investigated in three colon cancer cell lines.57 Incubation with the natural compound MK615 at 300 μg/mL results in an induction of autophagy as assessed by the presence of autophagosomes by electron microscopy and positive staining of Atg8 by immunofluorescence.57

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Patients with inflammatory bowel disease (IBD), in particular CD, may exhibit a severe deficiency in vitamins D and K.58 Vitamin D deficiency is a significant risk factor for metabolic bone disease. Vitamin D3 and vitamin K2 are able to induce autophagy in various cancer cells59 such as the human leukemia cell line HL-60.60,61 Their effects have been mainly evaluated in cancer cells62 because of the link between autophagy and cancer. Activation of autophagy by vitamin D3 contributes to innate response against mycobacteria through the induction of the cathelici-din LL-37. Further studies are now required to evaluate the effects of these nutrients in the context of intestinal inflammation and autophagy.

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Genome-wide association studies have highlighted the importance of autophagy in CD by the identification of susceptibility genes (ATG16L1, IRGM, ULK1) involved in autophagy.63–66 CD is also associated with defects in innate immunity response since mutations in Card15, the gene encoding for NOD2, have been shown as susceptibility factors for CD.67 As mentioned above, NOD2 is also implicated in autophagy, thus uniting NOD2 and autophagy pathways in explaining defective bacterial clearance.75–77 Furthermore, ileal CD is associated with a loss of Paneth cell function. A decreased production of α-defensin-5 and -6 by Paneth cells is observed in CD patients, particularly in those carrying the NOD2/Card15 mutation, but also ATG16L1 mutations. This loss of Paneth cell function may contribute to bacterial persistence and reduced clearance. Given the crucial role of Paneth cells in ileal CD, there is a need to develop therapeutic treatment restoring their function because current available treatments for ileal CD did not restore defensin production.68

ATG16L1 is a homologous gene to the yeast autophagy gene ATG16 and mutation in ATG16L1 predisposes to ileal CD.69 A single amino acid modification at position 300 in ATG16L1 predisposes toward CD: threonine (ATG16L1*300T) offers protection whereas alanine is deleterious (ATG16L1*300A). It has been shown in vitro in the intestinal epithelial line Caco-2 that ATG16L1*300A variant is impaired in its ability to mediate autophagy in response to Salmonella infection.70 Similarly, Tal et al71 identified that ATG5-deficient cells exhibit an amplified innate response to virus such as an increased type I IFN production.

The role of ATG16L1 in intestinal Paneth cells has been nicely demonstrated by Cadwell et al.41 They have shown that autophagy is altered in mouse embryonic fibroblasts from mice lines hypomorphic for ATG16L1 or ATG5.41 Moreover, they observed abnormalities of Paneth cell secretion in ATG16L1 hypomorphic mice and also in CD patients homozygous for the risk allele of ATG16L1. 41 In addition to its regulatory role of secretory function of Paneth cells, Saitoh et al72 elegantly demonstrated that autophagy also modulates the production of inflammatory cytokines in the intestine. Loss of autophagy in macrophages from Atg16L1-mutant mice dysregulated interleukin (IL)-1β and IL-18 production in response to lipopolysaccharide (LPS) and also induced Toll/IL-1 receptor domaincontaining adaptor inducing IFN-β (TRIF) dependent activation of caspase 1. Atg16L1 deficiency led to intestinal inflammation that can be reversed by administration of anti-IL-1β or anti-IL-18 antibodies.72

Autophagy plays a key role in host defense against mycobacteria, a pathogen that might be involved in CD pathogenesis. Jo73 has recently reviewed the contribution of vitamin D3 in innate response against mycobacteria through autophagy activation.

Inhibition of mTOR signaling may be promising in intestinal inflammation. Indeed, everomilus, an mTOR inhibitor, has been shown to be an effective antiinflammatory agent in experimental colitis in IL-10 knockout mice74 but also for maintaining remission in CD.75 In addition, a recent case report of a woman with severe CD has shown that the use of rapamycin for 6 months was able to improve CD inflammatory activity such as a net reduction of the inflammatory markers and also endoscopic appearance.76

Therefore, nutrient modulation of autophagy, as reviewed in this article, has the potential to be useful in diseases such as CD. Such modulation of autophagy by nutritional mechanisms as highlighted above may enhance microbial clearance and modulate proinflammatory cytokines and benefit inflammation.

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Given that mTOR can be modulated by nutrients, as discussed above, it raises the possibility of exploring this option with nutrients to modulate inflammation in CD and provide an alternative mechanism for explaining the efficacy of some defined formula diets as antiinflammatory agents in CD. Should future ileal CD treatment target autophagy to restore Paneth cell loss of function? This certainly is worth exploring utilizing not only drug development, but also the known function of nutrients on autophagy. Nutrient modulation of autophagy should attract more research attention.

Inducing autophagy through the administration of different nutrients may be beneficial for intestinal inflammation. Nutritional modulation of altered autophagy could represent a possible therapeutic target for CD. Nutritional intervention may be safer rather than pharmacological manipulation to induce autophagy because an overactivation of autophagy could lead to cell death by degradation of essential cell components. Nutritional manipulation on autophagy at a cytokine or signaling levels may lead to potential novel therapies to treat CD. A better understanding of the molecular mechanisms of autophagy in CD and the crosstalk between autophagy and nutrients will be necessary to accomplish this goal.

It has been recently demonstrated that NOD2 is induced by vitamin D and NOD2 mutation results in defective autophagy as does ATG16L1 mutation, both resulting in microbial clearance abnormalities.71,72 Thus, the important mutations in CD affect autophagy and may be modulated by nutrients.

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    autophagy; Crohn’s disease; nutrients; PPAR-γ

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