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Gut microbiome–short-chain fatty acids interplay in the context of iron deficiency anaemia

Abstract

Purpose

Anaemia is a global health concern, with iron deficiency anaemia (IDA) causing approximately 50% of cases. Affecting mostly the elderly, pregnant and adult women and children, physiopathology of IDA in relation to the gut microbiome is poorly understood. Therefore, the objective of this study is to analyse, in an animal model, the effect of IDA on the gut microbiome along the gastrointestinal tract, as well as to relate intestinal dysbiosis to changes in microbial metabolites such as short chain fatty acids (SCFA).

Methods

IDA was experimentally induced through an iron deficient diet for a period of 40 days, with twenty weaned male Wistar rats being randomly divided into control or anaemic groups. Blood samples were collected to control haematological parameters, and so were faecal and intestinal content samples to study gut microbial communities and SCFA, using 16S rRNA sequencing and HPLC–UV respectively.

Results

An intestinal dysbiosis was observed as a consequence of IDA, especially towards the distal segments of the gastrointestinal tract and the colon. An increase in SCFA was also noticed during IDA, with the major difference appearing in the colon and correlating with changes in the composition of the gut microbiome. Clostridium_sensu_stricto_1 and Clostridium_sensu_stricto_4 showed the greatest correlation with variations in butyric and propionic concentrations in the colon of anaemic animals.

Conclusions

Composition of intestinal microbial communities was affected by the generation of IDA. An enrichment in certain SCFA-producing genera and SCFA concentrations was found in the colon of anaemic animals, suggesting a trade-off mechanism against disease.

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Data availability

All datasets supporting the conclusions of this article will be made available in the Sequence Read Archive (SRA) of the National Centre for Biotechnology Information (NCBI) upon request. Authors can confirm that all relevant data are included in the article and/or its supplementary information files.

Code availability

Not applicable.

References

  1. Lopez A, Cacoub P, Macdougall IC, Peyrin-Biroulet L (2016) Iron deficiency anaemia. Lancet 387(10021):907–916. https://doi.org/10.1016/S0140-6736(15)60865-0

    CAS  Article  PubMed  Google Scholar 

  2. Percy L, Mansour D, Fraser I (2017) Iron deficiency and iron deficiency anaemia in women. Best Pract Res Clin Obstet Gynaecol 40:55–67. https://doi.org/10.1016/j.bpobgyn.2016.09.007

    Article  PubMed  Google Scholar 

  3. Paganini D, Zimmermann MB (2017) The effects of iron fortification and supplementation on the gut microbiome and diarrhea in infants and children: a review. Am J Clin Nutr 106(Suppl 6):1688S-1693S. https://doi.org/10.3945/ajcn.117.156067

    Article  PubMed  PubMed Central  Google Scholar 

  4. DeLoughery TG (2017) Iron deficiency anaemia. Med Clin North Am 101(2):319–332. https://doi.org/10.1016/j.mcna.2016.09.004

    Article  PubMed  Google Scholar 

  5. Karlsson T (2017) Evaluation of a competitive hepcidin ELISA assay in the differential diagnosis of iron deficiency anaemia with concurrent inflammation and anaemia of inflammation in elderly patients. J Inflamm 14(1):21. https://doi.org/10.1186/s12950-017-0166-3

    CAS  Article  Google Scholar 

  6. Fang S, Zhuo Z, Yu X, Wang H, Feng J (2018) Oral administration of liquid iron preparation containing excess iron induces intestine and liver injury, impairs intestinal barrier function and alters the gut microbiota in rats. J Trace Elem Med Biol 47:12–20. https://doi.org/10.1016/j.jtemb.2018.01.002

    CAS  Article  PubMed  Google Scholar 

  7. D’Argenio V, 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

    CAS  Article  PubMed  Google Scholar 

  8. Adak A, Khan MR (2019) An insight into gut microbiota and its functionalities. Cell Mol Life Sci 76(3):473–493. https://doi.org/10.1007/s00018-018-2943-4

    CAS  Article  PubMed  Google Scholar 

  9. Das NK, Schwartz AJ, Barthel G, Inohara N, Liu Q, Sankar A, Hill DR, Ma X, Lamberg O, Schnizlein MK, Arqués JL, Spence JR, Nunez G, Patterson AD, Sun D, Young VB, Shah YM (2020) Microbial metabolite signaling is required for systemic iron homeostasis. Cell Metab 31(1):115-130.e116. https://doi.org/10.1016/j.cmet.2019.10.005

