Systemic effect of combined microbiome-derived mediators on lupus

The gut microbiome is a community of small organisms that live in the body, including trillions of bacteria. They play a powerful role in shaping the immune system. Recent studies suggest that molecules produced by these microbes- microbiome-derived molecules (MDMs) may contribute to the development and severity of autoimmune diseases like lupus. In recent research, Dr. Babdor identified a group of healthy individuals who had a high-inflammatory immune states, marked by increased interferon levels, a key feature often seen in lupus. These individuals also had elevated levels of a specific combination of MDMs in their gut, pointing to a potential link between MDMs and immune states.

Building on these findings, Dr. Babdor will now explore whether the same combination of MDMs contributes to lupus in ways that influence how the disease starts, how severe it becomes, and how well people respond to treatment. His team will first test these molecules in model organisms with lupus to observe their effects on disease progression, immune alterations, and treatment efficacy. They will then investigate how MDMs create different immune states, exploring their impact on chromatin remodeling (the process of changing how DNA is packaged in the cell) in immune cells called monocytes. Uncovering how MDMs contribute to the complexity of lupus could lead to the development of personalized therapeutic approaches.

What this means for people with lupus:

Findings from Dr. Babdor’s study could help explain why lupus varies so widely from person to person and why some treatments work better for some than others. It may also open the door to new, more personalized therapies that consider the role of gut microbes in shaping the immune system.

The human microbiome profoundly influences immunity, with implications for autoimmune diseases like lupus. While individual microbiome-derived molecules (MDMs) have been linked to lupus development and severity, their systems-level role in shaping immune states remains underexplored. Our recent human cohort study identified a distinct immunological state marked by systemic interferon (IFN) activity, associated with elevated fecal levels of 11 MDMs spanning three classes: short-chain fatty acids, bile acids, and polyamines. Given the central role of IFN in lupus pathogenesis, we hypothesize that these combined MDMs synergistically drive high-IFN immune states, contributing to lupus heterogeneity and treatment response variability. Aim 1: To evaluate the effects of combined high-IFN-associated MDMs on lupus disease onset, severity, and treatment response, we will conduct in vivo experiments using lupus mouse models. Mice exposed to these MDMs will be monitored for disease progression, immune landscape alterations, and treatment efficacy. Preliminary data indicate these MDMs elevate baseline IFN-stimulated gene (ISG) expression and amplify immune responses to bacterial products in monocytes. Systems-level insights will reveal how microbiome-driven immune modulation contributes to clinical variability in lupus. Aim 2: To elucidate the systemic mechanisms by which high-IFN MDMs drive immune states, we will investigate their impact on chromatin remodeling in monocytes. Transcriptomic analyses from our cohort revealed differential expression of chromatin regulators, including IFN-responsive genes. Functional studies will assess the role of key regulators (e.g., XAF1, SP110) using CRISPRbased knockout models and CUT&RUN profiling. Additionally, a CRISPR-Cas9 screen targeting 396 chromatin regulators will identify pathways modulated by MDMs. These efforts aim to uncover epigenetic mechanisms linking microbiome cues to immune regulation. This study will provide unprecedented insight into how microbiome-derived signals orchestrate systemic immune states, revealing novel targets for therapeutic intervention. By decoding the interplay between MDMs, chromatin dynamics, and IFN-driven immunity, we aim to advance personalized approaches for lupus management, improving treatment outcomes and patient quality of life.