Butyrate Prevents the Pathogenic Anemia-Inflammation Circuit by Facilitating Macrophage Iron Export
- PMID: 38235606
- PMCID: PMC10966513
- DOI: 10.1002/advs.202306571
Butyrate Prevents the Pathogenic Anemia-Inflammation Circuit by Facilitating Macrophage Iron Export
Abstract
Most patients with inflammatory bowel disease (IBD) develop anemia, which is attributed to the dysregulation of iron metabolism. Reciprocally, impaired iron homeostasis also aggravates inflammation. How this iron-mediated, pathogenic anemia-inflammation crosstalk is regulated in the gut remains elusive. Herein, it is for the first time revealed that anemic IBD patients exhibit impaired production of short-chain fatty acids (SCFAs), particularly butyrate. Butyrate supplementation restores iron metabolism in multiple anemia models. Mechanistically, butyrate upregulates ferroportin (FPN) expression in macrophages by reducing the enrichment of histone deacetylase (HDAC) at the Slc40a1 promoter, thereby facilitating iron export. By preventing iron sequestration, butyrate not only mitigates colitis-induced anemia but also reduces TNF-α production in macrophages. Consistently, macrophage-conditional FPN knockout mice exhibit more severe anemia and inflammation. Finally, it is revealed that macrophage iron overload impairs the therapeutic effectiveness of anti-TNF-α antibodies in colitis, which can be reversed by butyrate supplementation. Hence, this study uncovers the pivotal role of butyrate in preventing the pathogenic circuit between anemia and inflammation.
Keywords: anemia; butyrate; ferroportin; inflammatory bowel disease; macrophages.
© 2024 The Authors. Advanced Science published by Wiley‐VCH GmbH.
Conflict of interest statement
The authors declare no conflict of interest.
Figures








Similar articles
-
Microbiota metabolite butyrate constrains neutrophil functions and ameliorates mucosal inflammation in inflammatory bowel disease.Gut Microbes. 2021 Jan-Dec;13(1):1968257. doi: 10.1080/19490976.2021.1968257. Gut Microbes. 2021. PMID: 34494943 Free PMC article.
-
Gut microbiota-derived butyrate improved acute leptospirosis in hamster via promoting macrophage ROS mediated by HDAC3 inhibition.mBio. 2024 Oct 16;15(10):e0190624. doi: 10.1128/mbio.01906-24. Epub 2024 Sep 17. mBio. 2024. PMID: 39287437 Free PMC article.
-
Sodium butyrate inhibits the NF-kappa B signaling pathway and histone deacetylation, and attenuates experimental colitis in an IL-10 independent manner.Int Immunopharmacol. 2017 Oct;51:47-56. doi: 10.1016/j.intimp.2017.07.023. Epub 2017 Aug 10. Int Immunopharmacol. 2017. PMID: 28802151
-
Gut Microbial Metabolite Butyrate and Its Therapeutic Role in Inflammatory Bowel Disease: A Literature Review.Nutrients. 2023 May 11;15(10):2275. doi: 10.3390/nu15102275. Nutrients. 2023. PMID: 37242159 Free PMC article. Review.
-
Iron Absorption in Celiac Disease and Nutraceutical Effect of 7-Hydroxymatairesinol. Mini-Review.Molecules. 2020 Apr 27;25(9):2041. doi: 10.3390/molecules25092041. Molecules. 2020. PMID: 32349426 Free PMC article. Review.
Cited by
-
Role of gut microbiota in thalassemia: a review of therapeutic prospects.Front Physiol. 2025 Mar 19;16:1523448. doi: 10.3389/fphys.2025.1523448. eCollection 2025. Front Physiol. 2025. PMID: 40177354 Free PMC article. Review.
-
Post-stroke butyrate treatment shows sex-dependent microglial responses but does not improve outcomes in a mouse model of endothelin-1 sensory motor stroke.BMC Neurosci. 2025 Jul 17;26(1):43. doi: 10.1186/s12868-025-00959-3. BMC Neurosci. 2025. PMID: 40676515 Free PMC article.
-
Increased Cadmium Load, Vitamin D Deficiency, and Elevated FGF23 Levels as Pathophysiological Factors Potentially Linked to the Onset of Acute Lymphoblastic Leukemia: A Review.J Pers Med. 2024 Sep 28;14(10):1036. doi: 10.3390/jpm14101036. J Pers Med. 2024. PMID: 39452542 Free PMC article. Review.
-
Dietary supplementation of vitamin B1 prevents the pathogenesis of osteoarthritis.Proc Natl Acad Sci U S A. 2024 Jul 23;121(30):e2408160121. doi: 10.1073/pnas.2408160121. Epub 2024 Jul 18. Proc Natl Acad Sci U S A. 2024. PMID: 39024114 Free PMC article.
-
Histone deacetylase in inflammatory bowel disease: novel insights.Therap Adv Gastroenterol. 2025 Feb 16;18:17562848251318833. doi: 10.1177/17562848251318833. eCollection 2025. Therap Adv Gastroenterol. 2025. PMID: 39963253 Free PMC article. Review.
References
-
- a) Winn N. C., Volk K. M., Hasty A. H., JCI Insight 2020, 5, e132964; - PMC - PubMed
- b) Sukhbaatar N., Weichhart T., Pharmaceuticals 2018, 11, 137; - PMC - PubMed
- c) Zhang Z., Zhang F., An P., Guo X., Shen Y., Tao Y., Wu Q., Zhang Y., Yu Y., Ning B., Nie G., Knutson M. D., Anderson G. J., Wang F., Blood 2011, 118, 1912; - PubMed
- d) Canny S. P., Orozco S. L., Thulin N. K., Hamerman J. A., Annu. Rev. Immunol. 2023, 41, 405,. - PMC - PubMed
-
- a) Li J.‐Y., Yu M., Pal S., Tyagi A. M., Dar H., Adams J., Weitzmann M. N., Jones R. M., Pacifici R., J. Clin. Invest. 2020, 130, 1767; - PMC - PubMed
- b) Tyagi A. M., Yu M., Darby T. M., Vaccaro C., Li J.‐Y., Owens J. A., Hsu E., Adams J., Weitzmann M. N., Jones R. M., Pacifici R., Immunity 2018, 49, 1116; - PMC - PubMed
- c) Uribe‐Herranz M., Rafail S., Beghi S., Gil‐De‐Gómez L., Verginadis I., Bittinger K., Pustylnikov S., Pierini S., Perales‐Linares R., Blair I. A., Mesaros C. A., Snyder N. W., Bushman F., Koumenis C., Facciabene A., J. Clin. Invest. 2020, 130, 466. - PMC - PubMed
MeSH terms
Substances
Grants and funding
- 2021KY749 2023KY804/Medical Science and Technology Project of Zhejiang Province
- LQ21H030013/Natural Science Foundation of Zhejiang Province
- 82171730/National Natural Science Foundation of China
- 81970484/National Natural Science Foundation of China
- 82100540/National Natural Science Foundation of China
LinkOut - more resources
Full Text Sources
Medical