Biomolecules & Therapeutics

The Korean Society of Applied Pharmacology (한국응용약물학회)
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Association between LEPR Genotype and Gut Microbiome in Healthy Non-Obese Korean Adults

  • Yoon Jung Cha (Clinical Trials Center, Chungnam National University Hospital) ;
  • In Ae Chang (Clinical Trials Center, Chungnam National University Hospital) ;
  • Eun-Heui Jin (Translational Immunology Institute, Chungnam National University College of Medicine) ;
  • Ji Hye Song (Clinical Trials Center, Chungnam National University Hospital) ;
  • Jang Hee Hong (Clinical Trials Center, Chungnam National University Hospital) ;
  • Jin-Gyu Jung (Department of Family Medicine, Chungnam National University Hospital) ;
  • Jung Sunwoo (Clinical Trials Center, Chungnam National University Hospital)
  • Received : 2023.06.16
  • Accepted : 2023.07.12
  • Published : 2024.01.01
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Abstract

The LEPR (leptin receptor) genotype is associated with obesity. Gut microbiome composition differs between obese and non-obese adults. However, the impact of LEPR genotype on gut microbiome composition in humans has not yet been studied. In this study, the association between LEPR single nucleotide polymorphism (rs1173100, rs1137101, and rs790419) and the gut microbiome composition in 65 non-obese Korean adults was investigated. Leptin, triglyceride, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol levels were also measured in all participants. Mean ± SD (standard deviation) of age, body mass index, and leptin hormone levels of participants was 35.2 ± 8.1 years, 21.4 ± 1.8 kg/m2, and 7989.1 ± 6687.4 pg/mL, respectively. Gut microbiome analysis was performed at the phylum level by 16S rRNA sequencing. Among the 11 phyla detected, only one showed significantly different relative abundances between LEPR genotypes. The relative abundance of Candidatus Saccharibacteria was higher in the G/A genotype group than in the G/G genotype group for the rs1137101 single nucleotide polymorphism (p=0.0322). Participant characteristics, including body mass index, leptin levels, and other lipid levels, were similar between the rs1137101 G/G and G/A genotypes. In addition, the relative abundances of Fusobacteria and Tenericutes showed significant positive relationship with plasma leptin concentrations (p=0.0036 and p=0.0000, respectively). In conclusion, LEPR genotype and gut microbiome may be associated even in normal-weight Korean adults. However, further studies with a greater number of obese adults are needed to confirm whether LEPR genotype is related to gut microbiome composition.

Keywords

Acknowledgement

This research was supported by the Basic Science Research Program through the National Research Foundation of Korea and was funded by the Ministry of Education (grant number: NRF-2022R1I1A1A01053088). We would like to thank Editage (www.editage.co.kr) for English language editing.

