Increasing Comparability and Utility of Gut Microbiome Studies in Parkinson's Disease: A Systematic Review

Jeffrey M Boertien, Pedro A B Pereira, Velma T E Aho, Filip Scheperjans, Jeffrey M Boertien, Pedro A B Pereira, Velma T E Aho, Filip Scheperjans

Abstract

Gut microbiota have been studied in relation to the pathophysiology of Parkinson's disease (PD) due to the early gastrointestinal symptomatology and presence of alpha-synuclein pathology in the enteric nervous system, hypothesized to ascend via the vagal nerve to the central nervous system. Accordingly, sixteen human case-control studies have published gut microbiome composition changes in PD and reported over 100 differentially abundant taxa covering all taxonomic levels from phylum to genus or species, depending on methodology. While certain findings were replicated across several studies, various contradictory findings were reported. Here, differences in methodologies and the presence of possible confounders in the study populations are assessed for their potential to confound the results of gut microbiome studies in PD. Gut microbiome studies in PD exhibited considerable variability with respect to the study population, sample transport conditions, laboratory protocols and sequencing, bioinformatics pipelines, and biostatistical methods. To move from the current heterogeneous dataset towards clinically relevant biomarkers and the identification of putative therapeutic targets, recommendations are derived from the limitations of the available studies to increase the future comparability of microbiome studies in PD. In addition, integration of currently available data on the gut microbiome in PD is proposed to identify robust gut microbiome profiles in PD. Furthermore, expansion of the current dataset with atypical parkinsonism cohorts, prodromal and treatment-naïve de novo PD subjects, measurements of fecal microbial concentrations and multi-omics assessments are required to provide clinically relevant biomarkers and reveal therapeutic targets within the gut microbiome of PD.

Keywords: Parkinson disease; case-control studies; gut microbiome; systematic review.

Conflict of interest statement

JMB has no conflicts of interest to report. PABP, VTEA, and FS have a patent FI127671B issued, a patent US10139408B2 issued, a patent US16/186,663 pending, and a patent EP3149205 pending.

FS is founder and CEO of NeuroInnovation Oy, has received a grant from Renishaw, consulting fees from Herantis Pharma and Orion, lecture fees from Abbvie, UCB, Zambon, and Orion, travel support from Abbvie, Herantis Pharma, Global Kinetics, UCB, NordicInfu Care, Zambon, and Medtronic. He is member of the scientific advisory boards of Axial Biotherapeutics and LivaNova.

Figures

Fig.1
Fig.1
Overview of screening procedure to identify case-control gut microbiome studies in Parkinson’s disease.
Fig.2
Fig.2
Differences in study populations and methodologies between gut microbiome studies in Parkinson’s disease (PD). (a) Study populations differed in age and sex distributions, sample size, geographical background, and the extent to which gastrointestinal confounders of gut microbiome composition were assessed. (b) Differences in PD subtypes, disease duration and PD medication regimen were linked to gut microbiome composition changes. (c) Sample collection procedures, transport conditions, DNA extraction, sequencing and the analytical and bio-informatics pipelines are known technical confounders of gut microbiome composition studies and differed across gut microbiome studies in PD. TD, tremor dominant subtype; AR/PIGD, akinetic rigid and/or postural instability and gait disorders subtypes; HC, healthy controls.

