The microbiome—the revealing of a long time unbeknownst factor for outcome in murine models of graft-versus-host disease

Abstract

The microbiome of the intestinal tract has been shown to have an extensive role in host health and various diseases [1]. It is highly diverse in people living in developing countries and contains larger population of beneficial bacteria due to poor hygiene conditions and lifestyle. In contrast, people living in developed countries have a less diverse microbiome due to western lifestyle, and moreover the microbiome is adoptive as shown by alterations of the microbiome in immigrants from South Asian to Western countries [2]. The microbiome has shown enormous impact on host physiology and seems as an important driver in health and disease [3, 4]. Therefore, it nowadays needs to be included in our understanding of systems biology, and research cannot be limited to nonmicrobial aspects of pathophysiology. Furthermore, the healthy microbial composition is not well understood and “one person’s healthy microbiome might not be healthy in another context” [5]. Murine models of graft-versus-host disease (GVHD) have been a major translational research tool to explore GVHD pathophysiology and have significantly contributed to its understanding [6–8]. However, for decades, due to lack of knowledge and lack of current molecular technology, the microbiome was ignored in this field, and only over the last few years, the interest for the microbiome in GVHD has rapidly grown [9–12]. The “earliest” phase of acute GVHD is initiated before the bone marrow transplantation due to underlying disease, infections, and their treatments, and by transplant-related conditioning regimens that include total body irradiation and/or chemotherapy. The pathophysiology of GVHD is considered in three phases that involve innate and adaptive immunity. (1) Activation of the antigen-presenting cells (APCs), (2) donor T-cell activation, differentiation, and migration, and (3) T-cell effector phase. These effects altogether cause critical changes to immune cells and endothelial and epithelial cells [6]. Gut integrity/injury, APC activation, and endothelial activation during GVHD pathogenesis are more prone to intereference by microbial changes [6, 7, 13–15]. Major organs affected by the microbiome might be gut and lung due to their direct and constant “contact” with the environment and with microbiomes [16–18]. Similarly, the skin as one of the most commonly affected target organs of GVHD, has its own microbiome and is constantly exposed to external modifying factors. Skin-resident microbes are involved in the regulation of immune responses by controlling the expression of antimicrobial peptides, as well as affecting components of the complement system and activation of lymphocytes. It has been reported that skin microbiome dysbiosis plays an important role in a murine model of atopic dermatitis [19]. The correlation between the skin microbiota and GVHD and their potential role in promoting injury is not defined, yet is currently being investigated (NCT04231500, “The Skin Microbiome in Graft Versus Host Disease”) [20]. The human gut microbiome constitutes a rich and complex ecosystem consisting of different species taxonomically classified by genus, family, order, and phyla. This microbial community consists of greater than 100 trillion microorganisms and encodes higher than 3 million genes. Genes harbored by gut microbes encode for thousands of microbial enzymes and metabolites [21–23]. These microbial metabolites help with digestion and absorption of various compounds, immune tolerance, nutrient synthesis, strengthening and development of immune system, and gut brain crosstalk [23]. Short-chain fatty acids (SCFAs) are small organic monocarboxylic acids with a chain length of up to six carbons atoms, and are generated from dietary fibers and resistant starch by microbial fermentation [24], * Gerhard Carl Hildebrandt [email protected]