Browsing by Author "Mu, Qinghui"

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    Antibiotics ameliorate lupus-like symptoms in mice
    Mu, Qinghui; Tavella, Vincent J.; Kirby, Jay L.; Cecere, Thomas E.; Chung, Matthias; Lee, Jiyoung; Li, Song; Ahmed, Sattar Ansar; Eden, Kristin; Allen, Irving C. (Nature, 2017-10-20)
    Gut microbiota and the immune system interact to maintain tissue homeostasis, but whether this interaction is involved in the pathogenesis of systemic lupus erythematosus (SLE) is unclear. Here we report that oral antibiotics given during active disease removed harmful bacteria from the gut microbiota and attenuated SLE-like disease in lupus-prone mice. Using MRL/lpr mice, we showed that antibiotics given after disease onset ameliorated systemic autoimmunity and kidney histopathology. They decreased IL-17-producing cells and increased the level of circulating IL-10. In addition, antibiotics removed Lachnospiraceae and increased the relative abundance of Lactobacillus spp., two groups of bacteria previously shown to be associated with deteriorated or improved symptoms in MRL/lpr mice, respectively. Moreover, we showed that the attenuated disease phenotype could be recapitulated with a single antibiotic vancomycin, which reshaped the gut microbiota and changed microbial functional pathways in a time-dependent manner. Furthermore, vancomycin treatment increased the barrier function of the intestinal epithelium, thus preventing the translocation of lipopolysaccharide, a cell wall component of Gram-negative Proteobacteria and known inducer of lupus in mice, into the circulation. These results suggest that mixed antibiotics or a single antibiotic vancomycin ameliorate SLE-like disease in MRL/lpr mice by changing the composition of gut microbiota.
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    Control of lupus nephritis by changes of gut microbiota
    Mu, Qinghui; Zhang, Husen; Liao, Xiaofeng; Lin, Kaisen; Liu, Hualan; Edwards, Michael R.; Ahmed, Sattar Ansar; Yuan, Ruoxi; Li, Liwu; Cecere, Thomas E.; Branson, David B.; Kirby, Jay L.; Goswami, Poorna; Leeth, Caroline M.; Read, Kaitlin A.; Oestreich, Kenneth J.; Vieson, Miranda D.; Reilly, Christopher M.; Luo, Xin M. (2017-07-11)
    Background: Systemic lupus erythematosus, characterized by persistent inflammation, is a complex autoimmune disorder with no known cure. Immunosuppressants used in treatment put patients at a higher risk of infections. New knowledge of disease modulators, such as symbiotic bacteria, can enable fine-tuning of parts of the immune system, rather than suppressing it altogether. Results: Dysbiosis of gut microbiota promotes autoimmune disorders that damage extraintestinal organs. Here we report a role of gut microbiota in the pathogenesis of renal dysfunction in lupus. Using a classical model of lupus nephritis, MRL/lpr, we found a marked depletion of Lactobacillales in the gut microbiota. Increasing Lactobacillales in the gut improved renal function of these mice and prolonged their survival. We used a mixture of 5 Lactobacillus strains (Lactobacillus oris, Lactobacillus rhamnosus, Lactobacillus reuteri, Lactobacillus johnsonii, and Lactobacillus gasseri), but L. reuteri and an uncultured Lactobacillus sp. accounted for most of the observed effects. Further studies revealed that MRL/lpr mice possessed a “leaky” gut, which was reversed by increased Lactobacillus colonization. Lactobacillus treatment contributed to an anti-inflammatory environment by decreasing IL-6 and increasing IL-10 production in the gut. In the circulation, Lactobacillus treatment increased IL-10 and decreased IgG2a that is considered to be a major immune deposit in the kidney of MRL/lpr mice. Inside the kidney, Lactobacillus treatment also skewed the Treg-Th17 balance towards a Treg phenotype. These beneficial effects were present in female and castrated male mice, but not in intact males, suggesting that the gut microbiota controls lupus nephritis in a sex hormone-dependent manner. Conclusions: This work demonstrates essential mechanisms on how changes of the gut microbiota regulate lupusassociated immune responses in mice. Future studies are warranted to determine if these results can be replicated in human subjects.
