Clinical trial NCT04781036: Foot-skin Microbiome and Metabolomics of Pitted Keratolysis
Official title: The Study of Foot-skin Microbiome and Metabolomics of Thai Naval Cadets With Pitted Keratolysis
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: NA
Conditions: Microbial Disease
Metabolomics
Keywords: Pitted keratolysis
Microbiome
Metabolomics
Lead sponsor: Mahidol University
Sponsor class: OTHER
First posted: 2021-03-04
Enrollment: 250
Sex: MALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: BASIC_SCIENCE

Brief summary: This study aimed to investigate the skin microbiome and metabolomics of patients with pitted keratolysis.

Detailed description: Pitted keratolysis is a skin infectious disease which can cause an unpleasant smell that can affect self-confidence and interpersonal relationships. The research problem was initiated through a community outreach program organized by the Department of Dermatology Siriraj Hospital, Thailand. From many years of experiences, our dermatologist teams observed that pitted keratolysis was a common disease among naval cadets who wore enclosed footwear for long hours, and it was more prevalent after a boot camp that spanned over months. This disease is chronic with no efficient standard treatment and limited information on the pathogenesis of the disease. Therefore, we propose to conduct a study on the pathogenesis of pitted keratolysis and malodorous feet through a longitudinal study of foot-skin microbiome and associated volatile metabolomic profiles of foot odor. With the unique population, with similar age range, daily activities, and diet, this study will allow to focus on the association of changes in microbiome in relation to pathogenesis of pitted keratolysis and malodorous feet, with fewer cofounding factors.

The skin microbiome is a group of various microorganisms, such as bacteria, fungi, and viruses, residing on skin. Human skin microbiome can differ with respect to age, ethnicity, diet, climate and environment. Recently, there have been numerous studies highlighting the association of microbes with pathogenesis of various skin diseases, such as atopic dermatitis, acne vulgaris, and psoriasis (references?). In this project, we hypothesize that the alteration of skin microbiome as well as changes in metabolite profiles can be associated with the mechanism of the disease. The skin microbiome data generated in this study will be analyzed for microbial profiles using the QIIME2, a next-generation microbiome bioinformatics platform, and a graphic software package, "Statistical Analysis of Taxonomic and Functional Profiles" (STAMP). In parallel, we will apply a high throughput gas chromatography mass-spectrometry-based metabolomics to detect volatile metabolites present in foot odor in association with the observed foot-skin microbiome. This metabolite information will not only provide an additional aspect of pathogenesis of the disease but also might offer a new standard indicator of foot odor that can be further used in clinical practice. Finally, skin microbiome and metabolomic data will be analyzed using various methods of correlation analysis as well as integrative analysis to gain deeper understanding of the disease mechanism at the molecular levels.

The outcomes of this project will provide insights into the pathogenesis of pitted keratolysis. The scientific knowledge gained from the study will be translated into a more effective treatment of the disease. The human microbiome of healthy population and the disease-specific microbiome data will lay the groundwork to develop a human microbiome database for Thai people. Additionally, the success of the project will allow the development of advanced instrumental methodology and an integrative analysis approach to analyze multi -omics data, which will be great assets in advancing multidisciplinary research.

Eligibility criteria: Inclusion Criteria:

* Naval rating cadets at Chumpol Naval Rating School, Thailand who volunteer to participate in this study. Informed consent will be obtained from all participants.
* Age ≥ 18 years.
* No underlying disease.
* Normal BMI (18.5-22.9 kg/m2).
* No previous history of pitted keratolysis.
* No previous history of dermatophytosis complex.
* Refrain from washing their feet for 12 hours prior to sampling.

Exclusion Criteria:

* Volunteers who have taken medication or topical antibiotics for pitted keratolysis within 2 weeks before the enrollment.
* Volunteers who have taken oral antibiotics within 2 weeks before enrollment.

