Certain Gut Bacteria May Promote Disease Activity in Patients With Lupus Nephritis

Blooms of the gut bacterium Ruminococcus (blautia) gnavus (RG) may be a prevalent motivator of clinical flares of often remitting-relapsing lupus disease, according to a study published in Annals of the Rheumatic Diseases. The findings emphasize the possible pathogenic properties of particular strains of gut bacteria in patients with active lupus nephritis (LN).

Study authors explored the relationships between microbiota community resilience and disease activity in what was the first longitudinal analysis of lupus gut microbiota communities to the authors' knowledge. The study was conducted because while genetic susceptibility for systemic lupus erythematosus (SLE) has been thoroughly investigated, the triggers for clinical disease flares have not been well-defined.

“Lupus nephritis (LN) is a serious illness, yet despite improvements in therapeutic interventions, many patients progress to renal failure [and] the causes of lupus flares are unknown,” explained the study authors.

First, they examined 2-6 fecal samples from 16 female patients, with 44 samples collected over 24-291 weeks. For comparison, 72 sequential samples from 22 healthy adult female control volunteers were evaluated. To review the diversity in the bacterial communities, fecal DNA was used to generate 16S rRNA gene-amplicon libraries.

Next, an observational study was conducted in which taxononomic analyses, including a multivariate analysis of ß-diversity, evaluated changes in fecal communities from patients and healthy controls over time. Strains were separated from gut blooms and genomes and associated glycans were analyzed.

Regarding the results, “Multivariate analyses documented that, unlike healthy controls, significant temporal community-wide ecological microbiota instability was common in SLE patients, and transient intestinal growth spikes of several pathogenic species were documented,” said the study authors.

Only RG, which is an anaerobic commensal, expanded at times of high disease activity, and RG expansions were seen in almost 50% of patients during LN disease flares.

Whole-genome sequence analysis of RG strains separated during these flares showed 34 genes thought to aid adaptation and expansion within a host with an inflammatory condition. The most specific feature of strains discovered during lupus flares was the expression of a novel type of cell membrane-associated lipoglycan, the expression of which is associated with high-level serum IgG2 antibodies that arose concurrently with RG blooms and lupus flares in the study.

The study authors notably indicated that instability, defined by the level of community variance over time, was not related to the number of samples from a donor, the timespan of sampling, or the disease activity features. Nor was the instability correlated with maximum systemic lupus erythematosus disease activity index (SLEDAI) disease score at sampling, or span from lowest to highest SLEDAI score in the person. Impaired gut community stability has not been considered before. Also, temporal microbiota instability did not seem to correlate with the ingested medication, that suggests that community instability could be an intrinsic feature to LN.

Even though the study authors’ knowledge of the diversity among RG strains is still relatively limited, their analysis of 9 RG strains from patients with inflammatory bowel disease found no detectable LG, although these studies are not exhaustive, they noted.

“Our studies document key structural features of the RG LG that display remarkable conservation between different LN-derived strains (figure 5),” continued the authors.

Additionally, the LG in this study that was purified and characterized, so far in 3 RG strains, was found to have a unique structure with multiple distinctive features that merit more study and clarification.

Disease flares might be influenced by ecological shifts in a microbiota community that is inclusive of a range of RG strains that differ based on genomic gene sets and expressed glycan properties. Preliminary studies have observed that as far as LG producing RG strains, there is a specific blood transcriptomic profile seen in patients with SLE with RG blooms parallel to disease flares, wich could be relevant to the pathogenesis of LN.

One limitation of this study is that it included a small cohort of only 9 patients with SLE and 22 healthy subjects were studied over time, and samples were obtained during routine clinical care. So, the true occurrence of disease flares with temporally linked RG blooms could have been underestimated, and authors were unable to evaluate the duration of bloom persistence.

“In conclusion, an individual RG strain can express different specific types of bacterial glycans, which include the novel LG expressed by lupus strains,” wrote the authors.

Reference

Azzouz DF, Chen Z, Izmirly PM, et al. Longitudinal gut microbiome analyses and blooms of pathogenic strains during lupus disease flares. Ann Rheum Dis. Published Online June 26, 2023. doi: 10.1136/ard-2023-223929