Diet as a Therapeutic Option for Adult Inflammatory Bowel Disease

Gastroenterology Clinics of North America - Tập 46 Số 4 - Trang 745-767 - 2017
Samir Kakodkar1, Ece Mutlu2
1Divison of Gastroenterology and Hepatology, Northwestern University Feinberg School of Medicine, 420 East Superior Street, Chicago, IL 60611, USA
2Division of Digestive Diseases & Nutrition, Rush University Medical Center, 1725 West Harrison Street, Suite 206, Chicago, IL 60612, USA

Tóm tắt

Từ khóa


Tài liệu tham khảo

Hou, 2011, Dietary intake and risk of developing inflammatory bowel disease: a systematic review of the literature, Am J Gastroenterol, 106, 563, 10.1038/ajg.2011.44

Thia, 2008, An update on the epidemiology of inflammatory bowel disease in Asia, Am J Gastroenterol, 103, 3167, 10.1111/j.1572-0241.2008.02158.x

McDonald, 1988, What can Crohn's patients eat?, Eur J Clin Nutr, 42, 703

Moser, 1996, Relationship between the use of unconventional therapies and disease-related concerns: a study of patients with inflammatory bowel disease, J Psychosom Res, 40, 503, 10.1016/0022-3999(95)00581-1

Gunasekeera, 2016, Treatment of Crohn's disease with an IgG4-guided exclusion diet: a randomized controlled trial, Dig Dis Sci, 61, 1148, 10.1007/s10620-015-3987-z

Chiba, 2010, Lifestyle-related disease in Crohn's disease: relapse prevention by a semi-vegetarian diet, World J Gastroenterol, 16, 2484, 10.3748/wjg.v16.i20.2484

Hunter, 2011

Cordain, 2010

Rubin, 2013

Klein, 2011

Allan, 2000

Sporen, 2013, Review article: the association of diet with onset and relapse in patient with inflammatory bowel disease, Aliment Pharmacol Ther, 38, 1172, 10.1111/apt.12501

Lewis, 2017, Diet as a trigger or therapy for inflammatory bowel disease, Gastroenterology, 152, 398, 10.1053/j.gastro.2016.10.019

Dixon, 2015, Combinatorial effects of diet and genetics on inflammatory bowel disease pathogenesis, Inflamm Bowel Dis, 21, 912, 10.1097/MIB.0000000000000289

Wedrychowicz, 2016, Advances in nutritional therapy in inflammatory bowel diseases: review, World J Gastroenterol, 22, 1045, 10.3748/wjg.v22.i3.1045

Riordan, 1998, A review of associations between Crohn's disease and consumption of sugars, Eur J Clin Nutr, 52, 229, 10.1038/sj.ejcn.1600556

Mayberry, 1981, Diet in Crohn’s disease, Dig Dis Sci, 26, 444, 10.1007/BF01313588

Panza, 1987, Dietary factors in aetiology of inflammatory bowel disease, Ital J Gastroenterol, 19, 205

Persson, 1992, Diet and inflammatory bowel disease: a case control study, Epidemiology, 3, 47, 10.1097/00001648-199201000-00009

Chan, 2014, Carbohydrate intake in the etiology of Crohn's disease and ulcerative colitis, Inflamm Bowel Dis, 20, 2013, 10.1097/MIB.0000000000000168

Reif, 1997, Pre-illness dietary factors in inflammatory bowel disease, Gut, 40, 754, 10.1136/gut.40.6.754

Shoda, 1996, Epidemiologic analysis of Crohn disease in Japan: increased dietary intake of n-6 polyunsaturated fatty acids and animal protein relates to the increased incidence of Crohn disease in Japan, Am J Clin Nutr, 63, 741, 10.1093/ajcn/63.5.741

Jantchou, 2010, Animal protein intake and risk of inflammatory bowel disease: the E3N Prospective Study, Am J Gastroenterol, 105, 2195, 10.1038/ajg.2010.192

Schmitz, 2008, The opposing effects of n-3 and n-6 fatty acids, Prog Lipid Res, 47, 147, 10.1016/j.plipres.2007.12.004

Ibrahim, 2011, Anti-inflammatory and antiangiogenic effect of long chain n-3 polyunsaturated fatty acids in intestinal microvascular endothelium, Clin Nutr, 30, 678, 10.1016/j.clnu.2011.05.002