Primary outcomes:
measure: Amount of skin microbiome
timeFrame: 2 months
measure: Composition of microbiota at skin
timeFrame: 2 months
Secondary outcomes:
measure: Amount of metabolite in foot odor
timeFrame: 2 months
Other outcomes:
Locations:
city: Bangkoknoi
country: Thailand
facility: Department of Dermatology Siriraj Hospital
state: Bangkok
city: Bangkok
country: Thailand
facility: Department of Dermatology Siriraj Hospital
Study officials:
affiliation: Mahidol University
name: Sumanas Bunyaratavej, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Grice EA, Segre JA. The skin microbiome. Nat Rev Microbiol. 2011 Apr;9(4):244-53. doi: 10.1038/nrmicro2537.
citation: Musthaq S, Mazuy A, Jakus J. The microbiome in dermatology. Clin Dermatol. 2018 May-Jun;36(3):390-398. doi: 10.1016/j.clindermatol.2018.03.012. Epub 2018 Mar 10.
citation: Perez Perez GI, Gao Z, Jourdain R, Ramirez J, Gany F, Clavaud C, Demaude J, Breton L, Blaser MJ. Body Site Is a More Determinant Factor than Human Population Diversity in the Healthy Skin Microbiome. PLoS One. 2016 Apr 18;11(4):e0151990. doi: 10.1371/journal.pone.0151990. eCollection 2016.
citation: Sander MA, Sander MS, Isaac-Renton JL, Croxen MA. The Cutaneous Microbiome: Implications for Dermatology Practice. J Cutan Med Surg. 2019 Jul/Aug;23(4):436-441. doi: 10.1177/1203475419839939. Epub 2019 Apr 2.
citation: Yu Y, Dunaway S, Champer J, Kim J, Alikhan A. Changing our microbiome: probiotics in dermatology. Br J Dermatol. 2020 Jan;182(1):39-46. doi: 10.1111/bjd.18088. Epub 2019 Jul 28.
citation: Szabo K, Erdei L, Bolla BS, Tax G, Biro T, Kemeny L. Factors shaping the composition of the cutaneous microbiota. Br J Dermatol. 2017 Feb;176(2):344-351. doi: 10.1111/bjd.14967. Epub 2017 Jan 23.
citation: Schoch JJ, Monir RL, Satcher KG, Harris J, Triplett E, Neu J. The infantile cutaneous microbiome: A review. Pediatr Dermatol. 2019 Sep;36(5):574-580. doi: 10.1111/pde.13870. Epub 2019 Jul 23.
citation: Iebba V, Totino V, Gagliardi A, Santangelo F, Cacciotti F, Trancassini M, Mancini C, Cicerone C, Corazziari E, Pantanella F, Schippa S. Eubiosis and dysbiosis: the two sides of the microbiota. New Microbiol. 2016 Jan;39(1):1-12.
citation: Thomas CL, Fernandez-Penas P. The microbiome and atopic eczema: More than skin deep. Australas J Dermatol. 2017 Feb;58(1):18-24. doi: 10.1111/ajd.12435. Epub 2016 Jan 28.
citation: Holmes E, Wilson ID, Nicholson JK. Metabolic phenotyping in health and disease. Cell. 2008 Sep 5;134(5):714-7. doi: 10.1016/j.cell.2008.08.026.
citation: Patti GJ, Yanes O, Siuzdak G. Innovation: Metabolomics: the apogee of the omics trilogy. Nat Rev Mol Cell Biol. 2012 Mar 22;13(4):263-9. doi: 10.1038/nrm3314.
citation: Melnik BC. Linking diet to acne metabolomics, inflammation, and comedogenesis: an update. Clin Cosmet Investig Dermatol. 2015 Jul 15;8:371-88. doi: 10.2147/CCID.S69135. eCollection 2015.
citation: Nordstrom KM, McGinley KJ, Cappiello L, Zechman JM, Leyden JJ. Pitted keratolysis. The role of Micrococcus sedentarius. Arch Dermatol. 1987 Oct;123(10):1320-5. doi: 10.1001/archderm.123.10.1320.
citation: Singh G, Naik CL. Pitted keratolysis. Indian J Dermatol Venereol Leprol. 2005 May-Jun;71(3):213-5. doi: 10.4103/0378-6323.16250. No abstract available.