    CAS  Article  PubMed  Google Scholar 

  10. Dostal A, Chassard C, Hilty FM, Zimmermann MB, Jaeggi T, Rossi S, Lacroix C (2012) Iron depletion and repletion with ferrous sulfate or electrolytic iron modifies the composition and metabolic activity of the gut microbiota in rats. J Nutr 142(2):271–277. https://doi.org/10.3945/jn.111.148643

    CAS  Article  PubMed  Google Scholar 

  11. McClorry S, Zavaleta N, Llanos A, Casapía M, Lönnerdal B, Slupsky CM (2018) Anemia in infancy is associated with alterations in systemic metabolism and microbial structure and function in a sex-specific manner: an observational study. Am J Clin Nutr 108(6):1238–1248. https://doi.org/10.1093/ajcn/nqy249

    Article  PubMed  PubMed Central  Google Scholar 

  12. Pallarés I, Lisbona F, Aliaga IL, Barrionuevo M, Alférez MJM, Campos MS (1993) Effect of iron deficiency on the digestive utilization of iron, phosphorus, calcium and magnesium in rats. Br J Nutr 70(2):609–620. https://doi.org/10.1079/bjn19930152

    Article  PubMed  Google Scholar 

  13. Reeves PG, Nielsen FH, Fahey GC Jr (1993) AIN-93 purified diets for laboratory rodents: final report of the american institute of nutrition Ad Hoc writing committee on the reformulation of the AIN-76A rodent diet. J Nutr 123(11):1939–1951. https://doi.org/10.1093/jn/123.11.1939

    CAS  Article  PubMed  Google Scholar 

  14. Soriano-Lerma A, Pérez-Carrasco V, Sánchez-Marañón M, Ortiz-González M, Sánchez-Martín V, Gijón J, Navarro-Mari JM, García-Salcedo JA, Soriano M (2020) Influence of 16S rRNA target region on the outcome of microbiome studies in soil and saliva samples. Sci Rep 10(1):13637. https://doi.org/10.1038/s41598-020-70141-8

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  15. Soriano-Lerma A, Magán-Fernández A, Gijón J, Sánchez-Fernández E, Soriano M, García-Salcedo JA, Mesa F (2020) Short-term effects of hyaluronic acid on the subgingival microbiome in peri-implantitis: a randomized controlled clinical trial. J Periodontol 91(6):734–745. https://doi.org/10.1002/JPER.19-0184

    CAS  Article  PubMed  Google Scholar 

  16. Douglas GM, Beiko RG, Langille MGI (2018) Predicting the functional potential of the microbiome from marker genes using PICRUSt. In: Beiko RG, Hsiao W, Parkinson J (eds) Microbiome analysis methods and protocols. Springer, pp 169–177

    Chapter  Google Scholar 

  17. Díaz-Faes L, Soriano-Lerma A, Magan-Fernandez A, López M, Gijon J, García-Salcedo JA, Soriano M, Mesa F (2021) Structural and functional microbial patterns in cohabitating family members with history of periodontitis. Oral Dis 00:1–5. https://doi.org/10.1111/odi.13786

    Article  Google Scholar 

  18. Hammer Ø, Harper DAT, Ryan PD (2001) Past: paleontological statistics software package for education and data analysis. Palaeontol Electron 4(1):9

    Google Scholar 

  19. Kumar S, Stecher G, Tamura K (2016) MEGA7: molecular evolutionary genetics analysis version 7.0 for bigger datasets. Mol Biol Evol 33(7):1870–1874. https://doi.org/10.1093/molbev/msw054

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  20. Segata N, Izard J, Waldron L, Gevers D, Miropolsky L, Garrett WS, Huttenhower C (2011) Metagenomic biomarker discovery and explanation. Genome Biol 12(6):R60–R60. https://doi.org/10.1186/gb-2011-12-6-r60

    Article  PubMed  PubMed Central  Google Scholar 

  21. Forrellat-Barrios M, Fernández-Delgado N, Hernández-Ramírez P (2012) Regulación de la hepcidina y homeostasia del hierro: avances y perspectivas. Rev Cubana Hematol Inmunol y Hemo 28(4):347–356

