The innate immune protein NLRP6, which plays a protective role in inflammatory bowel disease (IBD), appears to aggravate intestinal graft-vs.-host disease (GVHD).

Moreover, while the protective role of NLRP6 in IBD is affected by microbiome composition, its aggravation of GVHD was independent of the animals' microbiome.

The results, which were published in the March 11, 2019, online issue of Nature Microbiology, mark the first report of an effect of NLRP6 that was independent of the microbiome. "Everything else in the literature where NLRP6 has been shown to play a role, it's always in the context of microbiome changes," co-corresponding author Pavan Reddy, chief of the division of hematology/oncology and deputy director at the University of Michigan Comprehensive Cancer Center, told BioWorld.

Reddy, co-corresponding author Grace Chen and their colleagues were surprised both by the independence from microbiome composition, and also, more basically, by the nature of the effect. Given NLRP6's protective role in colitis, they expected to see a similar effect in GVHD.

Those results are in line with the observed effects of therapies for IBD and GVHD, respectively. Reddy said there is "some overlap, and yet some things don't work for one versus the other."

Still, given the surprising nature of the findings, the team tested combinations of NLRP6 knockout mice with multiple microbiome manipulations. Sometimes the mice were NLRP6 knockouts, whereas sometimes it was the transplanted cells that lacked NLRP6.

The upshot, Reddy said, was that there is a "tissue-intrinsic mechanism that distinguishes the autoimmune IBD from the alloimmune GVHD," independently of the microbiome composition. Knocking out NLRP6 decreased intestinal GVHD, without compromising graft-vs.-tumor effects that contribute to the method's effectiveness.

In their paper, Reddy and his team stressed that their findings do not contradict multiple findings that have shown that a role for microbiome changes in GVHD following allogeneic bone marrow transplantation.

"Our data do not indicate an absence of the contributing role by the microbiome to GVHD severity," they wrote in their paper; "rather, just that alterations in the gut microbiome, microbial dysbiosis, from either NLRP6 deficiency, allo-BMT or antibiotic treatment are not sufficient to modulate GVHD severity in the context of host NLRP6 deficiency."

The findings suggest that NLRP6 could be a target for the treatment or prevention of GVHD, which is one of the major complications of allogeneic bone marrow transplant. Somewhere between one-third and one-half of allogeneic transplant recipients develop acute GVHD, which develops in the first few months after a transplant and usually attacks only a few organs, including the intestines. Chronic GVHD, which occurs more than 90 days after a transplant, can attack many organs. Both kinds of GVHD can be fatal, and they contribute to the overall death rate of about 20 percent after allogeneic BMT.

Currently, GVHD is "treated with immunosuppressant medication, and the downstream effects are lots and lots of infections and relapse," Reddy said.

The researchers plan to further pursue two lines of research with respect to the work. First, they plan to identify the particular cell type where NLRP6 is affecting GVHD.

The other is to understand what NLRP6 is sensing that exacerbates NLRP6, given that the microbiome composition does not appear to play a role.

That work is part of a larger effort to "characterize the metabolites that are either good or bad for the host immune system," Reddy said.

So far, his team has identified taurine as one metabolite that is present in the relevant part of the gut and seems to activate NLRP6. The innate immune sensor may be acting by regulating the response to taurine metabolites, which could explain the team's observations.

"Taurine is bad for GVHD; it makes it worse," Reddy said. But so far, "we don't know why."