citation: Bolyen E, Rideout JR, Dillon MR, Bokulich NA, Abnet CC, Al-Ghalith GA, Alexander H, Alm EJ, Arumugam M, Asnicar F, Bai Y, Bisanz JE, Bittinger K, Brejnrod A, Brislawn CJ, Brown CT, Callahan BJ, Caraballo-Rodriguez AM, Chase J, Cope EK, Da Silva R, Diener C, Dorrestein PC, Douglas GM, Durall DM, Duvallet C, Edwardson CF, Ernst M, Estaki M, Fouquier J, Gauglitz JM, Gibbons SM, Gibson DL, Gonzalez A, Gorlick K, Guo J, Hillmann B, Holmes S, Holste H, Huttenhower C, Huttley GA, Janssen S, Jarmusch AK, Jiang L, Kaehler BD, Kang KB, Keefe CR, Keim P, Kelley ST, Knights D, Koester I, Kosciolek T, Kreps J, Langille MGI, Lee J, Ley R, Liu YX, Loftfield E, Lozupone C, Maher M, Marotz C, Martin BD, McDonald D, McIver LJ, Melnik AV, Metcalf JL, Morgan SC, Morton JT, Naimey AT, Navas-Molina JA, Nothias LF, Orchanian SB, Pearson T, Peoples SL, Petras D, Preuss ML, Pruesse E, Rasmussen LB, Rivers A, Robeson MS 2nd, Rosenthal P, Segata N, Shaffer M, Shiffer A, Sinha R, Song SJ, Spear JR, Swafford AD, Thompson LR, Torres PJ, Trinh P, Tripathi A, Turnbaugh PJ, Ul-Hasan S, van der Hooft JJJ, Vargas F, Vazquez-Baeza Y, Vogtmann E, von Hippel M, Walters W, Wan Y, Wang M, Warren J, Weber KC, Williamson CHD, Willis AD, Xu ZZ, Zaneveld JR, Zhang Y, Zhu Q, Knight R, Caporaso JG. Author Correction: Reproducible, interactive, scalable and extensible microbiome data science using QIIME 2. Nat Biotechnol. 2019 Sep;37(9):1091. doi: 10.1038/s41587-019-0252-6.
citation: Li M, Budding AE, van der Lugt-Degen M, Du-Thumm L, Vandeven M, Fan A. The influence of age, gender and race/ethnicity on the composition of the human axillary microbiome. Int J Cosmet Sci. 2019 Aug;41(4):371-377. doi: 10.1111/ics.12549.
citation: Zhu T, Liu X, Kong FQ, Duan YY, Yee AL, Kim M, Galzote C, Gilbert JA, Quan ZX. Age and Mothers: Potent Influences of Children's Skin Microbiota. J Invest Dermatol. 2019 Dec;139(12):2497-2505.e6. doi: 10.1016/j.jid.2019.05.018. Epub 2019 Aug 13.
citation: Shami A, Al-Mijalli S, Pongchaikul P, Al-Barrag A, AbduRahim S. The prevalence of the culturable human skin aerobic bacteria in Riyadh, Saudi Arabia. BMC Microbiol. 2019 Aug 16;19(1):189. doi: 10.1186/s12866-019-1569-5.
citation: Blaser MJ, Dominguez-Bello MG, Contreras M, Magris M, Hidalgo G, Estrada I, Gao Z, Clemente JC, Costello EK, Knight R. Distinct cutaneous bacterial assemblages in a sampling of South American Amerindians and US residents. ISME J. 2013 Jan;7(1):85-95. doi: 10.1038/ismej.2012.81. Epub 2012 Aug 16.
citation: Kong HH, Oh J, Deming C, Conlan S, Grice EA, Beatson MA, Nomicos E, Polley EC, Komarow HD; NISC Comparative Sequence Program; Murray PR, Turner ML, Segre JA. Temporal shifts in the skin microbiome associated with disease flares and treatment in children with atopic dermatitis. Genome Res. 2012 May;22(5):850-9. doi: 10.1101/gr.131029.111. Epub 2012 Feb 6.
citation: Tsilochristou O, du Toit G, Sayre PH, Roberts G, Lawson K, Sever ML, Bahnson HT, Radulovic S, Basting M, Plaut M, Lack G; Immune Tolerance Network Learning Early About Peanut Allergy Study Team. Association of Staphylococcus aureus colonization with food allergy occurs independently of eczema severity. J Allergy Clin Immunol. 2019 Aug;144(2):494-503. doi: 10.1016/j.jaci.2019.04.025. Epub 2019 May 31.
citation: Zheng Y, Wang Q, Ma L, Chen Y, Gao Y, Zhang G, Cui S, Liang H, He C, Song L. Alterations in the skin microbiome are associated with disease severity and treatment in the perioral zone of the skin of infants with atopic dermatitis. Eur J Clin Microbiol Infect Dis. 2019 Sep;38(9):1677-1685. doi: 10.1007/s10096-019-03598-9. Epub 2019 May 31.
