J Bacteriol Virol.  2016 Dec;46(4):307-311. 10.4167/jbv.2016.46.4.307.

Gut Microbiota in Graft-versus-Host Disease

• Kim YH

• KMID: 2366878
• DOI: http://doi.org/10.4167/jbv.2016.46.4.307

Abstract

Gut microbiota inhabit the host gastrointestinal (GI) tract and play roles in many aspects of metabolic and immunologic homeostasis. Understanding about gut microbiota composition in health and disease is accumulating with the advances in gene sequencing technology. Graft-versus-host disease (GVHD) is a major complication after allogenic bone marrow transplantation (allo-BMT), a gold standard clinical procedure to treat hematologic disorders such as leukemia and lymphomas. Recent studies have shown that a disturbance in the gut microbiota affects GVHD prognosis. Decrease in a compositional diversity is suggested as an independent predictor of GVHD and colonization of noncommensal Enterococcus is shown to be involved in unpleasant treatment outcomes. This article describes current understanding about allo-BMT-induced gut microbiota changes and its involvement in the incidence of GVHD. In addition, several putative therapeutic strategies to decrease GVHD-related mortality after allo-BMT are discussed.

Keyword

Gut microbiota; allo-BMT; GVHD; Enterococcus domination; VRE

MeSH Terms

Bone Marrow Transplantation
Colon
Enterococcus
Gastrointestinal Microbiome*
Graft vs Host Disease*
Homeostasis
Incidence
Leukemia
Lymphoma
Mortality
Prognosis

Reference

1). Jandhyala SM, Talukdar R, Subramanyam C, Vuyyuru H, Sasikala M, Nageshwar Reddy D. Role of the normal gut microbiota. World J Gastroenterol. 2015; 21:8787–803.

2). Manzo VE, Bhatt AS. The human microbiome in hematopoiesis and hematologic disorders. Blood. 2015; 126:311–8.

3). Jones JM, Wilson R, Bealmear PM. Mortality and gross pathology of secondary disease in germfree mouse radiation chimeras. Radiat Res. 1971; 45:577–88.

4). van Bekkum DW, Roodenburg J, Heidt PJ, van der Waaij D. Mitigation of secondary disease of allogeneic mouse radiation chimeras by modification of the intestinal microflora. J Natl Cancer Inst. 1974; 52:401–4.

5). Storb R, Prentice RL, Buckner CD, Clift RA, Appelbaum F, Deeg J, et al. Graft-versus-host disease and survival in patients with aplastic anemia treated by marrow grafts from HLA-identical siblings. Beneficial effect of a protective environment. N Engl J Med. 1983; 308:302–7.

6). Petersen FB, Buckner CD, Clift RA, Nelson N, Counts GW, Meyers JD, et al. Infectious complications in patients undergoing marrow transplantation: a prospective randomized study of the additional effect of decontamination and laminar air flow isolation among patients receiving prophylactic systemic antibiotics. Scand J Infect Dis. 1987; 19:559–67.

7). Round JL, Mazmanian SK. The gut microbiota shapes intestinal immune responses during health and disease. Nat Rev Immunol. 2009; 9:313–23.

8). Jenq RR, Ubeda C, Taur Y, Menezes CC, Khanin R, Dudakov JA, et al. Regulation of intestinal inflammation by microbiota following allogeneic bone marrow transplantation. J Exp Med. 2012; 209:903–11.

9). Taur Y, Jenq RR, Perales MA, Littmann ER, Morjaria S, Ling L, et al. The effects of intestinal tract bacterial diversity on mortality following allogeneic hematopoietic stem cell transplantation. Blood. 2014; 124:1174–82.

10). Holler E, Butzhammer P, Schmid K, Hundsrucker C, Koestler J, Peter K, et al. Metagenomic analysis of the stool microbiome in patients receiving allogeneic stem cell transplantation: loss of diversity is associated with use of systemic antibiotics and more pronounced in gastrointestinal graft-versus-host disease. Biol Blood Marrow Transplant. 2014; 20:640–5.

11). Taur Y, Xavier JB, Lipuma L, Ubeda C, Goldberg J, Gobourne A, et al. Intestinal domination and the risk of bacteremia in patients undergoing allogeneic hematopoietic stem cell transplantation. Clin Infect Dis. 2012; 55:905–14.

12). Jenq RR, Taur Y, Devlin SM, Ponce DM, Goldberg JD, Ahr KF, et al. Intestinal Blautia Is Associated with Reduced Death from Graft-versus-Host Disease. Biol Blood Marrow Transplant. 2015; 21:1373–83.

13). Atarashi K, Tanoue T, Oshima K, Suda W, Nagano Y, Nishikawa H, et al. Treg induction by a rationally selected mixture of Clostridia strains from the human microbiota. Nature. 2013; 500:232–6.

14). Mathewson ND, Jenq R, Mathew AV, Koenigsknecht M, Hanash A, Toubai T, et al. Gut microbiome-derived metabolites modulate intestinal epithelial cell damage and mitigate graft-versus-host disease. Nat Immunol. 2016; 17:505–13.

15). Zimmerman MA, Singh N, Martin PM, Thangaraju M, Ganapathy V, Waller JL, et al. Butyrate suppresses colonic inflammation through HDAC1-dependent Fas upregulation and Fas-mediated apoptosis of T cells. Am J Physiol Gastrointest Liver Physiol. 2012; 302:G1405–15.

16). Arias CA, Murray BE. The rise of the Enterococcus: beyond vancomycin resistance. Nat Rev Microbiol. 2012; 10:266–78.

17). Sava IG, Heikens E, Huebner J. Pathogenesis and immunity in enterococcal infections. Clin Microbiol Infect. 2010; 16:533–40.

18). Willems RJ, Homan W, Top J, van Santen-Verheuvel M, Tribe D, Manzioros X, et al. Variant esp gene as a marker of a distinct genetic lineage of vancomycin-resistant Enterococcus faecium spreading in hospitals. Lancet. 2001; 357:853–5.

19). Hendrickx AP, Bonten MJ, van Luit-Asbroek M, Schapendonk CM, Kragten AH, Willems RJ. Expression of two distinct types of pili by a hospital-acquired Enterococcus faecium isolate. Microbiology. 2008; 154:3212–23.

20). Hendrickx AP, van Wamel WJ, Posthuma G, Bonten MJ, Willems RJ. Five genes encoding surface-exposed LPXTG proteins are enriched in hospital-adapted Enterococcus faecium clonal complex 17 isolates. J Bacteriol. 2007; 189:8321–32.

21). Steck N, Hoffmann M, Sava IG, Kim SC, Hahne H, Tonkonogy SL, et al. Enterococcus faecalis metalloprotease compromises epithelial barrier and contributes to intestinal inflammation. Gastroenterology. 2011; 141:959–71.

22). Cash HL, Whitham CV, Behrendt CL, Hooper LV. Symbiotic bacteria direct expression of an intestinal bactericidal lectin. Science. 2006; 313:1126–30.

23). Brandl K, Plitas G, Mihu CN, Ubeda C, Jia T, Fleisher M, et al. Vancomycin-resistant enterococci exploit antibiotic-induced innate immune deficits. Nature. 2008; 455:804–7.

24). Kinnebrew MA, Ubeda C, Zenewicz LA, Smith N, Flavell RA, Pamer EG. Bacterial flagellin stimulates Toll-like receptor 5-dependent defense against vancomycin-resistant Enterococcus infection. J Infect Dis. 2010; 201:534–43.