Role of intestinal host-microbe interactions in lupus pathogenesis

Lupus is a complex disease where the immune system mistakenly targets the body’s own tissues (autoimmunity), causing chronic inflammation and damage to multiple organs. Although current treatments primarily aim to suppress the immune system, they often fail to address the underlying causes, which can result in harmful side effects. The role of genetic and environmental factors in lupus progression, including the gut microbiome, is an area of growing interest, as imbalances in gut bacteria (dysbiosis) are linked to the development and worsening of the disease.

Dr. Zegarra-Ruiz aims to understand how specific gut bacteria, known as pathobionts, contribute to the development and progression of lupus. Using mouse models of lupus, he plans to investigate how these bacteria alter the gut environment and potentially trigger widespread inflammation and immune responses associated with the disease. His research will also investigate how bacteria moving from the gut to other parts of the body—called bacterial translocation—could contribute to lupus symptoms. Additionally, he will explore how different diets influence the gut microbiome, with a particular focus on how they may promote the overgrowth and harmful behavior of pathobionts. The goal is to find out which dietary factors could help slow down or possibly worsen lupus progression. Ultimately, this study aims to deepen our understanding of the link between gut health and lupus, opening up new possibilities for interventions that could improve patient outcomes.

What this means for people with lupus:

Findings from Dr. Zegarra-Ruiz’s study could lead to new insights into how the gut microbiome affects lupus development and progression. By identifying how certain bacteria and dietary factors influence lupus, this study may open up new possibilities for more targeted and personalized treatments that could reduce disease severity and improve the quality of life for people living with lupus.

Autoimmune diseases are a significant health problem affecting over 200 million people worldwide and represent one of the leading causes of death for women under 65 years old. Although these pathologies are increasing in prevalence, current treatments are primarily aimed at suppressing the immune system without treating the cause, leading to serious side effects. Systemic lupus erythematosus (SLE) is a prototypical autoimmune disease leading to chronic inflammation in multiple organs due to adaptive immune responses to self-antigens. Although the etiology of autoimmunity remains unknown, numerous autoimmune diseases, including SLE, are linked with intestinal microbiota alterations, known as intestinal dysbiosis. In lupus, intestinal dysbiosis is characterized by a loss of beneficial commensals and an enrichment of bacteria that exacerbate pathogenesis, known as pathobionts. We previously found a diet-sensitive pathobiont that translocated to extraintestinal tissues and worsened lupus pathogenesis by exacerbating type I interferon secretion and increasing proinflammatory T cells. Further, we and others have found several additional pathobionts in the oral and intestinal mucosa of mouse models of lupus and SLE patients that can alter the initiation and propagation of systemic and tissue-specific autoimmunity through induction of interferons, T helper skewing, or cross-reactive adaptive immune responses. Using inducible and spontaneous mouse models of lupus based on dysregulated inflammatory pathways involved in clinical manifestations, we will test the hypothesis that intestinal pathobionts drive lupus development by altering the intestinal environment, which leads to microbial antigen spreading and proinflammatory pathobiont-specific T cell expansion. My research program will accomplish this by pursuing the following aims: 1. Intestinal dysbiosis, altered antimicrobial peptide expression, and dysregulation of tight junction proteins are found in mouse models of lupus. However, how intestinal microbes promote these dysregulations remains unknown. We will assess how lupus pathobionts and progression alter the intestinal milieu and how these changes exacerbate systemic autoimmunity. 2. Extraintestinal pathobiont translocation occurs in lupus. However, the role of microbes in normally sterile sites has yet to be established. We will determine how pathobiont translocation drives lupus pathogenesis. 3. Diet-induced short-chain fatty acids ameliorate lupus pathogenesis by suppressing Lactobacillus reuteri outgrowth and translocation. However, we have yet to discover the effects of various diets and microbial metabolites on this and other pathobionts. We will elucidate how diets regulate lupus progression by modulating the intestinal microbial landscape.