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    Gut Microbiota and Bacterial DNA Suppress Autoimmunity by Stimulating Regulatory B Cells in a Murine Model of Lupus
    Mu, Qinghui; Edwards, Michael R.; Swartwout, Brianna K.; Cabana-Puig, Xavier; Mao, Jiangdi; Zhu, Jing; Grieco, Joseph P.; Cecere, Thomas E.; Prakash, Meeta; Reilly, Christopher M.; Puglisi, Christopher; Bachali, Prathyusha; Grammer, Amrie C.; Lipsky, Peter E.; Luo, Xin M. (2020-11-10)
    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.
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    Lactobacillus spp. act in synergy to attenuate splenomegaly and lymphadenopathy in lupus-prone MRL/lpr mice
    Cabana-Puig, Xavier; Mu, Qinghui; Lu, Ran; Swartwout, Brianna; Abdelhamid, Leila; Zhu, Jing; Prakash, Meeta; Cecere, Thomas E.; Wang, Zhuang; Callaway, Sabrina; Sun, Sha; Reilly, Christopher M.; Ahmed, S. Ansar; Luo, Xin M. (Frontiers, 2022-07-28)
    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.
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    Pregnancy and lactation interfere with the response of autoimmunity to modulation of gut microbiota
    Mu, Qinghui; Cabana-Puig, Xavier; Mao, Jiangdi; Swartwout, Brianna K.; Abdelhamid, Leila; Cecere, Thomas E.; Wang, Haifeng; Reilly, Christopher M.; Luo, Xin M. (2019-07-16)
    Background Dysbiosis of gut microbiota exists in the pathogenesis of many autoimmune diseases, including systemic lupus erythematosus (lupus). Lupus patients who experienced pregnancy usually had more severe disease flares post-delivery. However, the possible role of gut microbiota in the link between pregnancy and exacerbation of lupus remains to be explored. Results In the classical lupus mouse model MRL/lpr, we compared the structures of gut microbiota in pregnant and lactating individuals vs. age-matched naïve mice. Consistent with studies on non-lupus mice, both pregnancy and lactation significantly changed the composition and diversity of gut microbiota. Strikingly, modulation of gut microbiota using the same strategy resulted in different disease outcomes in postpartum (abbreviated as “PP,” meaning that the mice had undergone pregnancy and lactation) vs. control (naïve; i.e., without pregnancy or lactation) MRL/lpr females; while vancomycin treatment attenuated lupus in naïve mice, it did not do so, or even exacerbated lupus, in PP mice. Lactobacillus animalis flourished in the gut upon vancomycin treatment, and direct administration of L. animalis via oral gavage recapitulated the differential effects of vancomycin in PP vs. control mice. An enzyme called indoleamine 2,3-dioxygenase was significantly inhibited by L. animalis; however, this inhibition was only apparent in PP mice, which explained, at least partially, the lack of beneficial response to vancomycin in these mice. The differential production of immunosuppressive IL-10 and proinflammatory IFNγ in PP vs. control mice further explained why the disease phenotypes varied between the two types of mice bearing the same gut microbiota remodeling strategy. Conclusions These results suggest that pregnancy and lactation interfere with the response of autoimmunity to modulation of gut microbiota. Further studies are necessary to better understand the complex relationship between pregnancy and lupus.
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    Quaternary Ammonium Compound Disinfectants Reduce Lupus-Associated Splenomegaly by Targeting Neutrophil Migration and T-Cell Fate
    Abdelhamid, Leila; Cabana-Puig, Xavier; Mu, Qinghui; Moarefian, Maryam; Swartwout, Brianna K.; Eden, Kristin; Das, Prerna; Seguin, Ryan P.; Xu, Libin; Lowen, Sarah; Lavani, Mital; Hrubec, Terry C.; Jones, Caroline N.; Luo, Xin M. (2020-10-21)
    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.
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    Regulation of neonatal IgA production by the maternal microbiota
    Mu, Qinghui; Swartwout, Brianna K.; Edwards, Michael R.; Zhu, Jing; Lee, Grace; Eden, Kristin; Cabana-Puig, Xavier; McDaniel, Dylan K.; Mao, Jiangdi; Abdelhamid, Leila; Brock, Rebecca M.; Allen, Irving C.; Reilly, Christopher M.; Luo, Xin M. (National Academy of Sciences, 2021-02-22)
    Infants are prone to enteric infections due to an underdeveloped immune system. The maternal microbiota, through shaping the neonatal microbiota, helps establish a strong immune system in infants. We and others have observed the phenomenon of enhanced early neonatal immunoglobulin A (IgA) production in preweaning immunocompetent mice nursed by immunodeficient dams. Here, we show that this enhancement of IgA in neonates results from maternally derived microbiota. In addition, we have found that the neonatal IgA production can be induced by Lactobacillus reuteri, which is enriched in the milk of immunodeficient dams. Moreover, we show that while the production of neonatal IgA is dependent on neonatal T cells, the immunodeficient maternal microbiota-mediated enhancement of neonatal IgA has a T cell– independent component. Indeed, this enhancement may be dependent on type 3 innate lymphoid cells in the neonatal small intestinal lamina propria. Interestingly, maternal microbiotainduced neonatal IgA does not cross-react with common enteric pathogens. Future investigations will determine the functional consequences of having this extra IgA.
