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Systemic lupus erythematosus (SLE) is a multi-system autoimmune disease. Despite years of study, the etiology of SLE is still unclear. Both genetic and environmental factors have been implicated in the disease mechanisms. In the past decade, a growing body of evidence has indicated an important role of gut microbes in the development of autoimmune diseases, including type 1 diabetes, rheumatoid arthritis and multiple sclerosis. However, such knowledge on SLE is little, though we have already known that environmental factors can trigger the development of lupus. Several recent studies have suggested that alterations of the gut microbial composition may be correlated with SLE disease manifestations, while the exact roles of either symbiotic or pathogenic microbes in this disease remain to be explored. Elucidation of the roles of gut microbes—as well as the roles of diet that can modulate the composition of gut microbes—in SLE will shed light on how this autoimmune disorder develops, and provide opportunities for improved biomarkers of the disease and the potential to probe new therapies. In this review, we aim to compile the available evidence on the contributions of diet and gut microbes to SLE occurrence and pathogenesis.

Systemic lupus erythematosus (SLE) is a systemic chronic disease initiated by an abnormal immune response to self and can affect multiple organs. SLE is characterized by the production of autoantibodies and the deposition of immune complexes. In regard to the clinical observations assessed by rheumatologists, several chemokines and cytokines also contribute to disease progression. One such chemokine and adhesion molecule is CX3CL1 (otherwise known as fractalkine). CX3CL1 is involved in cell trafficking and inflammation through recognition by its receptor, CX3CR1. The CX3CL1 protein consists of a chemokine domain and a mucin-like stalk that allows it to function both as a chemoattractant and as an adhesion molecule. In inflammation and specifically lupus, the literature displays contradictory evidence for the functions of CX3CL1/CX3CR1 interactions. In addition, the gut microbiota has been shown to play an important role in the pathogenesis of SLE. This review highlights current studies that illustrate the interactions of the gut microbiota and CX3CR1 in SLE.

IntroductionLeaky gut has been linked to autoimmune disorders including lupus. We previously reported upregulation of anti-flagellin antibodies in the blood of lupus patients and lupus-prone mice, which led to our hypothesis that a leaky gut drives lupus through bacterial flagellin-mediated activation of toll-like receptor 5 (TLR5).MethodsWe created MRL/lpr mice with global Tlr5 deletion through CRISPR/Cas9 and investigated lupus-like disease in these mice.ResultContrary to our hypothesis that the deletion of Tlr5 would attenuate lupus, our results showed exacerbation of lupus with Tlr5 deficiency in female MRL/lpr mice. Remarkably higher levels of proteinuria were observed in Tlr5-/- MRL/lpr mice suggesting aggravated glomerulonephritis. Histopathological analysis confirmed this result, and Tlr5 deletion significantly increased the deposition of IgG and complement C3 in the glomeruli. In addition, Tlr5 deficiency significantly increased renal infiltration of Th17 and activated cDC1 cells. Splenomegaly and lymphadenopathy were also aggravated in Tlr5-/- MRL/lpr mice suggesting impact on lymphoproliferation. In the spleen, significant decreased frequencies of regulatory lymphocytes and increased germinal centers were observed with Tlr5 deletion. Notably, Tlr5 deficiency did not change host metabolism or the existing leaky gut; however, it significantly reshaped the fecal microbiota.ConclusionGlobal deletion of Tlr5 exacerbates lupus-like disease in MRL/lpr mice. Future studies will elucidate the underlying mechanisms by which Tlr5 deficiency modulates host-microbiota interactions to exacerbate lupus.

IntroductionB cells can have both pathogenic and protective roles in autoimmune diseases, including systemic lupus erythematosus (SLE). Deficiencies in the number or immunosuppressive function of IL-10 producing regulatory B cells (Bregs) can cause exacerbated autoimmune inflammation. However, the exact role of Bregs in lupus pathogenesis has not been elucidated.MethodsWe carried out gene expression analysis by scRNA-seq to characterize differences in splenic Breg subsets and molecular profiles through stages of disease progression in lupus-prone mice. Transcriptome-based changes in Bregs from mice with active disease were confirmed by phenotypic analysis.ResultsWe found that a loss of marginal zone (MZ) lineage Bregs, an increase in plasmablast/plasma cell (PB-PC) lineage Bregs, and overall increases in inflammatory gene signatures were characteristic of active disease as compared to Bregs from the pre-disease stage. However, the frequencies of both MZ Bregs and PB-PCs expressing IL-10 were significantly decreased in active-disease mice.ConclusionOverall, we have identified changes to the repertoire and transcriptional landscape of Breg subsets associated with active disease that provide insights into the role of Bregs in lupus pathogenesis. These results could inform the design of Breg-targeted therapies and interventions to restore Breg suppressive function in autoimmunity.

