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. Author manuscript; available in PMC: 2020 Sep 23.
Published in final edited form as: Bone Marrow Transplant. 2019 Aug;54(Suppl 2):756–758. doi: 10.1038/s41409-019-0612-3

The intestinal flora is required for post-transplant hematopoiesis in recipients of a hematopoietic stem cell transplantation

Anna Staffas 1, Marcel van den Brink 2
PMCID: PMC7510168  NIHMSID: NIHMS1628376  PMID: 31431719

Abstract

Recent studies in both mice and humans have demonstrated that the intestinal microbiota can affect hematopoiesis. Here, we performed experiments in preclinical mouse models for syngeneic and allogeneic HCT. To study the metabolic effects of intestinal flora depletion on post-transplant hematopoiesis in humans, we performed HCT experiments using a metabolic chamber and bomb calorimetry of feces. Taken together, we show that the intestinal microbiota supports post-transplant hematopoietic reconstitution in HCT recipients through its role in dietary energy uptake.

Introduction

Because of its many (patho)physiological effects, the intestinal microbiota has been described as the “forgotten organ”. Recent studies have demonstrated that the intestinal microbiota can affect hematopoiesis [1–4]. Germ-free mice have fewer hematopoietic precursor cells (HPCs) [2], and intestinal microbiota can promote myelopoiesis and lymphopoiesis resulting in reduced susceptibility to infection in mice [1, 2, 5–8]. Treatment with oral antibiotics and subsequent depletion of the intestinal flora can result in suppression of hematopoiesis [2, 7, 9, 10], which was not due to a direct effect of the antibiotics on the HPCs [3]. Moreover, intestinal dysbiosis (defined as decreased bacterial diversity and commensal bacteria and increased pathobionts) has been associated both in mouse and human with decreased hematopoiesis [11].

In humans, microbiota-associated impaired hematopoiesis is often due to antibiotics. For example, in a retrospective analysis, the use of beta-lactam antibiotic treatment for >10 days was associated in 5–15% of patients with neutropenia, which recovered in 94% of patients after stopping of the antibiotic [12]. Importantly, decreased hematopoiesis is not restricted to any specific antibiotic and seems more related to the duration of treatment [11].

Several studies in mice have suggested that the mechanisms by which the intestinal flora supports hematopoiesis can involve stimulation of stromal cells, such as NOD1-dependent activation of mesenchymal stromal cells, to produce hematopoietic growth factors [1–4]. The signaling pathways that are implicated in this process include MyD88/TICAM1, NOD1, and STAT1 [11].

Results and discussion

We hypothesized that the intestinal flora can support hematopoietic engraftment and reconstitution after hematopoietic cell transplantation (HCT). We performed experiments in preclinical mouse models for syngeneic and allogeneic HCT [13]. Mice were treated with two different broad-spectrum antibiotic regimens from day −5 until day +28: Ampicillin/Enrofloxacin (absorbed) and Vancomycin/Amikacin (not absorbed). In both cases, “depletion of the intestinal microbiota resulted in impaired recovery of lymphocyte and neutrophil counts while recovery of the hematopoietic stem- and progenitor compartments and erythroid lineage were largely unaffected” [13]. In addition, similar experiments in recipients with an antibiotic-resistant flora did not result in an effect of antibiotics on post-transplant hematopoiesis.

We noted that HCT recipients with a depleted flora had reduced abdominal fat apart from delayed post-transplant hematopoiesis. Previous studies have shown that gut decontamination with antibiotics can result in reduced body fat [14], and that colonic bacteria are required for 10% of energy uptake from food by mediating the breakdown of dietary starch to short-chain fatty acids (SCFAs) and monosaccharides [15]. Importantly, SCFAs can contribute to the production of HPCs [16].

To study the metabolic effects of intestinal flora depletion on post-transplant hematopoiesis, we performed HCT experiments using a metabolic chamber and bomb calorimetry of feces. We found that HCT recipients without intestinal flora vs HCT recipients with intestinal flora had equal food/water intake and activity, but increased fatty acid metabolism (as measured by the VCO2/VO2 respiratory exchange ratio) and decreased energy expenditure from the diet (as measured by bomb calorimetry of feces) resulting in significantly higher excretion of dietary calories and 10% less energy absorption from their diet.

Based on these results, we performed experiments with caloric supplementation through sucrose (in the drinking water) and were able to correct the hematopoietic deficiency in HCT recipients treated with antibiotics.

Taken together, we show that the intestinal microbiota supports post-transplant hematopoietic reconstitution in HCT recipients through its role in dietary energy uptake (summarized in Fig. 1). Oral nutritional supplementation with sucrose can rescue abdominal fat loss and impaired post-transplant hematopoiesis in HCT recipients treated with antibiotics.

Fig. 1.

Fig. 1

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The role of intestinal flora in post-transplant hematopoiesis

Acknowledgments

Funding Publication of this supplement was sponsored by Gilead Sciences Europe Ltd, Cell Source, Inc., The Chorafas Institute for Scientific Exchange of the Weizmann Institute of Science, Kiadis Pharma, Miltenyi Biotec, Celgene, Centro Servizi Congressuali, Almog Diagnostic.

Conflict of interest MvdB received consulting fees from Seres Therapeutics, TTT Study Section, owns equity in Epiva & Evelo Theaputics, and received grant support from Seres Therapeutics, NIH, Susan and Peter Solomon Fund, and Parker Institute for Cancer Immunology. AS received grants from the Swedish research council (VR), the Swedish society for medical research (SSMF) and Assar Gabrielsson Foundation (AG Fond). There are no conflicts of interest to disclose.

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