Wang, 2006, CXCL1 induced by prostaglandin E2promotes angiogenesis in colorectal cancer, J Exp Med, 203, 941, 10.1084/jem.20052124

Aliberti, 2002, Lipoxin-mediated inhibition ofIL-12 production by DCs: a mechanism for regulation of microbial immunity, Nat Immunol, 3, 76, 10.1038/ni745

Wan, 2011, Leukotriene B4/antimicrobial peptideLL-37 proinflammatory circuits are mediated by BLT1 and FPR2/ALX and are counterregulated by lipoxin A4 and resolvin E1, FASEB J, 25, 1697, 10.1096/fj.10-175687

Pizato, 2006, Fish oil alters T-lymphocyte proliferation and macrophage responses in Walker 256 tumor-bearing rats, Nutrition, 22, 425, 10.1016/j.nut.2005.11.001

Draper, 2011, Omega-3 fatty acids attenuate dendritic cell function via NF-[kappa]B independent of PPAR[gamma], J Nutr Biochem, 22, 784, 10.1016/j.jnutbio.2010.06.009

Harvey, 2010, Oleic acid inhibits stearic acid-induced inhibition of cell growth and pro-inflammatory responses inhuman aortic endothelial cells, J Lipid Res, 51, 3470, 10.1194/jlr.M010371

Hassan, 2010, An alpha-linolenic acid-rich formula reduces oxidative stress and inflammation by regulating NF-kappaB in rats with TNBS-induced colitis, J Nutr, 140, 1714

Marion-Letellier, 2008, Am J Clin Nutr, 87, 939, 10.1093/ajcn/87.4.939

Kliewer, 1997, Fatty acids and eicosanoids regulate gene expression through direct interactions with peroxisome proliferator-activated receptors alpha and gamma, Proc Natl Acad Sci U S A, 94, 4318, 10.1073/pnas.94.9.4318

Miura, 1993, Increased proliferative response of lymphocytes from intestinal lymph during long chain fatty acid absorption, Immunology, 78, 142

Hoshimoto, 2002, Caprylic acid and medium-chain triglycerides inhibit IL-8 gene transcription in Caco-2 cells: comparison with the potent histone deacetylase inhibitor trichostatin A, Br J Pharmacol, 136, 280, 10.1038/sj.bjp.0704719

Mazzucchelli, 1994, Expression of interleukin-8 gene in inflammatory bowel disease is related to the histological grade of active inflammation, Am J Pathol, 144, 997

Jansson, 2009, Metabolomics reveals metabolic biomarkers of Crohn’s disease, PLoS One, 4, e6386, 10.1371/journal.pone.0006386

Hekmatdoost, 2008, The effect of dietary oils on cecal microflora in experimental colitis in mice, Indian J Gastroenterol, 27, 186

Knoch, 2010, Diversity of caecal bacteria is altered in interleukin-10 gene-deficient mice before and after colitis onset and when fed polyunsaturated fatty acids, Microbiology, 156, 3306, 10.1099/mic.0.041723-0

Zhao, 2007, Differential modulation of Nods signaling pathways by fatty acids in human colonic epithelial HCT116cells, J Biol Chem, 282, 11618, 10.1074/jbc.M608644200

Lee, 2003, Differential modulation of Toll-like receptors by fatty acids: preferential inhibition by n-3 polyunsaturated fatty acids, J Lipid Res, 44, 479, 10.1194/jlr.M200361-JLR200

Weatherill, 2005, Saturated and polyunsaturated fatty acids reciprocally modulate dendritic cell functions mediated through TLR4, J Immunol, 174, 5390, 10.4049/jimmunol.174.9.5390

de La Serre, 2010, Propensity to high-fat diet-induced obesity in rats is associated with changes in the gut microbiota and gut inflammation, Am J Physiol Gastrointest Liver Physiol, 299, G440, 10.1152/ajpgi.00098.2010

Suzuki, 2010, Dietary fat and bile juice, but not obesity, are responsible for the increase in small intestinal permeability induced through the suppression of tight junction protein expression in LETO and OLETF rats, Nutr Metab (Lond), 7, 19, 10.1186/1743-7075-7-19

Hou, 2014, Diet and inflammatory bowel disease: review of patient-targeted recommendations, Clin Gastroenterol Hepatol, 12, 1592, 10.1016/j.cgh.2013.09.063

