Author: Zhou Qinghe
This article is published by the author with the authorization of Medical Pulse, please do not reprint it without authorization.
Regarding what diseases can be caused by imbalances in the intestinal flora, the first thing you may think of is digestive system diseases, and with the continuous in-depth study of medicine, the function of the gut microbiome has completely subverted our cognition. The huge bacterial population exists in our intestines, silently controlling our metabolism and immune system, and now the gut microbiome has become a research hotspot in the field of cancer around the world, and in recent years, the relationship between the intestinal microbiota and malignant blood system diseases has slowly attracted people's attention.
Under physiological conditions, the gut microbiome is a highly diverse group of non-pathogenic symbiotic bacteria, mainly composed of Pachychobacterium, Bacteroides, Actinomycetes and Proteus. The gut microbiome resembles a signaling hub that integrates environmental inputs such as diet with genetic and immune signaling, which affects responses such as host metabolism and immunity. In general, the intestinal flora maintains a certain homeostasis, thereby maintaining the integrity and function of the intestinal mucosal barrier, when the intestinal flora is disturbed, it will affect the permeability of the intestinal mucosa, break the balance, thereby affecting the metabolism and immunity of the host, affecting the occurrence and development of tumors, metabolic and other diseases.
Recent research has found that gut microbes may lead to the occurrence and development of blood tumors by inducing genetic mutations, disrupting the balance of cell proliferation and apoptosis through chronic inflammation, and initiating unnecessary innate and adaptive immune responses[1]. However, hematologic malignant tumor diseases after multiple chemotherapy, transplantation and frequent use of broad-spectrum antibiotics will break the homeostasis of the intestinal flora, affect the diversity of the intestinal flora, lead to the disorder of the intestinal flora, affect the host's immune system and affect the host's hematopoietic recovery.
The intestinal flora is a key external regulator of innate and adaptive immunity and hematopoietic function[2]. Gut microbes mainly through its metabolite short chain fatty acid (SCFA) to exert immunomodulatory effects, studies have found that SCFA can downregulate pro-inflammatory cytokines IL-6 and TNF-α, upregulate anti-inflammatory cytokine IL-10, inhibit T and B lymphocyte proliferation, SCFA can upregulate Fas to promote T lymphocyte apoptosis and inhibit its aggregation in the inflammatory intestinal mucosa. The gut microbiome and SCFA regulate immunity by upregulating intestinal homing molecules and FoxP3 transcriptional molecules to induce differentiation and proliferation of intestinal regulatory T cells (Treg) cells[3]. The mechanism by which the host regulates hematopoiesis through the gut microbiome is that the bacterial metabolites enter the bone marrow through the bloodstream to activate the MyD88-dependent TLR pathway and the NOD1 pathway, induce bone marrow mesenchymal stem cells to produce interferons, activate the STAT1 signaling pathway, act on hematopoietic stem/progenitor cells, and in addition, the lipopolysaccharides in the metabolites can also act directly on hematopoietic stem/progenitor cells, inhibiting hematopoiesis by combining these two ways [4]. The changes in the structure and diversity of intestinal flora in patients with blood malignant disease are mainly manifested in: excessive growth trend of Escherichia coli, decreased or absent beneficial bacteria Clostridium supra, and specific growth of some bacteria in the intestine such as Enterococcus faecus, Enterococcus sulphur, and Acinetobacter yogeri, thereby affecting the occurrence and development of the disease, while increasing the occurrence of infection and the possibility of disease recurrence [5] (see Table 1).
Table 1 Main features of the microbiota of hematologic malignancies
For leukemia, the study found that there is an interaction between the intestinal microbiome and the treatment of leukemia, during chemotherapy, the microbiome will change, the richness of the intestinal microbiome will gradually decrease, but at the same time, the intestinal microbiota will also affect the efficacy and toxicity of chemotherapy drugs. Recent studies have found that the diversity and composition of the gut microbiota prior to chemotherapy can predict complications such as chemotherapy-related gastrointestinal responses, granulocytopenia, and bloodstream infections, and that these complications can be improved by modulating the gut microbiome [6]. After hematopoietic stem cell transplantation, Bacteroides decreased, microorganisms were dominated by Enterococcus, enterococcus and the toxins released by it could aggravate the damage to intestinal mucosal epithelial cells, in addition, the proportion of intestinal commensal bacteria decreased Treg cell production decreased, a variety of factors aggravated GVHD, and the risk of GVHD in transplant patients with intestinal microbial dysbiosis in the early stage of transplantation increased, and the GVHD-related mortality rate increased [7].
Changes in the gut microbiota during transplantation are also thought to be associated with the onset of infection and delayed immune reconstitution, and may also be potential targets for treatment. At present, the treatment strategies for intervening intestinal flora mainly include antibiotic application, dietary adjustment, probiotic therapy and fecal transplantation (FMT), of which FMT is increasingly valued as an alternative "organ transplant". In 2020, both the European Society of Blood and Bone Marrow Transplantation and the Hematology Branch of the Chinese Medical Association included FMT as one of the treatment options for hormone-resistant acute graft-versus-host disease (aGVHD). However, the mechanism of action of FMT for aGVHD is still unclear, and it is currently believed that fecal bacteria from healthy donors can restore the imbalance of intestinal flora structure and function in patients with aGVHD, thereby improving related clinical symptoms. In addition, supplementation of intestinal probiotics and their metabolites, regulation of intestinal regional immunity and systemic immune response, and colonization resistance of reduced flora may also be potential mechanisms for FMT to play a role. FMT affects the efficacy of tumor immunotherapy by altering the intestinal flora and immune response status. However, at present, the relevant research on intestinal microbiota and FMT in the immunotherapy of hematologic tumors is still relatively lacking, and may become a hot spot in future research. However, in the face of this special group of patients with blood diseases, there are still many questions about the safety and efficacy of FMT as a new technology application, and long-term, repeated and large-sample clinical trials are still needed to be demonstrated [8].
bibliography:
1. Yuan L, W ang W, Zhang W, et al. Gut Microbiota in Untreated Diffuse Large B Cell Lymphoma Patients. Front Microbiol.2021,12:646361.
2. Wei Tong,Xi Yaming,Mao Xiali,et al. Research Progress on the Relationship between Intestinal Microecology and Hematopoiesis[J]. Journal of Clinical Hematology,2020,33(3):229-232.
3. Mao Dan,Chen Yu,Sheng Lixia,et al. Research status of the relationship between intestinal microecology and immune function in patients with hematologic tumors[J]. International Journal of Blood Transfusion and Hematology,2020,43(5):5.
4. Hannah Y, Baldridge M T, King K Y. Hematopoiesis and the bacterial microbiome[J]. Blood, 2021,132(6):559-564.
5. D'Angelo Christopher R, Sudakaran Sailendharan, Callander Natalie S. Clinical effects and applications of the gut microbiome in hematologic malignancies[J]. Cancer, 2021,127: 679-687.
6. Mao Xiali,Xi Yaming,Wei Tong,et al. Research Progress on Intestinal Microecology and Leukemia[J].Chinese Journal of Microecology, 2020,32(12):1476-1481.
7. Wang Li,Gao Rui,Liu Shufeng,et al. Research progress on the role of intestinal microorganisms in hematopoietic stem cell transplantation[J].Chinese Journal of Experimental Hematology,2018,26(1):5.
8. WU Depei,ZHAO Ye. Attach importance to the value of fecal transplantation in the treatment of hematological diseases[J].Chinese Journal of Practical Internal Medicine,2021,1(4):265-267.