References

    1. Postuma RB, Berg D, Stern M, Poewe W, Olanow CW, Oertel W, Obeso J, Marek K, Litvan I, Lang AE, Halliday G, Goetz CG, Gasser T, Dubois B, Chan P, Bloem BR, Adler CH, Deuschl G (2015) MDS clinical diagnostic criteria for Parkinson’s disease. Mov Disord 30, 1591–1601.
    1. Postuma RB, Gagnon JF, Bertrand JA, Génier Marchand D, Montplaisir JY (2015) Parkinson risk in idiopathic REM sleep behavior disorder: Preparing for neuroprotective trials. Neurology 84, 1104–1113.
    1. Berg D, Postuma RB, Adler CH, Bloem BR, Chan P, Dubois B, Gasser T, Goetz CG, Halliday G, Joseph L, Lang AE, Liepelt-Scarfone I, Litvan I, Marek K, Obeso J, Oertel W, Olanow CW, Poewe W, Stern M, Deuschl G (2015) MDS research criteria for prodromal Parkinson’s disease. Mov Disord 30, 1600–1611.
    1. Postuma RB, Gagnon J-F, Pelletier A, Montplaisir J (2013) Prodromal autonomic symptoms and signs in Parkinson’s disease and dementia with Lewy bodies. Mov Disord 28, 597–604.
    1. Forsyth CB, Shannon KM, Kordower JH, Voigt RM, Shaikh M, Jaglin JA, Estes JD, Dodiya HB, Keshavarzian A (2011) Increased intestinal permeability correlates with sigmoid mucosa alpha-synuclein staining and endotoxin exposure markers in early Parkinson’s disease. PLoS One 6, e28032.
    1. Mulak A, Budrewicz S, Panek-Jeziorna M, Koszewicz M, Jasinska M, Marczak-Karpina B, Slotwinski K, Podemski R, Paradowski L (2017) Fecal biomarkers of gut inflammation and intestinal barrier dysfunction in Parkinson’s disease.S. Gastroenterology 152, 924.
    1. Stokholm MG, Danielsen EH, Hamilton-Dutoit SJ, Borghammer P (2016) Pathological α-synuclein in gastrointestinal tissues from prodromal Parkinson disease patients. Ann Neurol 79, 940–949.
    1. Svensson E, Horváth-Puhó E, Thomsen RW, Djurhuus JC, Pedersen L, Borghammer P, Sørensen HT (2015) Vagotomy and subsequent risk of Parkinson’s disease. Ann Neurol 78, 522–529.
    1. Liu B, Fang F, Pedersen NL, Tillander A, Ludvigsson JF, Ekbom A, Svenningsson P, Chen H, Karin W (2017) Vagotomy and Parkinson disease: A Swedish register-based matched-cohort study). Neurology 88, 1996–2002.
    1. Fraher MH, O’Toole PW, Quigley EMM (2012) Techniques used to characterize the gut microbiota: A guide for the clinician. Nat Rev Gastroenterol Hepatol 9, 312–322.
    1. Gerhardt S, Mohajeri MH (2018) Changes of colonic bacterial composition in Parkinson’s disease and other neurodegenerative diseases. Nutrients 10, 708.
    1. Sampson TR, Debelius JW, Thron T, Janssen S, Shastri GG, Ilhan ZE, Challis C, Schretter CE, Rocha S, Gradinaru V, Chesselet MF, Keshavarzian A, Shannon KM, Krajmalnik-Brown R, Wittung-Stafshede P, Knight R, Mazmanian SK (2016) Gut microbiota regulate motor deficits and neuroinflammation in a model of Parkinson’s disease. Cell 67, 1469–1480.e12.
    1. Chen SG, Stribinskis V, Rane MJ, Demuth DR, Gozal E, Roberts AM, Jagadapillai R, Liu R, Choe K, Shivakumar B, Son F, Jin S, Kerber R, Adame A, Masliah E, Friedland RP (2016) Exposure to the functional bacterial amyloid protein curli enhances alpha-synuclein aggregation in aged Fischer 344 rats and Caenorhabditis elegans. Sci Rep 6, 34477.
    1. Jellinger KA (2016) Accuracy of clinical diagnosis of Parkinson disease: A systematic review and meta-analysis. Neurology 87, 237–238.
    1. Heinzel S, Roeben B, Ben-Shlomo Y, Lerche S, Alves G, Barone P, Behnke S, Berendse HW, Bloem BR, Burn D, Dodel R, Grosset DG, Hu M, Kasten M, Krüger R, Moccia M, Mollenhauer B, Oertel W, Suenkel U, Walter U, Wirdefeldt K, Liepelt-Scarfone I, Maetzler W, Berg D (2016) Prodromal markers in Parkinson’s disease: Limitations in longitudinal studies and lessons learned. Front Aging Neurosci 8, 147.