Devkota, 2012, Dietary-fat-induced taurocholic acid promotes pathobiont expansion and colitis in Il10-/- mice, Nature, 487, 104, 10.1038/nature11225

Ji, 2011, Nutrient-induced inflammation in the intestine, Curr Opin Clin Nutr Metab Care, 14, 315, 10.1097/MCO.0b013e3283476e74

Keita, 2010, The intestinal barrier and its regulation by neuroimmune factors, Neurogastroenterol Motil, 22, 718, 10.1111/j.1365-2982.2010.01498.x

Chapman-Kiddell, 2010, Role of diet in the development of inflammatory bowel disease, Inflamm Bowel Dis, 16, 137, 10.1002/ibd.20968

de Silva, 2010, An association between dietary arachidonic acid, measured in adipose tissue, and ulcerative colitis, Gastroenterology, 139, 1912, 10.1053/j.gastro.2010.07.065

Hart, 2008, Diet in the aetiology of ulcerative colitis: a European prospective cohort study, Digestion, 77, 57, 10.1159/000121412

John, 2010, Dietary n-3 polyunsaturated fatty acids and the aetiology of ulcerative colitis: a UK prospective cohort study, Eur J Gastroenterol Hepatol, 22, 602, 10.1097/MEG.0b013e3283352d05

Tjonneland, 2009, Linoleic acid, a dietary n-6 polyunsaturated fatty acid, and the aetiology of ulcerative colitis: a nested case-control study within a European prospective cohort study, Gut, 58, 1606, 10.1136/gut.2008.169078

Amre, 2007, Imbalances in dietary consumption of fatty acids, vegetables, and fruits are associated with risk for Crohn’s disease in children, Am J Gastroenterol, 102, 2016, 10.1111/j.1572-0241.2007.01411.x

Sakamoto, 2005, Dietary risk factors for inflammatory bowel disease: a multicenter case-control study in Japan, Inflamm Bowel Dis, 11, 154, 10.1097/00054725-200502000-00009

Kasper, 1979, Dietary fiber and nutrient intake in Crohn’s disease, Am J Clin Nutr, 32, 1898, 10.1093/ajcn/32.9.1898

Thornton, 1979, Diet and Crohn’s disease: characteristics of the pre-illness diet, Br Med J, 2, 762, 10.1136/bmj.2.6193.762

Tragnone, 1995, Dietary habits as risk factors for inflammatory bowel disease, Eur J Gastroenterol Hepatol, 7, 47

Geerling, 2000, Diet as a risk factor for the development of ulcerative colitis, Am J Gastroenterol, 95, 1008, 10.1111/j.1572-0241.2000.01942.x

Sharon, 1978, Role of prostaglandins in ulcerative colitis. Enhanced production during active disease and inhibition by sulfasalazine, Gastroenterology, 75, 638, 10.1016/S0016-5085(19)31672-5

Ananthakrishnan, 2014, Long-term intake of dietary fat and risk of ulcerative colitis and Crohn’s disease, Gut, 63, 776, 10.1136/gutjnl-2013-305304

Feagan, 2008, Omega-3 free fatty acids for the maintenance of remission in Crohn disease: the EPIC randomized controlled trials, JAMA, 299, 1690, 10.1001/jama.299.14.1690

Turner, 2011, Maintenance of remission in inflammatory bowel disease using omega-3 fatty acids (fish oil): a systematic review and meta-analyses, Inflamm Bowel Dis, 17, 336, 10.1002/ibd.21374

Maslowski, 2011, Diet, gut microbiota and immune responses, Nat Immunol, 12, 5, 10.1038/ni0111-5

Roberts, 2010, Translocation of Crohn’s disease Escherichia coli across M-cells: contrasting effects of soluble plant fibres and emulsifiers, Gut, 59, 1331, 10.1136/gut.2009.195370

Ananthakrishnan, 2013, A prospective study of long-term dietary fiber and risk of Crohn’s disease and ulcerative colitis, Gastroenterology, 145, 970, 10.1053/j.gastro.2013.07.050

Li, 2015, Consumption of vegetables and fruit and the risk of inflammatory bowel disease: a meta-analysis, Eur J Gastroenterol Hepatol, 27, 623, 10.1097/MEG.0000000000000330

