Longitudinal gut microbiome analyses and blooms of pathogenic strains during lupus disease flares

Abstract

ObjectiveWhereas genetic susceptibility for systemic lupus erythematosus (SLE) has been well explored, the triggers for clinical disease flares remain elusive. To investigate relationships between microbiota community resilience and disease activity, we performed the first longitudinal analyses of lupus gut-microbiota communities.MethodsIn an observational study, taxononomic analyses, including multivariate analysis of ß-diversity, assessed time-dependent alterations in faecal communities from patients and healthy controls. From gut blooms, strains were isolated, with genomes and associated glycans analysed.ResultsMultivariate 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. Expansions of only the anaerobic commensal,Ruminococcus (blautia) gnavus(RG) occurred at times of high-disease activity, and were detected in almost half of patients during lupus nephritis (LN) disease flares. Whole genome sequence analysis of RG strains isolated during these flares documented 34 genes postulated to aid adaptation and expansion within a host with an inflammatory condition. Yet, the most specific feature of strains found during lupus flares was the common expression of a novel type of cell membrane-associated lipoglycan. These lipoglycans share conserved structural features documented by mass spectroscopy, and highly immunogenic repetitive antigenic-determinants, recognised by high-level serum IgG2 antibodies, that spontaneously arose, concurrent with RG blooms and lupus flares.ConclusionsOur findings rationalise how blooms of the RG pathobiont may be common drivers of clinical flares of often remitting-relapsing lupus disease, and highlight the potential pathogenic properties of specific strains isolated from active LN patients.

Dietary tryptophan and genetic susceptibility expand gut microbiota that promote systemic autoimmune activation

“…Overall, these results suggest that both dietary tryptophan and the origin of the microbiota shape the architecture of gut microbiome. This applies specifically to Rg , a group of bacteria now firmly associated with severe lupus 10 , which was found at a greater abundance in recipient microbiota of TC origin and was further enriched by high tryptophan.…”

“…The greater abundance of Rg in the recipients of TC microbiota suggested that these bacteria are enriched in TC mice. Since Rg blooms correspond to disease flares in SLE patients 10 , we speculated that Rg populations may expand with disease progression in TC mice. To test this hypothesis, we longitudinally tested Rg abundance in the feces of age-matched TC and B6 mice housed side by side, in two cohorts each housed in separate rooms.…”

“…These observations suggest that the combination of altered tryptophan metabolism and activated adaptive immunity enriches the Rg population in the gut of lupus-prone mice, which promotes autoimmunity, at least in part by targeting Treg cells. Considering the positive correlation between the abundance of fecal Rg and disease activity in SLE patients 10 , the results suggest a model in which genetic susceptibility drives the development of an inflammatory immune system that shapes the microbiome towards an altered tryptophan catabolism. This in turn favors the expansion of Rg populations, which independently activate autoimmune responses.…”

“…The abundance of fecal Ruminococcus (blautia) gnavus ( Rg ) was positively correlated with disease severity in lupus nephritis patients 9 . Moreover, longitudinal studies showed that bacterial blooms occurred during disease flares, with Rg being the most consistently expanded taxa 10 . Rg produces a highly immunogenic lipoglycan (LP), and high titers of anti-LP IgG2 also correlated with disease activity in these patients 10 .…”

Probiotics, prebiotics, and postbiotics in health and disease

“…44,45 In a 4-year study of 16 women with lupus from diverse ethnic backgrounds, five experienced a significant proliferation of the gut bacterium Ruminococcus blautia gnavus concurrent with disease flare-ups. 46 In gastrointestinal diseases, the decrease of butyrate-producing bacteria like Prevotella copri and Roseburia could influence the growth of colon cells and reduced mucus production. 47 Meanwhile, an increase in mucolytic bacteria like Ruminococcus species, virulent Escherichia coli, and Bacteroides fragilis might result in mucosal damage and exacerbated bacterial invasion.…”