    Google Scholar 

  22. Blacher E, Levy M, Tatirovsky E, Elinav E (2017) Microbiome-modulated metabolites at the interface of host immunity. J Immunol 198(2):572. https://doi.org/10.4049/jimmunol.1601247

    CAS  Article  PubMed  Google Scholar 

  23. Mu Q, Kirby J, Reilly CM, Luo XM (2017) Leaky gut as a danger signal for autoimmune diseases. Front Immunol 8:598–598. https://doi.org/10.3389/fimmu.2017.00598

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  24. Dongyao L, Haiqin C, Bingyong M, Qin Y, Jianxin Z, Zhennan G, Hao Z, Yong QC, Wei C (2017) Microbial biogeography and core microbiota of the rat digestive tract. Sci Rep 7(1):45840. https://doi.org/10.1038/srep45840

    CAS  Article  Google Scholar 

  25. Rivera-Chávez F, Zhang Lillian F, Faber F, Lopez Christopher A, Byndloss Mariana X, Olsan Erin E, Xu G, Velazquez Eric M, Lebrilla Carlito B, Winter Sebastian E, Bäumler Andreas J (2016) Depletion of butyrate-producing clostridia from the gut microbiota drives an aerobic luminal expansion of salmonella. Cell Host Microbe 19(4):443–454. https://doi.org/10.1016/j.chom.2016.03.004

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  26. Perez-Carrasco V, Soriano-Lerma A, Soriano M, Gutiérrez-Fernández J, Garcia-Salcedo JA (2021) Urinary microbiome: yin and yang of the urinary tract. Front Cell Infect Microbiol 11:617002–617002. https://doi.org/10.3389/fcimb.2021.617002

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  27. Tamanai-Shacoori Z, Smida I, Bousarghin L, Loreal O, Meuric V, Fong SB, Bonnaure-Mallet M, Jolivet-Gougeon A (2017) Roseburia spp.: a marker of health? Future Microbiol 12(2):157–170. https://doi.org/10.2217/fmb-2016-0130

    CAS  Article  PubMed  Google Scholar 

  28. Yang JY, Lee YS, Kim Y, Lee SH, Ryu S, Fukuda S, Hase K, Yang CS, Lim HS, Kim MS, Kim HM, Ahn SH, Kwon BE, Ko HJ, Kweon MN (2017) Gut commensal Bacteroides acidifaciens prevents obesity and improves insulin sensitivity in mice. Mucosal Immunol 10(1):104–116. https://doi.org/10.1038/mi.2016.42

    CAS  Article  PubMed  Google Scholar 

  29. Kotrba P, Inui M, Yukawa H (2001) Bacterial phosphotransferase system (PTS) in carbohydrate uptake and control of carbon metabolism. J Biosci Bioeng 92(6):502–517. https://doi.org/10.1016/S1389-1723(01)80308-X

    CAS  Article  PubMed  Google Scholar 

  30. Koh A, De Vadder F, Kovatcheva-Datchary P, Bäckhed F (2016) From dietary fiber to host physiology: short-chain fatty acids as key bacterial metabolites. Cell 165(6):1332–1345. https://doi.org/10.1016/j.cell.2016.05.041

    CAS  Article  PubMed  Google Scholar 

  31. Teufel R, Kung JW, Kockelkorn D, Alber BE, Fuchs G (2009) 3-hydroxypropionyl-coenzyme A dehydratase and acryloyl-coenzyme A reductase, enzymes of the autotrophic 3-hydroxypropionate/4-hydroxybutyrate cycle in the Sulfolobales. J Bacteriol 191(14):4572–4581. https://doi.org/10.1128/jb.00068-09

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  32. Seravalli J, Kumar M, Ragsdale SW (2002) Rapid kinetic studies of Acetyl-CoA synthesis: evidence supporting the catalytic intermediacy of a paramagnetic NiFeC species in the autotrophic wood−ljungdahl pathway. Biochemistry 41(6):1807–1819. https://doi.org/10.1021/bi011687i

    CAS  Article  PubMed  Google Scholar 

  33. Saad MJA, Santos A, Prada PO (2016) Linking gut microbiota and inflammation to obesity and insulin resistance. Physiology 31(4):283–293. https://doi.org/10.1152/physiol.00041.2015