Stein, 2014, Dietary fiber intake and Crohn's disease, Gastroenterology, 146, 1133, 10.1053/j.gastro.2013.12.044

Ardesia, 2015, Vitamin D and inflammatory bowel disease, Biomed Res Int, 2015, 470805, 10.1155/2015/470805

Ooi, 2013, Vitamin D regulates the gut microbiome and protects mice from dextran sodium sulfate-induced colitis, J Nutr, 143, 1679

Del Pinto, 2015, Association between inflammatory bowel disease and vitamin D deficiency: a systematic review and meta-analysis, Inflamm Bowel Dis, 21, 2708, 10.1097/MIB.0000000000000546

Ulitsky, 2011, Vitamin D deficiency in patients with inflammatory bowel disease: association with disease activity and quality of life, JPEN J Parenter Enteral Nutr, 35, 308, 10.1177/0148607110381267

Ananthakrishnan, 2014, Higher plasma vitamin D is associated with reduced risk of Clostridium difficile infection in patients with inflammatory bowel diseases, Aliment Pharmacol Ther, 39, 1136, 10.1111/apt.12706

Ananthakrishnan, 2013, Normalization of plasma 25-hydroxy vitamin D is associated with reduced risk of surgery in Crohn's disease, Inflamm Bowel Dis, 19, 1921

Ananthakrishnan, 2014, Association between reduced plasma 25-hydroxy vitamin D and increased risk of cancer in patients with inflammatory bowel diseases, Clin Gastroenterol Hepatol, 12, 821, 10.1016/j.cgh.2013.10.011

Gubatan, 2017, Low serum vitamin D during remission increases risk of clinical relapse in patients with ulcerative colitis, Clin Gastroenterol Hepatol, 15, 240, 10.1016/j.cgh.2016.05.035

Miheller, 2009, Comparison of the effects of 1,25 dihydroxyvitamin D and 25 hydroxyvitamin D on bone pathology and disease activity in Crohn's disease patients, Inflamm Bowel Dis, 15, 1656, 10.1002/ibd.20947

Jørgensen, 2010, Clinical trial: vitamin D3 treatment in Crohn's disease—a randomized double-blind placebo-controlled study, Aliment Pharmacol Ther, 32, 377, 10.1111/j.1365-2036.2010.04355.x

Yang, 2013, Therapeutic effect of vitamin D supplementation in a pilot study of Crohn's patients, Clin Transl Gastroenterol, 4, e33, 10.1038/ctg.2013.1

Stein, 2016, Northern latitude but not season is associated with increased rates of hospitalizations related to inflammatory bowel disease: results of a multi-year analysis of a national cohort, PLoS One, 11, e0161523, 10.1371/journal.pone.0161523

Voigt, 2016, Circadian rhythm and the gut microbiome, Int Rev Neurobiol, 131, 193, 10.1016/bs.irn.2016.07.002

Feldman, 2016

Vagianos, 2007, Nutrition assessment of patients with inflammatory bowel disease, JPEN J Parenter Enteral Nutr, 31, 311, 10.1177/0148607107031004311

Ojuawo, 2002, The serum concentrations of zinc, copper and selenium in children with inflammatory bowel disease, Cent Afr J Med, 48, 116

Alkhouri, 2013, Vitamin and mineral status in patients with inflammatory bowel disease, J Pediatr Gastroenterol Nutr, 56, 89, 10.1097/MPG.0b013e31826a105d

McClain, 1980, Zinc deficiency: a complication of Crohn’s disease, Gastroenterology, 78, 272, 10.1016/0016-5085(80)90576-4

Siva, 2017, Zinc deficiency is associated with poor clinical outcomes in patients with inflammatory bowel disease, Inflamm Bowel Dis, 23, 152, 10.1097/MIB.0000000000000989

Weisshof, 2015, Micronutrient deficiencies in inflammatory bowel disease, Curr Opin Clin Nutr Metab Care, 18, 576, 10.1097/MCO.0000000000000226

Dogan, 2014, Inflammation-associated adherent-invasive Escherichia coli are enriched in pathways for use of propanediol and iron and M-cell translocation, Inflamm Bowel Dis, 20, 1919, 10.1097/MIB.0000000000000183