citation: Quan C, Chen XY, Li X, Xue F, Chen LH, Liu N, Wang B, Wang LQ, Wang XP, Yang H, Zheng J. Psoriatic lesions are characterized by higher bacterial load and imbalance between Cutibacterium and Corynebacterium. J Am Acad Dermatol. 2020 Apr;82(4):955-961. doi: 10.1016/j.jaad.2019.06.024. Epub 2019 Jun 19.
citation: Dutkiewicz EP, Hsieh KT, Wang YS, Chiu HY, Urban PL. Hydrogel Micropatch and Mass Spectrometry-Assisted Screening for Psoriasis-Related Skin Metabolites. Clin Chem. 2016 Aug;62(8):1120-8. doi: 10.1373/clinchem.2016.256396. Epub 2016 Jun 20.
citation: Sitter B, Johnsson MK, Halgunset J, Bathen TF. Metabolic changes in psoriatic skin under topical corticosteroid treatment. BMC Dermatol. 2013 Aug 14;13:8. doi: 10.1186/1471-5945-13-8.
citation: Yan D, Afifi L, Jeon C, Trivedi M, Chang HW, Lee K, Liao W. The metabolomics of psoriatic disease. Psoriasis (Auckl). 2017;7:1-15. doi: 10.2147/PTT.S118348. Epub 2017 Jan 31.
citation: Longshaw CM, Wright JD, Farrell AM, Holland KT. Kytococcus sedentarius, the organism associated with pitted keratolysis, produces two keratin-degrading enzymes. J Appl Microbiol. 2002;93(5):810-6. doi: 10.1046/j.1365-2672.2002.01742.x.
citation: Woodgyer AJ, Baxter M, Rush-Munro FM, Brown J, Kaplan W. Isolation of Dermatophilus congolensis from two New Zealand cases of pitted keratolysis. Australas J Dermatol. 1985 Apr;26(1):29-35. doi: 10.1111/j.1440-0960.1985.tb01811.x. No abstract available.
citation: Svejgaard E, Christophersen J, Jelsdorf HM. Tinea pedis and erythrasma in Danish recruits. Clinical signs, prevalence, incidence, and correlation to atopy. J Am Acad Dermatol. 1986 Jun;14(6):993-9. doi: 10.1016/s0190-9622(86)70122-9.
citation: Bunyaratavej S, Leeyaphan C, Chanyachailert P, Pattanaprichakul P, Ongsri P, Kulthanan K. Clinical manifestations, risk factors and quality of life in patients with pitted keratolysis: a cross-sectional study in cadets. Br J Dermatol. 2018 Nov;179(5):1220-1221. doi: 10.1111/bjd.16923. Epub 2018 Sep 14. No abstract available.
citation: Kaptanoglu AF, Yuksel O, Ozyurt S. Plantar pitted keratolysis: a study from non-risk groups. Dermatol Reports. 2012 Feb 7;4(1):e4. doi: 10.4081/dr.2012.e4. eCollection 2012 Jan 2.
citation: Makhecha M, Dass S, Singh T, Gandhi R, Yadav T, Rathod D. Pitted keratolysis - a study of various clinical manifestations. Int J Dermatol. 2017 Nov;56(11):1154-1160. doi: 10.1111/ijd.13744. Epub 2017 Sep 18.
citation: Takama H, Tamada Y, Yano K, Nitta Y, Ikeya T. Pitted keratolysis: clinical manifestations in 53 cases. Br J Dermatol. 1997 Aug;137(2):282-5. doi: 10.1046/j.1365-2133.1997.18211899.x.
citation: Leeyaphan C, Bunyaratavej S, Taychakhoonavudh S, Kulthanachairojana N, Pattanaprichakul P, Chanyachailert P, Ongsri P, Arunkajohnsak S, Limphoka P, Kulthanan K. Cost-effectiveness analysis and safety of erythromycin 4% gel and 4% chlorhexidine scrub for pitted keratolysis treatment. J Dermatolog Treat. 2019 Sep;30(6):627-629. doi: 10.1080/09546634.2018.1543846. Epub 2018 Dec 11.
citation: Leung MH, Wilkins D, Lee PK. Insights into the pan-microbiome: skin microbial communities of Chinese individuals differ from other racial groups. Sci Rep. 2015 Jul 16;5:11845. doi: 10.1038/srep11845.