Bacteria may protect against GVHD-related mortality

The team killed off Blautia in mice using vancomycin and ampicillin, then introduced either murine Blautia or murine Enterococcus, transplanted the mice with MHC-disparate T cells, and monitored them for GVHD.

Mice that received Blautia had significantly better overall survival (at more than 80 days after transplant) than mice that received Enterococcus (P<0.001).

“So how is this happening?” Dr Jenq asked. “We think, potentially, it might be due to short-chain fatty acids . . . butyric acid, propionic acid, and acetic acid. These are metabolites that bacteria produce when they ferment glucose and other sugars.”

To test this theory, the researchers treated mice with antibiotics and introduced Blautia or Enterococcus.

Blautia increased the level of short-chain fatty acids (butyrate and propionate) when compared to Enterococcus, although levels were not as high as those observed in mice that did not receive antibiotics. Nevertheless, these results point to a possible mechanism, according to Dr Jenq.

Explaining Blautia reduction

Dr Jenq also noted that antibiotics may contribute to the decrease in Blautia observed in transplant patients. When patients come in for transplant, they often have more than 25% Blautia in their stool. But the bacteria decrease to negligible levels by day 2 after transplant.

To determine the role of antibiotics, the researchers treated mice with 4 different antibiotics and looked at the levels of different bacteria.

They found that aztreonam and cefepime increased the levels of Bacteroidales and Clostridiales (the family to which Blautia belongs), but imipenem and metronidazole decreased bacteria levels.

So antibiotics do affect Blautia levels, Dr Jenq said, but they’re only part of the problem. He noted that patients’ Blautia levels start to decrease before antibiotics are administered. So he and his colleagues believe nutrition might also play a part.

The team found a significant difference in Blautia abundance between patients who received total parenteral nutrition and those who did not (P<0.001).

The researchers also discovered that reduced caloric intake led to a loss of Blautia and other Clostridiales. They analyzed 50 samples from 5 patients and found that patients who consumed fewer than 500 calories had a marked reduction in Blautia (P<0.0001).

And experiments in mice confirmed this association. A week of calorie restriction significantly reduced the abundance of Blautia and other Clostridiales (P=0.0002).

“In GVHD, as we all know, patients and mice eat less because of the nausea,” Dr Jenq said. “And we found that GVHD itself can also lead to a reduction in Clostridiales, both in humans [P=0.02] and in mice [P=0.01].”

Protecting Blautia to prevent GVHD

Having confirmed the role of nutrition in Blautia reduction, the researchers set out to identify a nutrition-based intervention to support Blautia in transplant recipients.

They settled on a sugar called raffinose, which is found in beans, cruciferous vegetables, and whole grains. It passes undigested through the upper intestine but is fermented in the lower intestine and metabolized to produce short-chain fatty acids.

The team tested raffinose in mice by introducing it into their drinking water. At 100 days after transplant, mice that received raffinose had significantly better overall survival than controls (P<0.001).

Based on these results, Dr Jenq and his colleagues believe nutritional intervention can protect Blautia and, therefore, may prevent GVHD and related death. The team thinks encouraging eating, gastric nutritional supplementation, and flora-targeted nutritional supplements might all prove effective.

But other interventions might work as well, such as reintroducing endogenous flora (via autologous fecal microbiota transplant), reintroducing select bacteria with beneficial potential, selecting antibiotics that spare bacteria with beneficial potential, and identifying and introducing bacterial metabolites that mediate anti-inflammatory effects.