A single strain of Bacteroides fragilis protects gut integrity and reduces GVHD
M. Hanief Sofi, Yongxia Wu, Taylor Ticer, Steven Schutt, David Bastian, Hee-Jin Choi, Linlu Tian, Corey Mealer, Chen Liu, Caroline Westwater, Kent E. Armeson, Alexander V. Alekseyenko, Xue-Zhong Yu
M. Hanief Sofi, Yongxia Wu, Taylor Ticer, Steven Schutt, David Bastian, Hee-Jin Choi, Linlu Tian, Corey Mealer, Chen Liu, Caroline Westwater, Kent E. Armeson, Alexander V. Alekseyenko, Xue-Zhong Yu
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Research Article Immunology Transplantation

A single strain of Bacteroides fragilis protects gut integrity and reduces GVHD

Abstract

Graft-versus-host disease (GVHD) is a pathological process caused by an exaggerated donor lymphocyte response to host antigens after allogeneic hematopoietic cell transplantation (allo-HCT). Donor T cells undergo extensive clonal expansion and differentiation, which culminate in damage to recipient target organs. Damage to the gastrointestinal tract is a main contributor to morbidity and mortality. The loss of diversity among intestinal bacteria caused by pretransplant conditioning regimens leads to an outgrowth of opportunistic pathogens and exacerbated GVHD after allo-HCT. Using murine models of allo-HCT, we found that an increase of Bacteroides in the intestinal microbiota of the recipients was associated with reduced GVHD in mice given fecal microbial transplantation. Administration of Bacteroides fragilis through oral gavage increased gut microbiota diversity and beneficial commensal bacteria and significantly ameliorated acute and chronic GVHD development. Preservation of gut integrity following B. fragilis exposure was likely attributed to increased short chain fatty acids, IL-22, and regulatory T cells, which in turn improved gut tight junction integrity and reduced inflammatory cytokine production of pathogenic T cells. The current study provides a proof of concept that a single strain of commensal bacteria can be a safe and effective means to protect gut integrity and ameliorate GVHD after allo-HCT.

Authors

M. Hanief Sofi, Yongxia Wu, Taylor Ticer, Steven Schutt, David Bastian, Hee-Jin Choi, Linlu Tian, Corey Mealer, Chen Liu, Caroline Westwater, Kent E. Armeson, Alexander V. Alekseyenko, Xue-Zhong Yu

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Figure 3

B. fragilis ameliorates GVHD.

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B. fragilis ameliorates GVHD. BALB/c (A and B) or BD2F1 (C and D) mice ...
BALB/c (A and B) or BD2F1 (C and D) mice were preconditioned and BMT performed as described in Figure 1. The recipients were administered thrice a week through oral gavage with approximately 109 live B. fragilis CFU (WT B. fragilis) from 2 weeks before BMT and then weekly until up to a month after BMT. Recipients were monitored for clinical score (A–C) and survival (B–D) until 80 days post-BMT (n = 10 per group). Data shown were pooled from 2 replicate experiments. In a similar setting, liver, lung, SI, colon, and skin were collected from the recipients 3 weeks post-BMT. Pathological score means ± SD of GVHD target organs are depicted (E). Data shown as mean ± SEM were pooled from 3 replicate experiments. Asterisks indicate statistical significance *P < 0.05, **P < 0.01.