Gut Microbiome Instability Associated With Lupus Nephritis Flares

A certain type of intestinal microflora may be a trigger for lupus nephritis flares, researchers found.

Serial fecal samples from 16 women with systemic lupus erythematosus (SLE), taken over periods ranging from 6 months to 5-plus years, showed substantial variability in microbial composition over time, according to Gregg Silverman, MD, of New York University in New York City, and colleagues -- far more variability than was seen in samples from healthy women.

Moreover, "blooms" of one particular microbial species, Ruminococcus gnavus, were associated with onset of lupus nephritis flares, the group reported in Annals of the Rheumatic Diseases. Four patients with lupus nephritis had "dramatic" increases in R. gnavus abundance, by an average of ninefold over other periods with less active disease in these individuals.

Silverman and colleagues also observed that certain R. gnavus strains appeared more disease-inducing than others. These strains express lipoglycans that act as non-protein antigens, and thus provoke an immune response, the researchers determined. This was demonstrated by lab studies showing immunoreactivity with these lipoglycans in serum from lupus nephritis patients.

And, patients with high levels of R. gnavus in their microbiomes also had very high titers of immunoglobulin G antibodies that recognize the lipoglycans.

"Based in part on the magnitude of these responses, we postulate that host immune responses to the novel [R. gnavus] lupus strain-associated lipoglycans may contribute to immune-complex mediated pathogenetic pathways implicated in lupus disease flares," Silverman's group wrote.

Notably, though, several patients with lupus nephritis who provided fecal samples showed only low and stable levels of R. gnavus over time, "suggesting not all [lupus nephritis] flares are associated with [R. gnavus] blooms, which could mean other, undetected, disease drivers are involved," the researchers observed.

Recent years have seen an explosion of interest in the gut microbiome, with mounting evidence that it can affect functions throughout the body, not just digestive physiology. Autoimmune diseases are no exception -- recently, several studies have implicated the microbiome in rheumatoid arthritis, for example. In many of these situations, it's been proposed that "dysbiosis" results in increased gut-wall permeability, allowing bacterial components to leak into circulation where they cause havoc in distant organ systems.

Silverman and colleagues suggested that, for lupus nephritis, the effect is to prompt an innate immune response to the R. gnavus lipoglycans. That the body regards these substances as hostile is well known: Gram-negative sepsis, for example, is a reaction to lipopolysaccharides in bacterial cell walls.

With regard to lupus nephritis, the findings raise the possibility that flares might be abrogated with treatments targeting R. gnavus or its lipoglycans, in place of the immunosuppressants now used in these cases.

Silverman's group noted several limitations to their study: the small number of patients and the even smaller number with active lupus nephritis and high abundance of R. gnavus. Intervals between fecal sample collection varied and were not necessarily tied to patients' disease activity.

"In these patients with established disease, we were unable to identify when such anti-pathobiont antibody responses first arose, and how long they may persist," the researchers acknowledged. They also noted that diet, prior antibiotic exposure, and over-the-counter medication use were not tracked and could have influenced the results.

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