Broad-Spectrum Antibiotics Deplete Bone Marrow Regulatory T Cells

Abstract

Bone marrow suppression, including neutropenia, is a major adverse effect of prolonged antibiotic use that impairs the clinical care and outcomes of patients with serious infections. The mechanisms underlying antibiotic-mediated bone marrow suppression remain poorly understood, with initial evidence indicating that depletion of the intestinal microbiota is an important factor. Based on our earlier studies of blood and bone marrow changes in a mouse model of prolonged antibiotic administration, we studied whether changes in megakaryocytes or regulatory T cells (Tregs), two cell types that are critical in the maintenance of hematopoietic stem cells, contribute to antibiotic-mediated bone marrow suppression. Despite increased platelet numbers, megakaryocytes were unchanged in the bone marrow of antibiotic-treated mice; however, Tregs were found to be significantly depleted. Exogenous addition of Tregs was insufficient to rescue the function of bone marrow from antibiotic-treated mice in both colony formation and transplantation assays. These findings indicate that the intestinal microbiota support normal Treg development to protect healthy hematopoiesis, but that the restoration of Tregs alone is insufficient to restore normal bone marrow function.

The bacterial microbiota regulates normal hematopoiesis via metabolite-induced type 1 interferon signaling

“…However, recent research by our group and others has both demonstrated a lack of direct antibiotic-mediated cytotoxicity for hematopoietic progenitor populations 16,17 and identified indirect mechanisms of antibiotic-mediated bone marrow suppression. 18 Specifically, antibiotics have been shown to disrupt healthy steady-state hematopoiesis by suppressing microbial populations in the intestine. 5,10,[19][20][21] The complex community of gut microbes exerts a plethora of local and systemic effects on host immunity, including regulating the development and maturation of immune cells.…”

“…However, research by our group and others has both shown both a lack of direct antibiotic-mediated cytotoxicity for hematopoietic progenitor populations 16,17 and identified indirect mechanisms of antibiotic-mediated bone marrow suppression. 18 Specifically, antibiotics have been shown to disrupt healthy steady-state hematopoiesis by suppressing microbial populations in the intestine. 5,10 , 19-21 …”

Correlations Between Intestinal Microbial Community and Hematological Profile in Native Tibetans and Han Immigrants

“…Hematopoietic changes are associated with a significant contraction of the fecal microbiome and are partially rescued by the transfer of fecal microbiota. Platelet counts (PLTs) are consistently and significantly increased in antibiotic-treated mice compared with those in control mice ( Josefsdottir et al, 2017 ; Staffas et al, 2018 ; Han et al, 2021 ). Metabolites from the intestinal microbiota, such as short-chain fatty acids (SCFAs), contribute to the production of hematopoietic precursors in specific-pathogen-free (SPF) mice ( Trompette et al, 2014 ).…”

Antimicrobial‐induced oral dysbiosis exacerbates naturally occurring alveolar bone loss

“…Interestingly, we found that minocycline decreased the frequency of both T H 17 and T REG cells in femoral long bone marrow. Prior work has demonstrated that antibiotic perturbation of the gut microbiota impairs hematopoiesis and depletes T REG cells in long bone marrow 75,76 . Furthermore, antibiotics have recently been shown to have immunosuppressive actions on T H 17 cells, which occur independent of their antimicrobial activity 77 .…”

“…Prior work has demonstrated that antibiotic perturbation of the gut microbiota impairs hematopoiesis and depletes T REG cells in long bone marrow. 75,76 Furthermore, antibiotics have recently been shown to have immunosuppressive actions on T H 17 cells, which occur independent of their antimicrobial activity. 77 The balance of pro-osteoclastic T H 17 cells/anti-osteoclastic T REG cells has been purported to regulate osteoclastogenesis.…”