Microbiota-derived lactate promotes hematopoiesis and erythropoiesis by inducing stem cell factor production from leptin receptor+ niche cells

Yong-Soo Lee,Seungil Kim,Yeji Kim,Bo O Zhou,O Eunju,Su-Hyun Lee,Mi-Na Kweon,Kwang Soon Kim,Tae-Young Kim,Sang-Uk Seo

doi:10.1038/s12276-021-00667-y

Abstract

Although functional interplay between intestinal microbiota and distant sites beyond the gut has been identified, the influence of microbiota-derived metabolites on hematopoietic stem cells (HSCs) remains unclear. This study investigated the role of microbiota-derived lactate in hematopoiesis using mice deficient in G-protein-coupled receptor (Gpr) 81 (Gpr81−/−), an established lactate receptor. We detected significant depletion of total HSCs in the bone marrow (BM) of Gpr81−/− mice compared with heterogenic (Gpr81+/−) mice in a steady state. Notably, the expression levels of stem cell factor (SCF), which is required for the proliferation of HSCs, decreased significantly in leptin receptor-expressing (LepR+) mesenchymal stromal cells (MSCs) around the sinusoidal vessels of the BM from Gpr81−/− mice compared with Gpr81+/− mice. Hematopoietic recovery and activation of BM niche cells after irradiation or busulfan treatment also required Gpr81 signals. Oral administration of lactic acid-producing bacteria (LAB) activated SCF secretion from LepR+ BM MSCs and subsequently accelerated hematopoiesis and erythropoiesis. Most importantly, LAB feeding accelerated the self-renewal of HSCs in germ-free mice. These results suggest that microbiota-derived lactate stimulates SCF secretion by LepR+ BM MSCs and subsequently activates hematopoiesis and erythropoiesis in a Gpr81-dependent manner.

Highlights

The mammalian intestine is a hub for commensal microbiota, which are important modulators of host physiology, metabolism, and immunity[1,2,3]
Feeding accelerated the self-renewal of hematopoietic stem cells (HSCs) in germ-free mice. These results suggest that microbiota-derived lactate stimulates stem cell factor (SCF) secretion by leptin receptor (LepR)+ bone marrow (BM) mesenchymal stromal cells (MSCs) and subsequently activates hematopoiesis and erythropoiesis in a Gpr81-dependent manner
We used Gpr81+/− mice as controls because there were no differences in BM cellularity or HSC subsets compared with wild-type (WT) mice (Supplementary Fig. 1a, b)

Summary

Introduction

The mammalian intestine is a hub for commensal microbiota, which are important modulators of host physiology, metabolism, and immunity[1,2,3]. Recent studies have highlighted the functional interplay between intestinal microbiota and the host immune system beyond the gut, wherein intestinal microbiota-derived metabolites can likely impact disease pathophysiology at distant sites, including the lungs, liver, pancreas, skin, and bone marrow (BM)[4,5,6,7,8]. A suggested mechanism for this functional interplay is that microbiota-derived metabolites found in circulating blood indirectly affect target organs by modulating hematopoiesis at the BM. Exacerbation of inflammation in various disease models, such as colitis, arthritis, and asthma in Gpr43−/− mice, suggests that SCFA-

Methods

Results

Conclusion