Jaeggi, 2015, Iron fortification adversely affects the gut microbiome, increases pathogen abundance and induces intestinal inflammation in Kenyan infants, Gut, 64, 731, 10.1136/gutjnl-2014-307720

Tobacman, 2001, Review of harmful gastrointestinal effects of carrageenan in animal experiments, Environ Health Perspect, 109, 983, 10.1289/ehp.01109983

Bhattacharyya, 2017, A randomized trial of the effects of the no-carrageenan diet on ulcerative colitis disease activity, Nutr Healthy Aging, 4, 181, 10.3233/NHA-170023

Martino, 2017, The role of carrageenan and carboxymethyl cellulose in the development of intestinal inflammation, Front Pediatr, 96, 10.3389/fped.2017.00096

Bhattacharyya, 2013, Carrageenan-induced colonic inflammation is reduced in Bcl10 null mice and increased in IL-10-deficient mice, Mediators Inflamm, 2013, 397642, 10.1155/2013/397642

Nickerson, 2015, Deregulation of intestinal anti-microbial defense by the dietary additive, maltodextrin, Gut Microbes, 6, 78, 10.1080/19490976.2015.1005477

Nickerson, 2012, Crohn's disease-associated adherent-invasive Escherichia coli adhesion is enhanced by exposure to the ubiquitous dietary polysaccharide maltodextrin, PLoS One, 7, e52132, 10.1371/journal.pone.0052132

Söderholm, 2002, Augmented increase in tight junction permeability by luminal stimuli in the non-inflamed ileum of Crohn's disease, Gut, 50, 307, 10.1136/gut.50.3.307

Chassaing, 2015, Dietary emulsifiers impact the mouse gut microbiota promoting colitis and metabolic syndrome, Nature, 519, 92, 10.1038/nature14232

Swidsinski, 2009, Bacterial overgrowth and inflammation of small intestine after carboxymethyl cellulose ingestion in genetically susceptible mice, Inflamm Bowel Dis, 15, 359, 10.1002/ibd.20763

Dziechciarz, 2007, Meta-analysis: enteral nutrition in active Crohn's disease in children, Aliment Pharmacol Ther, 26, 795, 10.1111/j.1365-2036.2007.03431.x

Zachos, 2007, Enteral nutritional therapy for induction of remission in Crohn's disease, Cochrane Database Syst Rev, 10.1002/14651858.CD000542.pub2

Lochs, 2006, ESPEN guidelines on enteral nutrition: gastroenterology, Clin Nutr, 25, 260, 10.1016/j.clnu.2006.01.007

Gerasimidis, 2014, Decline in presumptively protective gut bacterial species and metabolites are paradoxically associated with disease improvement in pediatric Crohn's disease during enteral nutrition, Inflamm Bowel Dis, 20, 861, 10.1097/MIB.0000000000000023

Kaakoush, 2015, Effect of exclusive enteral nutrition on the microbiota of children with newly diagnosed Crohn's disease, Clin Transl Gastroenterol, 6, e71, 10.1038/ctg.2014.21

Afzal, 2004, Improvement in quality of life of children with acute Crohn’s disease does not parallel mucosal healing after treatment with exclusive enteral nutrition, Aliment Pharmacol Ther, 20, 167, 10.1111/j.1365-2036.2004.02002.x

Fell, 2000, Mucosal healing and a fall in mucosal pro-inflammatory cytokine mRNA induced by a specific oral polymeric diet in paediatric Crohn’s disease, Aliment Pharmacol Ther, 14, 281, 10.1046/j.1365-2036.2000.00707.x

Bannerjee, 2004, Anti-inflammatory and growth-stimulating effects precede nutritional restitution during enteral feeding in Crohn disease, J Pediatr Gastroenterol Nutr, 38, 270, 10.1097/00005176-200403000-00007

Verma, 2000, Polymeric versus elemental diet as primary treatment in active Crohn's disease: a randomized, double-blind trial, Am J Gastroenterol, 95, 735, 10.1111/j.1572-0241.2000.01527.x

Hwang, 2014, Popular exclusionary diets for inflammatory bowel disease: the search for a dietary culprit, Inflamm Bowel Dis, 20, 732, 10.1097/01.MIB.0000438427.48726.b0