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    Role of Lactobacillus reuteri in Human Health and Diseases
    Mu, Qinghui; Tavella, Vincent J.; Luo, Xin M. (Frontiers, 2018-04-19)
    Lactobacillus reuteri (L. reuteri) is a well-studied probiotic bacterium that can colonize a large number of mammals. In humans, L. reuteri is found in different body sites, including the gastrointestinal tract, urinary tract, skin, and breast milk. The abundance of L. reuteri varies among different individuals. Several beneficial effects of L. reuteri have been noted. First, L. reuteri can produce antimicrobial molecules, such as organic acids, ethanol, and reuterin. Due to its antimicrobial activity, L. reuteri is able to inhibit the colonization of pathogenic microbes and remodel the commensal microbiota composition in the host. Second, L. reuteri can benefit the host immune system. For instance, some L. reuteri strains can reduce the production of pro-inflammatory cytokines while promoting regulatory T cell development and function. Third, bearing the ability to strengthen the intestinal barrier, the colonization of L. reuteri may decrease the microbial translocation from the gut lumen to the tissues. Microbial translocation across the intestinal epithelium has been hypothesized as an initiator of inflammation. Therefore, inflammatory diseases, including those located in the gut as well as in remote tissues, may be ameliorated by increasing the colonization of L. reuteri. Notably, the decrease in the abundance of L. reuteri in humans in the past decades is correlated with an increase in the incidences of inflammatory diseases over the same period of time. Direct supplementation or prebiotic modulation of L. reuteri may be an attractive preventive and/or therapeutic avenue against inflammatory diseases.
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    The role of gut microbiota in systemic lupus erythematosus
    Mu, Qinghui (Virginia Tech, 2018-04-19)
    Systemic lupus erythematosus (SLE) is a multi-system autoimmune disease with no known cure. Despite years of study, the etiology of SLE is still unclear. Both genetic and environmental factors have been implicated in the disease mechanisms. Gut microbiota as an environmental factor and the immune system interact to maintain tissue homeostasis, but whether this interaction is involved in the pathogenesis of SLE is unclear. In a classical model of lupus nephritis, MRL/lpr, we found decrease of Lactobacillales but increase of Lachnospiraceae in the gut microbiota. Increasing Lactobacillales in the gut by suppling a mixture of 5 Lactobacillus strains improved renal function of these mice and prolonged their survival. Further studies revealed that MRL/lpr mice possessed a "leaky" gut, which was reversed by increased Lactobacillus colonization. Inside the kidney, oral Lactobacillus treatment also skewed the Treg-Th17 balance towards a Treg phenotype. To remove Lachnospiraceae that was higher in lupus-prone mice than controls, we administered vancomycin orally to MRL/lpr mice after disease onset from 9 to 15 weeks of age. Vancomycin functions by removing Gram-positive bacteria such as Lachnospiraceae but sparing Lactobacillus spp. The treatment during active lupus reshaped the gut microbiota and significantly ameliorated systemic autoimmunity and kidney histopathology at 15 weeks of age. However, when vancomycin treatment was initiated from a very early age, the beneficial effect was not observed. Strikingly, mice given vancomycin only at the young age exhibited an even worse disease outcome. Indeed, regulatory B (Breg) cells were found to be reduced after the vancomycin treatment at young age. Importantly, adoptive transfer of Breg cells at 6-7 weeks of age rescued the beneficial effect, which indicates that Breg cells, inducible by vancomycin-sensitive gut microbiota, plays an important role in suppressing lupus disease initiation and progression. Finally, we demonstrated that bacterial DNA from the gut microbiota might be the inducer of Breg cells, as bacterial DNA administration at young age reproduced the beneficial effect seen in the Breg adoptive transfer experiment. Future studies are required to examine the clinical efficacy of targeting gut microbiota as a novel treatment against SLE.