Gut microbiome alteration may improve survival in graft-versus-host disease [PreClinical]

1. Decreased levels of the molecule butyrate and its receptors were found in mice that received an allogeneic bone marrow transplant (BMT).

2. The addition of butyrate-producing bacteria increased the function of the intestinal epithelium as well as survival in mice that received transplants.

Evidence Rating Level: 1 (Excellent)

Study Rundown: Although BMTs are beneficial treatments for patients with malignancies or other blood-related conditions, they can result in the complication of graft-versus-host disease (GVHD). Based on the role of the gut microbiome in GVHD pathology, this study developed a potential therapy for the complication.

The researchers first showed that in mice that received allogeneic BMTs, butyrate was the only microbe-produced compound that was decreased in the gut. In addition, the concentration of butyrate transporters and receptors was decreased, a result that was ameliorated upon the addition of butyrate. Butyrate administration also decreased the weight loss associated with GVHD and increased the survival of the mice. Experiments to determine the function of butyrate showed that the compound increased levels of anti-apoptotic proteins, decreased levels of pro-apoptotic proteins, and restored the expression of junctional proteins in the mouse intestinal epithelium. Together, these changes promoted the integrity of the intestinal epithelium. Finally, bacterial strains known to produce butyrate were introduced into the intestines of mice that received BMTs. Similar results were seen with these experiments as with the addition of butyrate alone, showing a significant decrease in GVHD severity.

Further studies will need to determine the effect of butyrate on other cells in the gastrointestinal tract, as well as any systemic effects of the microbiome alteration. However, this study shows the potential of altering the microbiome to reduce the complications associated with BMTs.

Click to read the study in Nature Immunology

Relevant Reading: Regulation of intestinal inflammation by microbiota following allogeneic bone marrow transplantation

In-Depth [animal study]: In order to induce GVHD in mice, major histocompatibility complex-mismatched BMTs were performed. Using mass spectrometry, the concentrations of microbial fatty acids in the gut were compared between the transplanted and control mice, with the only difference being a significant decrease in transplant recipient butyrate levels (p<0.05). This finding led the researchers to test the effect of butyrate administration on GVHD severity. Butyrate was administered to transplanted mice via intragastric gavage daily for 1 week and then every other day for the remaining weeks of the experiment. A significant decrease in weight loss (p<0.0001) and an increase in survival (p<0.00001) were noted in mice given butyrate.

The mechanisms of butyrate function were then determined in an in vitro culture of mouse intestinal epithelial cells as well as the in vivo mouse model of GVHD. After the addition of butyrate in both models, qPCR analysis showed a significant increase in the mRNA levels of BCL-B, an anti-apoptotic protein, and decreases in Bak1 and Bax, pro-apototic proteins (p<0.05). In addition, immunoblotting showed a significant increase in occludin, JAM, and E-cadherin following butyrate administration (p<0.05).

Finally, strains of Clostridia bacteria known to produce high amounts of butyrate were introduced into the intestines of mice via intragastric gavage, on alternating days from 14 days before the BMT until 21 days after. Upon addition of these bacteria, there was a significant increase in butyrate within the intestinal lumen and tissues (p<0.05). Compared to mice that did not receive bacteria, those that did showed a significant decrease in GVHD severity (p<0.05) and increase in survival (p<0.0001).

Image: PD

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