NLRP12 has dual roles in shaping inflammation. We hypothesized that NLRP12 would modulate myeloid cells and T cell function to control systemic autoimmunity. Contrary to our hypothesis, the deficiency of Nlrp12 in autoimmune-prone B6.Faslpr/lpr mice ameliorated autoimmunity in males but not females. Nlrp12 deficiency dampened B cell terminal differentiation, germinal center reaction, and survival of autoreactive B cells leading to decreased production of autoantibodies and reduced renal deposition of IgG and complement C3. In parallel, Nlrp12 deficiency reduced the expansion of potentially pathogenic T cells, including double-negative T cells and T follicular helper cells. Furthermore, reduced pro-inflammatory innate immunity was observed, where the gene deletion decreased in-vivo expansion of splenic macrophages and mitigated ex-vivo responses of bone marrow-derived macrophages and dendritic cells to LPS stimulation. Interestingly, Nlrp12 deficiency altered the diversity and composition of fecal microbiota in both male and female B6/lpr mice. Notably, however, Nlrp12 deficiency significantly modulated small intestinal microbiota only in male mice, suggesting that the sex differences in disease phenotype might be gut microbiota-dependent. Together, these results suggest a potential pathogenic role of NLRP12 in promoting systemic autoimmunity in males. Future studies will investigate sex-based mechanisms through which NLRP12 differentially modulates autoimmune outcomes.

Commensal bacteria and the immune system have a close and strong relationship that maintains a balance to control inflammation. Alterations of the microbiota, known as dysbiosis, can direct reactivity to self-antigens not only in the intestinal mucosa but also at the systemic level. Our laboratory previously reported gut dysbiosis, particularly lower abundance of bacteria in the family Lactobacillaceae, in lupus-prone MRL/lpr mice, a model of systemic autoimmunity. Restoring the microbiota with a mix of 5 different Lactobacillus species (spp.), L. reuteri, L. oris, L. johnsonii, L. gasseri and L. rhamnosus, attenuated lupus-liked clinical signs, including splenomegaly and lymphadenopathy. However, our understanding of the mechanism was limited. In this study, we first investigated the effects of individual species. Surprisingly, none of the species individually recapitulated the benefits of the mix. Instead, Lactobacillus spp. acted synergistically to attenuate splenomegaly and renal lymphadenopathy through secreted factors and a CX3CR1-dependent mechanism. Interestingly, oral administration of MRS broth exerted the same benefits likely through increasing the relative abundance of endogenous Lactobacillus spp. Mechanistically, we found increased percentages of FOXP3-negative type 1 regulatory T cells with administration of the mix in both spleen and mesenteric lymph nodes. In addition, oral gavage of Lactobacillus spp. decreased the percentage of central memory T cells while increasing that of effector memory T cells in the lymphoid organs. Furthermore, a decreased percentage of double negative T cells was observed in the spleen with the mix. These results suggest that Lactobacillus spp. might act on T cells to attenuate splenomegaly and lymphadenopathy. Together, this study advances our understanding of how Lactobacillus spp. attenuate lupus in MRL/lpr mice. The synergistic action of these bacteria suggests that multiple probiotic bacteria in combination may dampen systemic autoimmunity and benefit lupus patients.

With the rising prevalence of autoimmune diseases, the role of the environment, specifically the gut microbiota, in disease development has grown to be a major area of study. Recent advances show a relationship and possible cause and effect between the gut microbiota and the initiation or exacerbation of autoimmune diseases. Furthermore, microbial dysbiosis and leaky gut are frequent phenomena in both human autoimmune diseases and the murine autoimmunity models. This review will focus on literature in recent years concerning the gut microbiota and leaky gut in relation to the autoimmune diseases, including systemic lupus erythematosus, type 1 diabetes, and multiple sclerosis.

The immune system is an efficiently toned machinery that discriminates between friends and foes for achieving both host defense and homeostasis. Deviation of immune recognition from foreign to self and/or long-lasting inflammatory responses results in the breakdown of tolerance. Meanwhile, educating the immune system and developing immunological memory are crucial for mounting defensive immune responses while protecting against autoimmunity. Still to elucidate is how diverse environmental factors could shape autoimmunity. The emergence of a world pandemic such as SARS-CoV-2 (COVID-19) not only threatens the more vulnerable individuals including those with autoimmune conditions but also promotes an unprecedented shift in people’s dietary approaches while urging for extraordinary hygiene measures that likely contribute to the development or exacerbation of autoimmunity. Thus, there is an urgent need to understand how environmental factors modulate systemic autoimmunity to better mitigate the incidence and or severity of COVID-19 among the more vulnerable populations. Here, we discuss the effects of diet (macronutrients and micronutrients) and hygiene (the use of disinfectants) on autoimmunity with a focus on systemic lupus erythematosus.