Nakayuenyongsuk, 2017, Diet to the rescue: cessation of pharmacotherapy after initiation of exclusive enteral nutrition (EEN) followed by strict and liberalized specific carbohydrate diet (SCD) in Crohn's disease, Dig Dis Sci, 10.1007/s10620-016-4446-1

Sigall-Boneh, 2014, Partial enteral nutrition with a Crohn's disease exclusion diet is effective for induction of remission in children and young adults with Crohn's disease, Inflamm Bowel Dis, 20, 1353, 10.1097/MIB.0000000000000110

Riordan, 1993, Treatment of active Crohn's disease by exclusion diet: East Anglian multicentre controlled trial, Lancet, 342, 1131, 10.1016/0140-6736(93)92121-9

Yamamoto, 2013, Enteral nutrition to suppress postoperative Crohn's disease recurrence: a five-year prospective cohort study, Int J Colorectal Dis, 28, 335, 10.1007/s00384-012-1587-3

Hirai, 2013, Effectiveness of concomitant enteral nutrition therapy and infliximab for maintenance treatment of Crohn's disease in adults, Dig Dis Sci, 58, 1329, 10.1007/s10620-012-2374-2

Nguyen, 2015, Specialized enteral nutrition therapy in Crohn's disease patients on maintenance infliximab therapy: a meta-analysis, Therap Adv Gastroenterol, 8, 168, 10.1177/1756283X15578607

Haas, 1951

Gottschall, 2012

Suskind, 2016, Patients perceive clinical benefit with the specific carbohydrate diet for inflammatory bowel disease, Dig Dis Sci, 61, 3255, 10.1007/s10620-016-4307-y

Kakodkar, 2012, The effect of the specific carbohydrate diet (SCD) on gut bacterial fingerprints in inflammatory bowel disease, Gastroenterology, 142, S395, 10.1016/S0016-5085(12)61500-5

Kakodkar, 2013, The bacterial microbiome of inflammatory bowel disease patients on the Specific Carbohydrate Diet (SCD), Gastroenterology, 144, S552

Kakodkar, 2015, The specific carbohydrate diet for inflammatory bowel disease: a case series, J Acad Nutr Diet, 115, 1226, 10.1016/j.jand.2015.04.016

Obih, 2016, Specific carbohydrate diet for pediatric inflammatory bowel disease in clinical practice within an academic IBD center, Nutrition, 32, 418, 10.1016/j.nut.2015.08.025

Burgis, 2016, Response to strict and liberalized specific carbohydrate diet in pediatric Crohn's disease, World J Gastroenterol, 22, 2111, 10.3748/wjg.v22.i6.2111

Cohen, 2014, Clinical and mucosal improvement with specific carbohydrate diet in pediatric Crohn disease, J Pediatr Gastroenterol Nutr, 59, 516, 10.1097/MPG.0000000000000449

Olendzki, 2014, An anti-inflammatory diet as treatment for inflammatory bowel disease: a case series report, Nutr J, 13, 5, 10.1186/1475-2891-13-5

Crohn’s & Colitis Foundation. First-ever national study of dietary interventions to treat Crohn's disease receives funding. Available at: http://www.ccfa.org/news/dietstudy.html. Accessed May 1, 2017.

Rao, 2015, Systematic review: dietary fibre and FODMAP-restricted diet in the management of constipation and irritable bowel syndrome, Aliment Pharmacol Ther, 41, 1256, 10.1111/apt.13167

Simren, 2002, Quality of life in inflammatory bowel disease in remission: the impact of IBS-like symptoms and associated psychological factors, Am J Gastroenterol, 97, 389, 10.1111/j.1572-0241.2002.05475.x

Gearry, 2009, Reduction of dietary poorly absorbed short-chain carbohydrates (FODMAPs) improves abdominal symptoms in patients with inflammatory bowel disease-a pilot study, J Crohns Colitis, 3, 8, 10.1016/j.crohns.2008.09.004

Cooke, 1979, Pig Bel, Perspect Pediatr Pathol, 5, 137

Mutlu, 2016, Dietary treatment of Crohn's disease: a randomized, placebo-controlled, double-blinded clinical trial, Am J Gastroenterol, 150, S778

Seok, 2013, Inflammation and Host Response to Injury, Large Scale Collaborative Research Program. Genomic responses in mouse models poorly mimic human inflammatory diseases, Proc Natl Acad Sci U S A, 110, 3507, 10.1073/pnas.1222878110