    1. Scheperjans F, Aho V, Pereira PAB, Koskinen K, Paulin L, Pekkonen E, Haapaniemi E, Kaakkola S, Eerola-Rautio J, Pohja M, Kinnunen E, Murros K, Auvinen P (2015) Gut microbiota are related to Parkinson’s disease and clinical phenotype. Mov Disord 30, 350–358.
    1. Hill-Burns EM, Debelius JW, Morton JT, Wissemann WT, Lewis MR, Wallen ZD, Peddada SD, Factor SA, Molho E, Zabetian CP, Knight R, Payami H (2017) Parkinson’s disease and Parkinson’s disease medications have distinct signatures of the gut microbiome. Mov Disord 32, 739–749.
    1. Barichella M, Severgnini M, Cilia R, Cassani E, Bolliri C, Caronni S, Ferri V, Cancello R, Ceccarani C, Faierman S, Pinelli G, De Bellis G, Zecca L, Cereda E, Consolandi C, Pezzoli G (2019) Unraveling gut microbiota in Parkinson’s disease and atypical parkinsonism. Mov Disord 34, 396–405.
    1. Petrov VA, Saltykova IV, Zhukova IA, Alifirova VM, Zhukova NG, Dorofeeva YB, Tyakht AV, Kovarsky BA, Alekseev DG, Kostryukova ES, Mironova YS, Izhboldina OP, Nikitina MA, Perevozchikova TV, Fait EA, Babenko VV, Vakhitova MT, Govorun VM, Sazonov AE (2017) Analysis of gut microbiota in patients with Parkinson’s disease. Bull Exp Biol Med 162, 734–737.
    1. Pietrucci D, Cerroni R, Unida V, Farcomeni A, Pierantozzi M, Mercuri NB, Biocca S, Stefani A, Desideri A (2019) Dysbiosis of gut microbiota in a selected population of Parkinson’s patients. Parkinsonism Relat Disord–10.1016/j.parkreldis.2019.06.003.
    1. Lin A, Zheng W, He Y, Tang W, Wei X, He R, Huang W, Su Y, Huang Y, Zhou H, Xie H (2018) Gut microbiota in patients with Parkinson’s disease in southern China. Parkinsonism Relat Disord 53, 82–88.
    1. Qian Y, Yang X, Xu S, Wu C, Song Y, Qin N, Di Chen S, Xiao Q (2018) Alteration of the fecal microbiota in Chinese patients with Parkinson’s disease. Brain Behav Immun 70, 194–202.
    1. Hasegawa S, Goto S, Tsuji H, Okuno T, Asahara T, Nomoto K, Shibata A, Fujisawa Y, Minato T, Okamoto A, Ohno K, Hirayama M (2015) Intestinal dysbiosis and lowered serum lipopolysaccharide-binding protein in Parkinson’s disease. PLoS One 10, e0142164.
    1. Unger MM, Spiegel J, Dillmann KU, Grundmann D, Philippeit H, Bürmann J, Faßbender K, Schwiertz A, Schäfer KH (2016) Short chain fatty acids and gut microbiota differ between patients with Parkinson’s disease and age-matched controls. Parkinsonism Relat Disord 32, 66–72.
    1. Keshavarzian A, Green SJ, Engen PA, Voigt RM, Naqib A, Forsyth CB, Mutlu E, Shannon KM (2015) Colonic bacterial composition in Parkinson’s disease. Mov Disord 30, 1351–1360.
    1. Heintz-Buschart A, Pandey U, Wicke T, Sixel-Döring F, Janzen A, Sittig-Wiegand E, Trenkwalder C, Oertel WH, Mollenhauer B, Wilmes P (2018) The nasal and gut microbiome in Parkinson’s disease and idiopathic rapid eye movement sleep behavior disorder. Mov Disord 33, 88–98.
    1. Bedarf JR, Hildebrand F, Coelho LP, Sunagawa S, Bahram M, Goeser F, Bork P, Wüllner U (2017) Functional implications of microbial and viral gut metagenome changes in early stage L-DOPA-naïve Parkinson’s disease patients. Genome Med 9, 39.
    1. Hopfner F, Künstner A, Müller SH, Künzel S, Zeuner KE, Margraf NG, Deuschl G, Baines JF, Kuhlenbäumer G (2017) Gut microbiota in Parkinson disease in a northern German cohort. Brain Res 1667, 41–45.
    1. Li W, Wu X, Hu X, Wang T, Liang S, Duan Y, Jin F, Qin B (2017) Structural changes of gut microbiota in Parkinson’s disease and its correlation with clinical features. Sci China Life Sci 60, 1223–1233.