Background: Intermittent fasting (IF) can reduce energy intake and body weight (BW). Melatonin has many known functions, which include reducing appetite and preventing excessive weight gain.Objective: This study aimed to investigate the effects of IF on body fat and the gut microbiota and metabolome as well as a potential interaction with melatonin.Methods: Male C57BL/6J mice (23.0 ± 0.9 g, 6 wk old) were randomly assigned into four groups (12 mice/group): control (C), intermittent fasting (F), melatonin (M), and intermittent fasting plus melatonin (MF). The C and M groups mice were provided with ad libitum access to food and water, while the F and MF groups underwent alternative-day feed deprivation (15 cycles total). Melatonin was administered in the drinking water of the M and MF groups. Blood, epididymal fat, liver tissue, and intestinal tissue and contents were collected for lab measurements, histology, and microbiota and metabolome analysis. Main effects and interactions were tested by 2-factor ANOVA.Results: IF significantly reduced BW gain and serum glucose, total cholesterol (TC) and triglyceride (TG) levels. Adipocyte size significantly decreased with IF, then the number of adipocytes per square millimeter significantly increased (P < 0.05). Compared to the C group, the M and MF groups had significantly higher serum melatonin levels (17 and 21%, respectively), although melatonin monotherapy had no effect on serum parameters and adipocytes. There was no interaction between IF and melatonin on BW gain and serum parameters except for on adipocyte area and number per square millimeter, Bacteroidetes and Akkermansia bacterial abundance, and the levels of the intestinal metabolites alanine, valine and isoleucine. IF changed the intestinal microbiota structure, with the F and MF groups clearly separating from the C and M groups. Metabolomic analysis showed that there was obvious separation between all four groups.Conclusions: IF, but neither melatonin nor the interaction between IF and melatonin, could alter intestinal microbiota and metabolism and prevent obesity by reducing BW gain, serum glucose, TC, and TG, and adipocyte size in mice.

Autoimmune diseases, such as systemic lupus erythematosus, are characterized by excessive inflammation in response to self-antigens. Loss of appropriate immunoregulatory mechanisms contribute to disease exacerbation. We previously showed the suppressive effect of vancomycin treatment during the “active-disease” stage of lupus. In this study, we sought to understand the effect of the same treatment given before disease onset. To develop a model in which to test the regulatory role of the gut microbiota in modifying autoimmunity, we treated lupus-prone mice with vancomycin in the period before disease development (3–8 weeks of age). We found that administration of vancomycin to female MRL/lpr mice early, only during the pre-disease period but not from 3 to 15 weeks of age, led to disease exacerbation. Early vancomycin administration also reduced splenic regulatory B (Breg) cell numbers, as well as reduced circulating IL-10 and IL-35 in 8-week old mice. Further, we found that during the pre-disease period, administration of activated IL-10 producing Breg cells to mice treated with vancomycin suppressed lupus initiation, and that bacterial DNA from the gut microbiota was an inducer of Breg function. Oral gavage of bacterial DNA to mice treated with vancomycin increased Breg cells in the spleen and mesenteric lymph node at 8 weeks of age and reduced autoimmune disease severity at 15 weeks. This work suggests that a form of oral tolerance induced by bacterial DNA-mediated expansion of Breg cells suppress disease onset in the autoimmune-prone MRL/lpr mouse model. Future studies are warranted to further define the mechanism behind bacterial DNA promoting Breg cells.

Hypersensitivity reactions and immune dysregulation have been reported with the use of quaternary ammonium compound disinfectants (QACs). We hypothesized that QAC exposure would exacerbate autoimmunity associated with systemic lupus erythematosus (lupus). Surprisingly, however, we found that compared to QAC-free mice, ambient exposure of lupus-prone mice to QACs led to smaller spleens with no change in circulating autoantibodies or the severity of glomerulonephritis. This suggests that QACs may have immunosuppressive effects on lupus. Using a microfluidic device, we showed that ambient exposure to QACs reduced directional migration of bone marrow-derived neutrophils toward an inflammatory chemoattractant ex vivo. Consistent with this, we found decreased infiltration of neutrophils into the spleen. While bone marrow-derived neutrophils appeared to exhibit a pro-inflammatory profile, upregulated expression of PD-L1 was observed on neutrophils that infiltrated the spleen, which in turn interacted with PD-1 on T cells and modulated their fate. Specifically, QAC exposure hindered activation of splenic T cells and increased apoptosis of effector T-cell populations. Collectively, these results suggest that ambient QAC exposure decreases lupus-associated splenomegaly likely through neutrophil-mediated toning of T-cell activation and/or apoptosis. However, our findings also indicate that even ambient exposure could alter immune cell phenotypes, functions, and their fate. Further investigations on how QACs affect immunity under steady-state conditions are warranted.

