A Song of Marrow and Microbes

Stem cells! Iron! Macrophages! Red blood cells! Butyrate! Gut microbiota! 
No, we are not just blurting out random terms (stick with us till the end to read the full story). These keywords summarize a study by Zhang and colleagues that was published in Cell Stem Cell earlier this month. However, summarizing the work in a single sentence would take out the fun from this fascinating study, and also leave you scratching your head. So instead, I present to you, the song of Marrow & Microbes!

Hematopoietic Stem Cells (HSCs) are the stem cells that give rise to everything that falls under the purview of “Blood cells”. They sit at the top of the pyramid and differentiate into common myeloid progenitors (producing Red Blood cells, platelets, mast cells, and granulocytes) and lymphoid progenitors (producing B, T cells & Natural Killer cells). HSCs station in the bone marrow throughout our life, and they make sure that the populations of blood cells are maintained in a certain quantity during normal or inflammatory conditions. Given that HSCs are the main reserve of blood cells, they remain non-dividing when everything is fine i.e., at homeostasis. But during infections or bone marrow injury, HSCs re-enter the cell cycle to proliferate, and simultaneously, also differentiate into progenitors to keep up with the demand and restore cell numbers to normal.

In this peaceful job of stem cells of the bone marrow, what role do their distant stakeholders- the gut microbiome- play?
Seems unlikely, but the microbes have invested major stocks in the HSCs’ job. When Zhang and colleagues depleted the gut microbiome of mice by treatment with antibiotics, they observed that under stress conditions, instead of differentiating and repopulating the immune cell repertoire, the HSCs just kept multiplying to produce more HSCs.

In recent years, researchers described extensively how microbes that live in our gut produce short-chain fatty acids (SCFAs) by anaerobic fermentation of dietary fibers. These SCFAs are absorbed by the intestine and through blood, travel to different parts of the body (including the brain) and influence the functioning of the host cells. One of the SCFAs, butyrate, strongly influences the epigenetics of the phagocyting immune cells- macrophages. Macrophages are very exciting because they are present pretty much everywhere in the body – including the bone marrow – where they carry out functions highly specific to their microenvironment.

Macrophages in the bone marrow, spleen, and liver eat up old (and dying) red blood cells (RBCs), a process aptly called erythrophagocytosis. RBCs are rich in one of the most important metal ions – Iron – and through erythrophagocytosis, macrophages scavenge off and recycle the iron. This recycled iron is distributed locally through proteins like ferritin and ferroprotein and made available for use to other local cells, such as HSCs. Zhang et al showed that taking up butyrate from blood enhances the expression of RBC-recycling genes in these macrophages.

Putting all this together: Under stress, bone marrow macrophages increase the rate of RBC recycling to increase iron levels locally, and hence foster differentiation of the HSCs for immune population regeneration. HSCs take their iron supply exclusively from macrophages because when macrophages were deleted, the HSC differentiation was impaired despite iron levels being normal in the blood. Most importantly, butyrate is necessary for the macrophages to efficiently carry out this scavenging-recycling process.

In one sentence that should now make sense:
To regenerate immune cell populations, Hematopoietic Stem cells require Iron from bone marrow Macrophages which is produced by scavenging of Red Blood Cells in presence of gut-microbiota-derived-butyrate.

This paper sheds light on another important role of the microbiome and its SCFAs on the immune system and reveals a physiological process that begs for further exploration in different disease settings like cancer. Another key finding of this paper was that HSCs can be expanded in vitro by supplying them with iron-deficient media. This finding could have massive implications on how HSCs are expanded for bone marrow transplantations in the future. Lastly, it raises awareness on how iron deficiencies, anemia, and microbiota disturbance can affect patients recovering from chemotherapy or bone marrow transplantations.

How iron affects HSCs’ cell fate decisions remain unknown for now. The bone marrow has many more cell types except for HSCs and macrophages, and how iron distribution takes place amongst them all would need further investigation too. But for now, we can marvel at how complex and deep (till our marrow) our relationship with our gut microorganisms is! 


Zhang D, Gao X, Li H, Borger DK, Wei Q, Yang E, Xu C, Pinho S, Frenette PS. The microbiota regulates hematopoietic stem cell fate decisions by controlling iron availability in bone marrow. Cell Stem Cell. 2022 Feb 3;29(2):232-247.e7. doi: 10.1016/j.stem.2021.12.009

Article author: Kevin Merchant. Kevin is a MS student at LMU Munich, Germany, who is passionate about Immunology and writing. He aims to simplify latest research so that it becomes accessible to all.

Editor: Sutonuka Bhar. Sutonuka is a PhD candidate at the University of Florida. Her work focuses on host immune responses against viruses and bacterial membrane vesicles.

Check out Antibuddies’ blog post “A Song of Marrow and Microbes”.

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