    1. Aho VTEA, Pereira PAB, Voutilainen S, Paulin L, Pekkonen E, Auvinen P, Scheperjans F (2019) Gut microbiota in Parkinson’s disease: Temporal stability and relations to disease progression. EBioMedicine 44, 691–707.
    1. Li F, Wang P, Chen Z, Sui X, Xie X, Zhang J (2019) Alteration of the fecal microbiota in North-Eastern Han Chinese population with sporadic Parkinson’s disease. Neurosci Lett 707, 134297.
    1. Voigt AY, Costea PI, Kultima JR, Li SS, Zeller G, Sunagawa S, Bork P (2015) Temporal and technical variability of human gut metagenomes. Genome Biol 16, 73.
    1. Gaulke CA, Sharpton TJ (2018) The influence of ethnicity and geography on human gut microbiome composition. Nat Med 24, 1495–1496.
    1. He Y, Wu W, Zheng HM, Li P, McDonald D, Sheng HF, Chen MX, Chen ZH, Ji GY, Zheng ZDX, Mujagond P, Chen XJ, Rong ZH, Chen P, Lyu LY, Wang X, Bin Wu C, Yu N, Xu YJ, Yin J, Raes J, Knight R, Ma WJ, Zhou HW (2018) Regional variation limits applications of healthy gut microbiome reference ranges and disease models. Nat Med 24, 1532–1535.
    1. Zhernakova A, Kurilshikov A, Bonder MJ, Tigchelaar EF, Schirmer M, Vatanen T, Mujagic Z, Vila AV, Falony G, Vieira-Silva S, Wang J, Imhann F, Brandsma E, Jankipersadsing SA, Joossens M, Cenit MC, Deelen P, Swertz MA, Weersma RK, Feskens EJMM, Netea MG, Gevers D, Jonkers D, Franke L, Aulchenko YS, Huttenhower C, Raes J, Hofker MH, Xavier RJ, Wijmenga C, Fu J (2016) Population-based metagenomics analysis reveals markers for gut microbiome composition and diversity. Science 352, 565–569.
    1. Falony G, Joossens M, Vieira-Silva S, Wang J, Darzi Y, Faust K, Kurilshikov A, Bonder MJ, Valles-Colomer M, Vandeputte D, Tito RY, Chaffron S, Rymenans L, Verspecht C, De Sutter L, Lima-Mendez G, D’hoe K, Jonckheere K, Homola D, Garcia R, Tigchelaar EF, Eeckhaudt L, Fu J, Henckaerts L, Zhernakova A, Wijmenga C, Raes J (2016) Population-level analysis of gut microbiome variation. Science 352, 560–564.
    1. Van Rooden SM, Colas F, Martínez-Martín P, Visser M, Verbaan D, Marinus J, Chaudhuri RK, Kok JN, Van Hilten JJ (2011) Clinical subtypes of Parkinson’s disease. Mov Disord 26, 51–58.
    1. Minato T, Maeda T, Fujisawa Y, Tsuji H, Nomoto K, Ohno K, Hirayama M (2017) Progression of Parkinson’s disease is associated with gut dysbiosis: Two-year follow-up study. PLoS One 12, e0187307.
    1. Nalls MA, Blauwendraat C, Vallerga CL, Heilbron K, Bandres-Ciga S, Chang D, Tan M, Kia DA, Noyca AJ, Xue A, Bras J, Young E, von Coelln R, Simón-Sánchez J, Schulte C, Sharma M, Krohn L, Pihlstrom L, Siitonen A, Iwaki H, Leonard H, Faghri F, Gibbs JR, Hernandez DG, Scholz SW, Botia JA, Martinez M, Corvol JC, Lesage S, Jankovic J, Shulman LM, The 23andMe Research Team, System Genomics of Parkinson’s Disease (SGPD) Consortium, Sutherland M, Tienari P, Majamaa K, Toft M, Brice A, Yang J, Gan-Or Z, Gasser T, Heutink P, Shulman JM, Wood N, Hinds DA, Hardy J, Morris HR, Gratten J, Visscher PM, Graham RR, Singleton AB, for the International Parkinson’s Disease Genomics Consortium (2018) Parkinson’s disease genetics: Identifying novel risk loci, providing causal insights and improving estimates of heritable risk. bioRxiv, 10.1101/388165.
    1. Bonder MJ, Kurilshikov A, Tigchelaar EF, Mujagic Z, Imhann F, Vila AV, Deelen P, Vatanen T, Schirmer M, Smeekens SP, Zhernakova D V, Jankipersadsing SA, Jaeger M, Oosting M, Cenit MC, Masclee AAM, Swertz MA, Li Y, Kumar V, Joosten L, Harmsen H, Weersma RK, Franke L, Hofker MH, Xavier RJ, Jonkers D, Netea MG, Wijmenga C, Fu J, Zhernakova A (2016) The effect of host genetics on the gut microbiome. Nat Genet 48, 1407–1412.
