Microbiota and Mucosal Immunity Effects on BMT Outcomes

The intestinal epithelium, composed of intestinal epithelial cells (IECs) connected by tight junctions, creates a physical and biochemical barrier to separate luminal organisms from intestinal tissues. The intestinal mucosa is in contact with harmless commensal bacteria as well as potential pathogens, thereby functioning to immunologically survey the intestinal lumen.

IECs monitor the tone of the lumen, recognizing a variety of microbial products in both antigen-independent and antigen-dependent manners to participate in coordinated immune tolerance or, alternatively, immune response. Interestingly, many aspects of intestinal immune homeostasis fail to develop in the absence of the intestinal microbiota. Germ-free mice show extensive defects and impaired development of gut-associated lymphoid tissues and antibody production. Adding to the complexity of microbiota composition are host and environmental factors, which can modulate microbiota composition and include age, antimicrobial use, disease, inflammation, metabolites, stress, and diet, particularly malnourishment.

Jonathan U. Peled, Robert R. Jenq, Ernst Holler & Marcel R. M. van den Brink. Role of gut flora after bone marrow transplantation. Nature Microbiology Vol1 April 2016.

A role for the microbiota has been examined in relation to a variety of clinical outcomes, ranging from obesity and atherosclerosis, to allergies and asthma, and even to cancer development and autism. Hematopoietic stem cell transplantation (HSCT) has been no exception, with several groups recently uncovering important relationships between the microbiota and outcomes in HSCT recipients.

In a paper by Robert Jenq et al. we demonstrated that in murine and human recipients of HSCT, intestinal inflammation secondary to GVHD is associated with major shifts in the composition of the intestinal microbiota, and, in turn, gut flora can modulate the severity of intestinal inflammation. Mice that developed GVHD exhibited a reduction in flora diversity with an expansion in the order of Lactobacillales and decrease in the order of Clostridiales. This change in microbiota diversity was also observed in human settings in patients with GVHD.

Patients receiving an allogeneic hematopoietic stem cell transplant often develop neutropenic fever, which is treated with antibiotics. Such antibiotic treatment also may inadvertently wipe out beneficial intestinal bacteria that reduce gut inflammation. The work by Yusuke Shono et al. demonstrated that transplant patients treated with certain broad-spectrum antibiotics show an increase in graft-versus-host disease in the colon. Analysis of a mouse model revealed that this was due to loss of beneficial gut bacteria and overgrowth of bacterial strains that consumed the protective mucus layer of the colon rendering it more susceptible to inflammation and injury.

The healthy bacteria in our guts have an important influence on many aspects of health. In this study of over 500 MSKCC patients, a certain group of gut bacteria were found to predict whether relapse of leukemia would occur after bone marrow transplantation. This group of bacteria, whose presence or abundance predicts less relapse and improved survival after allo-HSCT, includes the commensal organism Eubacterium limosum and several other related species. This paves the way for future studies that will optimize intestinal bacteria to improve patient health.

Nutritional support from the intestinal microbiota improves hematopoietic reconstitution after bone marrow transplantation in mice. Staffas A, Burgos da Silva M, Slingerland AE, Lazrak A, Bare CJ, Holman CD, Docampo MD, Shono Y, Durham B, Pickard AJ, Cross JR, Stein-Thoeringer C, Velardi E, Tsai JJ, Jahn J, Jay H, Lieberman S, Smith OM, Pamer EG, Peled JU, Cohen DE, Jenq RR, van den Brink MRM. Cell Host & Microbiome. 2018; doi:10.1016/j.chom.2018.03.002. PMID: 29576480; NIHMS953922.
Intestinal microbiota and relapse after hematopoietic-cell transplantation. Peled JU, Devlin SM, Staffas A, Lumish M, Khanin R, Littmann ER, Ling L, Kosuri K, Maloy M, Slingerland JB, Ahr KF, Porosnicu-Rodriguez KA, Shono Y, Slingerland A, Docampo MD, Sung AD, Weber D, Alousi AM, Gyurkocza B, Ponce DM, Barker JN, Perales MA, Giralt SA, Taur Y, Pamer EG, Jenq RR*, van den Brink MRM. *These authors contributed equally. J Clin Oncol. 2017; 25(15):1650-1659. PMID: 28296584; PMC5455763.
Increased GVHD-related mortality with broad-spectrum antibiotic use after allogeneic hematopoietic stem cell transplantation in human patients and mice.
Shono Y, Docampo MD, Peled JU, Perobelli SM, Velardi E, Tsai JJ, Slingerland AE, Smith OM, Young LF, Gupta J, Lieberman SR, Jay HV, Ahr KF, Porosnicu Rodriguez KA, Xu K, Calarfiore M, Poeck H, Caballero S, Devlin SM, Rapaport F, Dudakov JA, Hanash AM, Gyurkocza B, Murphy GF, Gomes C, Liu C, Moss EL, Falconer SB, Bhatt AS, Taur Y, Pamer EG, van den Brink MR, Jenq RR. Sci Transl Med. 2016; May 18;8(339):339ra71. doi: 10.1126/scitranslmed.aaf2311. PMID: 27194729; PMC4991773.
Role of gut flora after bone marrow transplantation. Jonathan U. Peled, Robert R. Jenq, Ernst Holler & Marcel R. M. van den Brink. Nature Microbiology. 2016; 1:16036. PMID: 27572448; PMC5027134.
Intestinal Blautia Is Associated with Reduced Death from Graft-versus-Host Disease. Jenq R, Taur Y, Devlin S, Ponce D, Goldberg J, Ahr KF, Littmann ER, Ling L, Gobourne AC, Miller LC, Docampo MD, Peled JU, Arpaia N, Cross J, Peets TK, Lumish MA, Shono Y, Dudakov JA, Poeck H, Hanash AM, Barker JN, Perales MA, Giralt SA, Pamer EG, van den Brink MR. Biol Blood Marrow Transplant. 2015; 21(8):1373-83. PMID: 25977230; PMC4516127.
Regulation of intestinal inflammation by microbiota following allogeneic bone marrow transplantation. Jenq RR, Ubeda C, Taur Y, Menezes CC, Khanin R, Dudakov JA, Liu C, West ML, Singer NV, Equinda MJ, Gobourne A, Lipuma L, Young LF, Smith OM, Ghosh A, Hanash AM, Goldberg JD, Aoyama K, Blazar BR, Pamer EG, van den Brink MR. J Exp Med. 2012; 209:903-11. doi: 10.1084/jem.20112408. Epub 2012 Apr 30. PMID: 22547653; PMC3348096.