References

  1. Abdel-Rahman, A. A., Hamouda, H. E., Zeid, I. F., Amal, M. and Al-Ashwah, A. A. (2020) Impact of obesity on leptin, leptin receptor gene polymorphism, and some adipokines in egyptian patients with knee osteoarthritis. Indian J. Rheumatol. 15, 84-91.  https://doi.org/10.4103/injr.injr_71_19
  2. Abed, J., Maalouf, N., Manson, A. L., Earl, A. M., Parhi, L., Emgard, J. E., Klutstein, M., Tayeb, S., Almogy, G., Atlan, K. A. and Chaushu, S. (2020) Colon cancer-associated Fusobacterium nucleatum may originate from the oral cavity and reach colon tumors via the circulatory system. Front. Cell Infect. Microbiol. 10, 400. 
  3. Andoh, A., Nishida, A., Takahashi, K., Inatomi, O., Imaeda, H., Bamba, S., Kito, K., Sugimoto, M. and Kobayashi, T. (2016) Comparison of the gut microbial community between obese and lean peoples using 16S gene sequencing in a Japanese population. J. Clin. Biochem. Nutr. 59, 65-70.  https://doi.org/10.3164/jcbn.15-152
  4. Assmann, G. and Schulte, H. (1992) Relation of high-density lipoprotein cholesterol and triglycerides to incidence of atherosclerotic coronary artery disease (the PROCAM experience). Am. J. Cardiol. 70, 733-737.  https://doi.org/10.1016/0002-9149(92)90550-I
  5. Bokulich, N. A., Kaehler, B. D., Rideout, J. R., Dillon, M., Bolyen, E., Knight, R., Huttley, G. A. and Gregory Caporaso, J. (2018) Optimizing taxonomic classification of marker-gene amplicon sequences with QIIME 2's q2-feature-classifier plugin. Microbiome 6, 90. 
  6. Bolyen, E., Rideout, J. R., Dillon, M. R., Bokulich, N. A., Abnet, C. C., Al-Ghalith, G. A., Alexander, H., Alm, E. J., Arumugam, M. and Asnicar, F. (2019) Reproducible, interactive, scalable and extensible microbiome data science using QIIME 2. Nat. Biotechnol. 37, 852-857.  https://doi.org/10.1038/s41587-019-0209-9
  7. Callahan, B. J., McMurdie, P. J., Rosen, M. J., Han, A. W., Johnson, A. J. A. and Holmes, S. P. (2016) DADA2: high-resolution sample inference from Illumina amplicon data. Nat. Methods 13, 581-583.  https://doi.org/10.1038/nmeth.3869
  8. Choi, J. W., Choe, H.-W. and Pai, S. H. (2003) Serum lipid concentrations correlate more strongly with total body fat than with body mass index in obese humans. Clin. Chim. Acta 329, 83-87.  https://doi.org/10.1016/S0009-8981(03)00018-4
  9. D'Argenio, V. and Salvatore, F. (2015) The role of the gut microbiome in the healthy adult status. Clin. Chim. Acta 451, 97-102.  https://doi.org/10.1016/j.cca.2015.01.003
  10. Duranti, S., Ferrario, C., Van Sinderen, D., Ventura, M. and Turroni, F. (2017) Obesity and microbiota: an example of an intricate relationship. Genes Nutr. 12, 18. 
  11. El Fessikh, M., Elkarhat, Z., Flatters, D., Camproux, A.-C., Belghiti, H., Guerinech, H., Bakri, Y., Dakka, N. and El Baghdadi, J. (2022) Association study of leptin receptor polymorphisms in women with obesity and their impact on protein domains: a case-control study and in silico analyses. J. Biomol. Struct. Dyn. doi: 10.1080/07391102.2022.2109755 [Online ahead of print]. 
  12. Fan, S.-H. and Say, Y.-H. (2014) Leptin and leptin receptor gene polymorphisms and their association with plasma leptin levels and obesity in a multi-ethnic Malaysian suburban population. J. Physiol. Anthropol. 33, 15. 
  13. Gao, B., Chi, L., Mahbub, R., Bian, X., Tu, P., Ru, H. and Lu, K. (2017) Multi-omics reveals that lead exposure disturbs gut microbiome development, key metabolites, and metabolic pathways. Chem. Res. Toxicol. 30, 996-1005.  https://doi.org/10.1021/acs.chemrestox.6b00401
  14. Gomes, A. C., Hoffmann, C. and Mota, J. F. (2020) Gut microbiota is associated with adiposity markers and probiotics may impact specific genera. Eur. J. Nutr. 59, 1751-1762.  https://doi.org/10.1007/s00394-019-02034-0
  15. Hajdarovic, K. H., Yu, D. and Webb, A. E. (2022) Understanding the aging hypothalamus, one cell at a time. Trends Neurosci. 45, 942-954.  https://doi.org/10.1016/j.tins.2022.10.004
  16. Huang, Y.-C., Huang, L.-T., Sheen, J.-M., Hou, C.-Y., Yeh, Y.-T., Chiang, C.-P., Lin, I.-C., Tiao, M.-M., Tsai, C.-C. and Lin, Y.-J. (2020) Resveratrol treatment improves the altered metabolism and related dysbiosis of gut programed by prenatal high-fat diet and postnatal high-fat diet exposure. J. Nutr. Biochem. 75, 108260. 
  17. Jungner, I., Walldius, G., Holme, I., Kolar, W. and Steiner, E. (1992) Apolipoprotein B and A-I in relation to serum cholesterol and triglycerides in 43 000 Swedish males and females. Int. J. Clin. Lab. Res. 21, 247-255.  https://doi.org/10.1007/BF02591655