    CAS  Article  PubMed  Google Scholar 

  34. O’Keefe SJD (2016) Diet, microorganisms and their metabolites, and colon cancer. Nat Rev Gastroenterol Hepatol 13(12):691–706. https://doi.org/10.1038/nrgastro.2016.165

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  35. Parada Venegas D, De la Fuente MK, Landskron G, González MJ, Quera R, Dijkstra G, Harmsen HJM, Faber KN, Hermoso MA (2019) Short chain fatty acids (SCFAs)-mediated gut epithelial and immune regulation and its relevance for inflammatory bowel diseases. Front Immunol 10 (277). https://doi.org/10.3389/fimmu.2019.00277

    Article  PubMed  PubMed Central  Google Scholar 

  36. Santos-Marcos JA, Perez-Jimenez F, Camargo A (2019) The role of diet and intestinal microbiota in the development of metabolic syndrome. J Nutr Biochem 70:1–27. https://doi.org/10.1016/j.jnutbio.2019.03.017

    CAS  Article  PubMed  Google Scholar 

  37. Bach Knudsen KE, Lærke HN, Hedemann MS, Nielsen TS, Ingerslev AK, Gundelund Nielsen DS, Theil PK, Purup S, Hald S, Schioldan AG, Marco ML, Gregersen S, Hermansen K (2018) Impact of diet-modulated butyrate production on intestinal barrier function and inflammation. Nutrients 10(10):1499. https://doi.org/10.3390/nu10101499

    CAS  Article  PubMed Central  Google Scholar 

  38. Morrison DJ, Preston T (2016) Formation of short chain fatty acids by the gut microbiota and their impact on human metabolism. Gut Microbes 7(3):189–200. https://doi.org/10.1080/19490976.2015.1134082

    Article  PubMed  PubMed Central  Google Scholar 

  39. Soliman AT, De Sanctis V, Yassin M, Soliman N (2017) Iron deficiency anemia and glucose metabolism. Acta Biomed 88(1):112–118. https://doi.org/10.23750/abm.v88i1.6049

    CAS  Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

A.S.L is grateful for the help provided by the PhD programme “Nutrition and Food technology” from the University of Granada. The authors thank Dr Ana Lerma Herrera for her contribution in the development of the animal model. The results presented in this article are part of A.S.L’s doctoral thesis.

Funding

This work was financially supported by the local government Junta de Andalucía through research projects (Ref: P11-AGR-7648) and PAIDI research groups (BIO344 and AGR206), and the Ministry of Economy and Competitiveness of Spain co-financed with European Regional Development Funds (Ref: CGL2015-71709-R, PEJ2018-004702-A). This project was supported by Carlos III Health Institute (AC18-00008), under the frame of EuroNanoMed III. A.S.L., M.G.B and V.S.M. were supported by a fellowship from the Ministry of Education, Culture and Sport (FPU 17/05413, FPU 16/05954 and FPU 16/05822). M.O.G acknowledges for the funds received by the F.P.U. fellowship provided by University of Almería.

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Authors and Affiliations

Authors

Contributions

MS, JAGS and ILA developed the original idea, contributed to the design of the study and critically revised the manuscript. A.S.L, M.J.M.A and M.G.B participated in the in vivo model of iron deficiency. VPC, VSM, ALR and MOG did the laboratory analysis and produced the experimental data. A.S.L performed the bioinformatic and statistical analysis and wrote the original draft. MS, JAGS and ILA equally contributed and jointly supervised this work.

Corresponding authors

Correspondence to Miguel Soriano or José Antonio García-Salcedo.

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Conflict of interest

The authors declare that they have no conflict of interest.

Ethics approval

Experimental procedures described in this study have been performed in accordance with European guidelines (Declaration of Helsinki; Directive 2010/63/EU) and approved by the Ethics Committee of the University of Granada and the local government Junta de Andalucía (ref 06/06/2019/100).

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Cite this article

Soriano-Lerma, A., García-Burgos, M., Alférez, M.J. et al. Gut microbiome–short-chain fatty acids interplay in the context of iron deficiency anaemia. Eur J Nutr 61, 399–412 (2022). https://doi.org/10.1007/s00394-021-02645-6

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  • DOI: https://doi.org/10.1007/s00394-021-02645-6

Keywords

  • Iron deficiency anaemia
  • Gut microbiome
  • Short-chain fatty acids
  • Intestinal microbial community
  • Microbial metabolites