The intestine is a particularly dynamic environment in which the host constantly interacts with trillions of symbiotic bacteria called the microbiota. Using quorum sensing (QS) communication, bacteria can coordinate their social behavior and influence host cell activities in a non-invasive manner. Nowadays, a large amount of research has greatly spurred the understanding of how bacterial QS communication regulates bacterial cooperative behaviors due to coexistence and host-microbe interactions. In this review, we discuss bacterial QS in the gut and its role in biofilm formation. As a biological barrier, the mucosal immune system can effectively prevent pathogenic microorganisms and other immunogenic components from entering the internal environment of the host. We focus on the relationship between biofilm and intestinal mucosal immunity, and how probiotic bacteria may regulate them. This review is to provide a theoretical basis for the development of new techniques including probiotics targeting the intestinal barrier function, thereby improving gut health.

We previously showed that all-trans-retinoic acid (tRA), an active metabolite of vitamin A, exacerbated pre-existing autoimmunity in lupus; however, its effects before the development of autoimmunity are unknown. Here, using a pristane-induced model, we show that tRA exerts differential effects when given at the initiation vs. continuation phase of lupus. Unlike tRA treatment during active disease, pre-pristane treatment with tRA aggravated glomerulonephritis through increasing renal expression of pro-fibrotic protein laminin β1, activating bone marrow conventional dendritic cells (cDCs), and upregulating the interaction of ICAM-1 and LFA-1 in the spleen, indicating an active process of leukocyte activation and trafficking. Transcriptomic analysis revealed that prior to lupus induction, tRA significantly upregulated the expression of genes associated with cDC activation and migration. Post-pristane tRA treatment, on the other hand, did not significantly alter the severity of glomerulonephritis; rather, it exerted immunosuppressive functions of decreasing circulatory and renal deposition of autoantibodies as well as suppressing the renal expression of proinflammatory cytokines and chemokines. Together, these findings suggest that tRA differentially modulate lupus-associated kidney inflammation depending on the time of administration. Interestingly, both pre- and post-pristane treatments with tRA reversed pristane-induced leaky gut and modulated the gut microbiota in a similar fashion, suggesting a gut microbiota-independent mechanism by which tRA affects the initiation vs. continuation phase of lupus.

Probiotics are being investigated for the treatment of autoimmune disease by re-balancing dysbiosis induced changes in the immune system. Pregnancy is a health concern surrounding autoimmune disease, both for the mother and her child. Probiotics for maternity are emerging on the market and have gained significant momentum in the literature. Thus far, evidence supports that probiotics alter the structure of the normal microbiota and the microbiota changes significantly during pregnancy. The interaction between probiotics-induced changes and normal changes during pregnancy is poorly understood. Furthermore, there is emerging evidence that the maternal gut microbiota influences the microbiota of offspring, leading to questions on how maternal probiotics may influence the health of neonates. Underpinning the development and balance of the immune system, the microbiota, especially that of the gut, is significantly important, and dysbiosis is an agent of immune dysregulation and autoimmunity. However, few studies exist on the implications of maternal probiotics for the outcome of pregnancy in autoimmune disease. Is it helpful or harmful for mother with autoimmune disease to take probiotics, and would this be protective or pathogenic for her child? Controversy surrounds whether probiotics administered maternally or during infancy are healthful for allergic disease, and their use for autoimmunity is relatively unexplored. This review aims to discuss the use of maternal probiotics in health and autoimmune disease and to investigate their immunomodulatory properties.

The intestinal epithelial lining, together with factors secreted from it, forms a barrier that separates the host from the environment. In pathologic conditions, the permeability of the epithelial lining may be compromised allowing the passage of toxins, antigens, and bacteria in the lumen to enter the blood stream creating a “leaky gut.” In individuals with a genetic predisposition, a leaky gut may allow environmental factors to enter the body and trigger the initiation and development of autoimmune disease. Growing evidence shows that the gut microbiota is important in supporting the epithelial barrier and therefore plays a key role in the regulation of environmental factors that enter the body. Several recent reports have shown that probiotics can reverse the leaky gut by enhancing the production of tight junction proteins; however, additional and longer term studies are still required. Conversely, pathogenic bacteria that can facilitate a leaky gut and induce autoimmune symptoms can be ameliorated with the use of antibiotic treatment. Therefore, it is hypothesized that modulating the gut microbiota can serve as a potential method for regulating intestinal permeability and may help to alter the course of autoimmune diseases in susceptible individuals.