  18. Kang, S. H., Lee, J.-i., Han, H. R., Soh, M. and Hong, J. P. (2014) Polymorphisms of the leptin and HTR2C genes and clozapine-induced weight change and baseline BMI in patients with chronic schizophrenia. Psychiatr. Genet. 24, 249-256.  https://doi.org/10.1097/YPG.0000000000000053
  19. King, M., H. Hurley, K. R. Davidson, E. C. Dempsey, M. A. Barron, E. D. Chan and A. Frey (2020) The link between Fusobacteria and colon cancer: a fulminant example and review of the evidence. Immune Netw. 20, e30. 
  20. Kolic, I., Stojkovic, L., Stankovic, A., Stefanovic, M., Dincic, E. and Zivkovic, M. (2021) Association study of rs7799039, rs1137101 and rs8192678 gene variants with disease susceptibility/severity and corresponding LEP, LEPR and PGC1A gene expression in multiple sclerosis. Gene 774, 145422. 
  21. Mahmoudi, T., Farahani, H., Nobakht, H., Dabiri, R. and Zali, M. R. (2016) Genetic variations in leptin and leptin receptor and susceptibility to colorectal cancer and obesity. Iran. J. Cancer Prev. 9, e7013. 
  22. Manju, S. K., Anilkumar, T. R., Vysakh, G., Leena, B. K., Lekshminarayan, V., Kumar, P. G. and Shenoy, T. K. (2022) A case-control study of the association of leptin gene polymorphisms with plasma leptin levels and obesity in the kerala population. J. Obes. 2022, 1040650. 
  23. McLean, J. S., Bor, B., Kerns, K. A., Liu, Q., To, T. T., Solden, L., Hendrickson, E. L., Wrighton, K., Shi, W. and He, X. (2020) Acquisition and adaptation of ultra-small parasitic reduced genome bacteria to mammalian hosts. Cell Rep. 32, 107939. 
  24. Obradovic, M., Sudar-Milovanovic, E., Soskic, S., Essack, M., Arya, S., Stewart, A. J., Gojobori, T. and Isenovic, E. R. (2021) Leptin and obesity: role and clinical implication. Front. Endocrinol. 12, 585887.
  25. OECD (2021) OECD Health Statistics 2021. 
  26. Korea National Statistical Office (2023) Obesity Rate. Available from: https://www.index.go.kr/unify/idx-info.do?idxCd=8021/ [retrieved 2023 Jun 12]. 
  27. Panta, A. and Dasb, B. (2022) Microbiome-based therapeutics: opportunity and challenges. Prog. Mol. Biol. Transl. Sci. 191, 229-262.  https://doi.org/10.1016/bs.pmbts.2022.07.006
  28. Park, K. S., Shin, H. D., Park, B. L., Cheong, H. S., Cho, Y. M., Lee, H. K., Lee, J.-Y., Lee, J.-K., Oh, B. and Kimm, K. (2006) Polymorphisms in the leptin receptor (LEPR)-putative association with obesity and T2DM. J. Hum. Genet. 51, 85-91.  https://doi.org/10.1007/s10038-005-0327-8
  29. Pedersen, R., Ingerslev, H.-C., Sturek, M., Alloosh, M., Cirera, S., Christoffersen, B. O., Moesgaard, S. G., Larsen, N. and Boye, M. (2013) Characterisation of gut microbiota in Ossabaw and Gottingen minipigs as models of obesity and metabolic syndrome. PLoS One 8, e56612. 
  30. Ranji, P., Agah, S., Heydari, Z., Rahmati-Yamchi, M. and Alizadeh, A. M. (2019) Effects of Lactobacillus acidophilus and Bifidobacterium bifidum probiotics on the serum biochemical parameters, and the vitamin D and leptin receptor genes on mice colon cancer. Iran. J. Basic Med. Sci. 22, 631-636. 
  31. Souren, N., Paulussen, A., Steyls, A., Loos, R., Stassen, A., Gielen, M., Smeets, H., Beunen, G., Fagard, R. and Derom, C. (2008) Common SNPs in LEP and LEPR associated with birth weight and type 2 diabetes-related metabolic risk factors in twins. Int. J. Obes. (Lond.) 32, 1233-1239.  https://doi.org/10.1038/ijo.2008.68
  32. Tremmel, M., Gerdtham, U.-G., Nilsson, P. M. and Saha, S. (2017) Economic burden of obesity: a systematic literature review. Int. J. Environ. Res. Public Health 14, 435. 
  33. Vauthier, V., Jaillard, S., Journel, H., Dubourg, C., Jockers, R. and Dam, J. (2012) Homozygous deletion of an 80 kb region comprising part of DNAJC6 and LEPR genes on chromosome 1P31.3 is associated with early onset obesity, mental retardation and epilepsy. Mol. Genet. Metab. 106, 345-350.  https://doi.org/10.1016/j.ymgme.2012.04.026
  34. Waldram, A., Holmes, E., Wang, Y., Rantalainen, M., Wilson, I. D., Tuohy, K. M., McCartney, A. L., Gibson, G. R. and Nicholson, J. K. (2009) Top-down systems biology modeling of host metabotype-microbiome associations in obese rodents. J. Proteome Res. 8, 2361-2375.  https://doi.org/10.1021/pr8009885
  35. Wang, N. and Fang, J. Y. (2022) Fusobacterium nucleatum, a key pathogenic factor and microbial biomarker for colorectal cancer. Trends Microbiol. 31, 159-172.  https://doi.org/10.1016/j.tim.2022.08.010
  36. Yuan, X., Chen, R., McCormick, K. L., Zhang, Y., Lin, X. and Yang, X. (2021) The role of the gut microbiota on the metabolic status of obese children. Microb. Cell Fact. 20, 53. 
  37. Zhang, Y. and Scarpace, P. J. (2006) The role of leptin in leptin resistance and obesity. Physiol. Behav. 88, 249-256.  https://doi.org/10.1016/j.physbeh.2006.05.038