Gut microbial functional remodeling and butyrate depletion amplify anti-Ro/La antibody-driven type I interferon activation in neonatal lupus, supporting 'a microbiota-associated butyrate-type I interferon pathway that may amplify maternal autoantibody-dependent immune activation and contribute to the clinical manifestation of NLE.'
Key Findings
Results
Neonatal gut microbiome composition showed progressive remodeling across healthy controls, anti-Ro/La-exposed neonates without neonatal lupus erythematosus (No-NLE), and neonates with NLE.
Study included 90 neonates, 30 per group: healthy controls, No-NLE, and NLE.
Shotgun metagenomic profiling was used to characterize gut microbial communities.
Anti-Ro/La exposure was associated with depletion of early-life commensal-associated taxa including Bifidobacterium, Rothia, and Clostridium.
Enrichment of taxa with opportunistic potential, including Klebsiella and Enterococcus, was observed.
Greatest ecological divergence was observed in neonates with NLE.
Results
Functional profiling identified altered microbial carbohydrate-processing capacity in NLE, marked by enrichment of glycosyltransferase family 4 (GT4) and depletion of GT2.
Functional profiling was performed via shotgun metagenomic profiling.
GT4 was enriched in NLE neonates relative to controls and No-NLE neonates.
GT2 was depleted in NLE neonates.
These alterations in glycosyltransferase families reflect broad changes in microbial carbohydrate-processing capacity.
Results
Plasma short-chain fatty acid (SCFA) metabolites, most prominently butyrate, were broadly reduced in NLE neonates, coinciding with increased serum IgG and IFN-α and decreased complement component 4 (C4).
Broad reductions in plasma SCFAs were observed across the NLE group.
Butyrate was identified as the most prominently depleted SCFA.
Increased serum immunoglobulin G (IgG) and interferon-α (IFN-α) were detected in NLE neonates.
Decreased complement component 4 (C4) was also observed in NLE neonates.
Results
A GT4-Klebsiella-Rothia-IFN-α signature distinguished NLE from No-NLE neonates with an AUC of 0.883.
The composite signature included GT4 functional enrichment, Klebsiella abundance, Rothia depletion, and IFN-α levels.
AUC = 0.883; 95% CI, 0.799–0.967.
This signature distinguished NLE from No-NLE neonates, both of whom had maternal anti-Ro/La antibody exposure.
Results
Pooled bacteria-depleted fecal filtrates from NLE neonates potentiated IFN-α production by neonatal peripheral blood mononuclear cells (PBMCs) in the presence of anti-Ro/La-positive plasma.
Functional assays used bacteria-depleted fecal filtrates from NLE neonates.
Filtrates were combined with anti-Ro/La-positive plasma and applied to neonatal PBMCs.
NLE fecal filtrates potentiated IFN-α production compared to conditions without filtrate or with anti-Ro/La-negative plasma.
This finding supports a functional role for soluble microbial factors (not bacteria themselves) in amplifying autoantibody-driven IFN-α activation.
Results
Sodium butyrate suppressed anti-Ro/La-associated IFN-α production and reduced 28 inflammation-related proteins including CXCL10, ADA, and PD-L1.
Sodium butyrate was applied in functional assays to PBMCs stimulated with anti-Ro/La-positive plasma.
Butyrate treatment suppressed IFN-α production in this context.
28 inflammation-related proteins were reduced by sodium butyrate treatment.
Proteins reduced included CXCL10, ADA, and PD-L1, involved in cytokine, IL-17, and TNF signaling pathways.
These findings provide functional evidence for butyrate as a suppressor of autoantibody-driven type I interferon activation.
What This Means
This research suggests that the community of bacteria living in a newborn's gut may play an important role in determining whether babies born to mothers with lupus-related antibodies (anti-Ro/La antibodies) develop a condition called neonatal lupus erythematosus (NLE). By comparing the gut bacteria, their functional capabilities, and blood metabolites of 90 newborns—healthy babies, babies exposed to the antibodies but without NLE, and babies with NLE—the researchers found that NLE was associated with a distinct pattern of gut bacteria: fewer beneficial microbes like Bifidobacterium and more potentially problematic bacteria like Klebsiella. This shift in bacteria also corresponded to lower levels of a protective gut-derived molecule called butyrate, higher levels of an immune-activating protein called interferon-alpha (IFN-α), and higher antibody levels in the blood.
In laboratory experiments, the researchers showed that gut fluid from NLE babies (with the bacteria removed) made immune cells produce more IFN-α when combined with the mothers' lupus antibodies, suggesting that small molecules secreted by the gut microbiome—not the bacteria themselves—help amplify the immune response. When sodium butyrate was added, it reduced IFN-α production and dampened the activity of 28 other inflammation-related proteins, pointing to butyrate as a key molecule that may normally help protect against this immune overactivation.
This research suggests that the early-life gut microbiome, through its impact on butyrate production, may act as an important modifier of whether maternal lupus antibodies cause disease in newborns. A combination of bacterial, functional, and IFN-α markers distinguished NLE from antibody-exposed but healthy babies with high accuracy (AUC = 0.883), raising the possibility that gut microbiome-based approaches could one day help identify at-risk babies or inform new therapeutic strategies for neonatal lupus.
Sun W, Li Y, Liu X, Yu S, Li W, Wang H, et al.. (2026). Gut microbiota functional remodeling and butyrate depletion amplify anti-Ro/La antibody-driven type I interferon activation in neonatal lupus.. Gut microbes. https://doi.org/10.1080/19490976.2026.2728464