    1. Wang J, Thingholm LB, Skiecevičie J, Rausch P, Kummen M, Hov JR, Degenhardt F, Heinsen FA, Rühlemann MC, Szymczak S, Holm K, Esko T, Sun J, Pricop-Jeckstadt M, Al-Dury S, Bohov P, Bethune J, Sommer F, Ellinghaus D, Berge RK, Hübenthal M, Koch M, Schwarz K, Rimbach G, Hübbe P, Pan WH, Sheibani-Tezerji R, Häsler R, Rosenstiel P, D’Amato M, Cloppenborg-Schmidt K, Künzel S, Laudes M, Marschall HU, Lieb W, Nöthlings U, Karlsen TH, Baines JF, Franke A (2016) Genome-wide association analysis identifies variation in Vitamin D receptor and other host factors influencing the gut microbiota. Nat Genet 48, 1396–1406.
    1. Turpin W, Espin-Garcia O, Xu W, Silverberg MS, Kevans D, Smith MI, Guttman DS, Griffiths A, Panaccione R, Otley A, Xu L, Shestopaloff K, Moreno-Hagelsieb G, Paterson AD, Croitoru K (2016) Association of host genome with intestinal microbial composition in a large healthy cohort. Nat Genet 48, 1413–1417.
    1. Shi L, Webb BD, Birch AH, Elkhoury L, McCarthy J, Cai X, Oishi K, Mehta L, Diaz GA, Edelmann L, Kornreich R (2017) Comprehensive population screening in the Ashkenazi Jewish population for recurrent disease-causing variants. Clin Genet 91, 599–604.
    1. Knudsen K, Fedorova TD, Bekker AC, Iversen P, Østergaard K, Krogh K, Borghammer P (2017) Objective colonic dysfunction is far more prevalent than subjective constipation in Parkinson’s disease: A colon transit and volume study. J Parkinsons Dis 7, 359–367.
    1. Vandeputte D, Falony G, Vieira-Silva S, Tito RY, Joossens M, Raes J (2016) Stool consistency is strongly associated with gut microbiota richness and composition, enterotypes and bacterial growth rates. Gut 65, 57–62.
    1. Tigchelaar EF, Zhernakova A, Dekens JAM, Hermes G, Baranska A, Mujagic Z, Swertz MA, Muñoz AM, Deelen P, Cénit MC, Franke L, Scholtens S, Stolk RP, Wijmenga C, Feskens EJM (2015) Cohort profile: LifeLines DEEP, a prospective, general population cohort study in the northern Netherlands: Study design and baseline characteristics. BMJ Open 5, e006772.
    1. Vandeputte D, Kathagen G, D’Hoe K, Vieira-Silva S, Valles-Colomer M, Sabino J, Wang J, Tito RY, De Commer L, Darzi Y, Vermeire S, Falony G, Raes J (2017) Quantitative microbiome profiling links gut community variation to microbial load. Nature 551, 507–511.
    1. Kowalkowska J, Slowinska MA, Slowinski D, Dlugosz A, Niedzwiedzka E, Wadolowska L (2013) Comparison of a full food-frequency questionnaire with the three-day unweighted food records in young Polish adult women: Implications for dietary assessment. Nutrients 5, 2747–2776.
    1. Wu GD, Lewis JD, Hoffmann C, Chen YY, Knight R, Bittinger K, Hwang J, Chen J, Berkowsky R, Nessel L, Li H, Bushman FD (2010) Sampling and pyrosequencing methods for characterizing bacterial communities in the human gut using 16S sequence tags. BMC Microbiol 10, 206.
    1. Wang Z, Zolnik CP, Qiu Y, Usyk M, Wang T, Strickler HD, Isasi CR, Kaplan RC, Kurland IJ, Qi Q, Burk RD (2018) Comparison of fecal collection methods for microbiome and metabolomics studies. Front Cell Infect Microbiol 8, 301.
    1. Wu WK, Chen CC, Panyod S, Chen RA, Wu MS, Sheen LY, Chang SC (2019) Optimization of fecal sample processing for microbiome study — The journey from bathroom to bench. J Formos Med Assoc 118, 545–555.
    1. Flores R, Shi J, Yu G, Ma B, Ravel J, Goedert JJ, Sinha R (2015) Collection media and delayed freezing effects on microbial composition of human stool. Microbiome 3, 33.
    1. Salter SJ, Cox MJ, Turek EM, Calus ST, Cookson WO, Moffatt MF, Turner P, Parkhill J, Loman NJ, Walker AW (2014) Reagent and laboratory contamination can critically impact sequence-based microbiome analyses. BMC Biol 12, 87.
    1. Wang J, Kurilshikov A, Radjabzadeh D, Turpin W, Croitoru K, Bonder MJ, Jackson MA, Medina-Gomez C, Frost F, Homuth G, Rühlemann M, Hughes D, Kim HN, MiBioGen Consortium Initiative, Spector TD, Bell JT, Steves CJ, Timpson N, Franke A, Wijmenga C, Meyer K, Kacprowski T, Franke L, Paterson AD, Raes J, Kraaij R, Zhernakova A (2018) Meta-analysis of human genome-microbiome association studies: The MiBioGen consortium initiative. Microbiome 6, 101.
    1. Graspeuntner S, Loeper N, Künzel S, Baines JF, Rupp J (2018) Selection of validated hypervariable regions is crucial in 16S-based microbiota studies of the female genital tract. Sci Rep 8, 9678.
    1. Ibrahim N, Kusmirek J, Struck A, Floberg J, Perlman S, Gallagher C, Hall L (2016) The sensitivity and specificity of F-DOPA PET in a movement disorder clinic. Am J Nucl Med Mol Imaging 6, 102–109.
    1. Engen PA, Dodiya HB, Naqib A, Forsyth CB, Green SJ, Voigt RM, Kordower JH, Mutlu EA, Shannon KM, Keshavarzian A (2017) The potential role of gut-derived inflammation in multiple system atrophy. J Parkinsons Dis 7, 331–346.
    1. Levin J, Kurz A, Arzberger T, Giese A, Höglinger GU (2016) The differential diagnosis and treatment of atypical parkinsonism. Dtsch Arztebl Int 113, 61–69.
    1. Duvallet C, Gibbons SM, Gurry T, Irizarry RA, Alm EJ (2017) Meta-analysis of gut microbiome studies identifies disease-specific and shared responses. Nat Commun 8, 1784.
    1. Burgess S, Foley CN, Zuber V (2018) Inferring causal relationships between risk factors and outcomes from genome-wide association study data. Annu Rev Genomics Hum Genet 19, 303–327.
    1. Pinu FR, Beale DJ, Paten AM, Kouremenos K, Swarup S, Schirra HJ, Wishart D (2019) Systems biology and multi-omics integration: Viewpoints from the metabolomics research community. Metabolites 9, E76.
    1. Browne HP, Forster SC, Anonye BO, Kumar N, Neville BA, Stares MD, Goulding D, Lawley TD (2016) Culturing of “unculturable” human microbiota reveals novel taxa and extensive sporulation. Nature 533, 543–546.
    1. Wang S, Li N, Zou H, Wu M (2019) Gut microbiome-based secondary metabolite biosynthetic gene clusters detection in Parkinson’s disease. Neurosci Lett, 696, 93–98.
    1. Watson CL, Mahe MM, Múnera J, Howell JC, Sundaram N, Poling HM, SchweitzerJI, Vallance JE, Mayhew CN, Sun Y, Grabowski G, Finkbeiner SR, Spence JR, Shroyer NF, Wells JM, Helmrath MA (2014) An in vivo model of human small intestine using pluripotent stem cells. Nat Med 20, 1310–1314.
    1. Schlieve CR, Fowler KL, Thornton M, Huang S, Hajjali I, Hou X, Grubbs B, Spence JR, Grikscheit TC (2017) Neural crest cell implantation restores enteric nervous system function and alters the gastrointestinal transcriptome in human tissue-engineered small intestine. Stem Cell Reports 9, 883–896.
    1. Hill DR, Huang S, Nagy MS, Yadagiri VK, Fields C, Mukherjee D, Bons B, Dedhia PH, Chin AM, Tsai YH, Thodla S, Schmidt TM, Walk S, Young VB, Spence JR (2017) Bacterial colonization stimulates a complex physiological response in the immature human intestinal epithelium. Elife 6, e29132.

Source: PubMed

Szponzorok és közreműködők

Egészségi állapot

Kábítószer-beavatkozások

3
Iratkozz fel