Phenotypic Drift in Lupus-Prone MRL/lpr Mice: Potential Roles of MicroRNAs and Gut Microbiota

Cabana-Puig, Xavier; Bond, Jacob M.; Wang, Zhuang; Dai, Rujuan; Lu, Ran; Lin, Amy; Oakes, Vanessa J.; Rizzo, Amy; Swartwout, Brianna; Abdelhamid, Leila; Mao, Jiangdi; Prakash, Meeta; Sangmeister, Constanza; Cheung, Nathaniel; Cowan, Catharine; Reilly, Christopher M.; Sun, Sha; Ahmed, S. Ansar; Luo, Xin

doi:10.4049/immunohorizons.2100082

Cited by 8 publications

(6 citation statements)

References 30 publications

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“…We thus tested the levels of proteinuria, but no differences were found except for L. johnsonii , which significantly exacerbated glomerulonephritis over the PBS control ( Figure 1E ). Notably, the MRL/ lpr mice in our in-house colony, similar to those housed at The Jackson Laboratory, have lost the kidney disease phenotype ( 25 ), leading to low levels of proteinuria throughout the experiment. As expected, kidney histopathological analysis revealed no difference in glomerular and tubulointerstitial lesions as well as leukocyte infiltration ( Supplementary Figure 1 ).…”

Section: Resultsmentioning

confidence: 99%

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Lactobacillus spp. act in synergy to attenuate splenomegaly and lymphadenopathy in lupus-prone MRL/lpr mice

Cabana-Puig

et al. 2022

Front. Immunol.

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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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Section: Resultsmentioning

confidence: 99%

“…We recently published a study where disease manifestations in MRL/ lpr mice can differ among animal facilities, suggesting a role for environment factors ( 25 ). Notably, the gene loci responsible for splenomegaly and lymphadenopathy, which are chromosomes 4, 5 and 7, are not the same as that for glomerulonephritis, which is chromosome 10.…”

Section: Discussionmentioning

confidence: 99%

Lactobacillus spp. act in synergy to attenuate splenomegaly and lymphadenopathy in lupus-prone MRL/lpr mice

Cabana-Puig

et al. 2022

Front. Immunol.

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“…It has also been recently shown that Alcaligenaceae , Lachnospiraceae, and Ruminococcus torques groups had a tendency to causally decrease the risk of CKD [ 75 ]. Lower levels of Lachnospiraceae are linked to diseases such as splenomegaly, lymphadenopathy, glomerulonephritis, and other renal diseases [ 76 ]. Our finding of a strong correlation between low Lachnospiraceae abundance in GWI+ AB mice and higher miR-21 levels and kidney pathology provides a further mechanistic understanding of the risk of CKD in GWI veterans.…”

Section: Discussionmentioning

confidence: 99%

Prolonged Antibiotic Use in a Preclinical Model of Gulf War Chronic Multisymptom-Illness Causes Renal Fibrosis-like Pathology via Increased micro-RNA 21-Induced PTEN Inhibition That Is Correlated with Low Host Lachnospiraceae Abundance

Trivedi,

Bose,

Saha

et al. 2023

Cells

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Gulf War (GW) veterans show gastrointestinal disturbances and gut dysbiosis. Prolonged antibiotic treatments commonly employed in veterans, especially the use of fluoroquinolones and aminoglycosides, have also been associated with dysbiosis. This study investigates the effect of prolonged antibiotic exposure on risks of adverse renal pathology and its association with gut bacterial species abundance in underlying GWI and aims to uncover the molecular mechanisms leading to possible renal dysfunction with aging. Using a GWI mouse model, administration of a prolonged antibiotic regimen involving neomycin and enrofloxacin treatment for 5 months showed an exacerbated renal inflammation with increased NF-κB activation and pro-inflammatory cytokines levels. Involvement of the high mobility group 1 (HMGB1)-mediated receptor for advanced glycation end products (RAGE) activation triggered an inflammatory phenotype and increased transforming growth factor-β (TGF-β) production. Mechanistically, TGF-β- induced microRNA-21 upregulation in the renal tissue leads to decreased phosphatase and tensin homolog (PTEN) expression. The above event led to the activation of protein kinase-B (AKT) signaling, resulting in increased fibronectin production and fibrosis-like pathology. Importantly, the increased miR-21 was associated with low levels of Lachnospiraceae in the host gut which is also a key to heightened HMGB1-mediated inflammation. Overall, though correlative, the study highlights the complex interplay between GWI, host gut dysbiosis, prolonged antibiotics usage, and renal pathology via miR-21/PTEN/AKT signaling.

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“…The connection between gut microbiota and lupus phenotype was further reinforced by the observation that a colony of MRL/lpr mice with a milder disease phenotype had an altered gut microbiota profile [23].…”

Section: Gut Bacterial Compositionmentioning

confidence: 99%

“…A total of 29 studies were included in this review, twelve of which used mouse models [14][15][16][17][18][19][20][21][22][23][24][25], fifteen included SLE patients [26][27][28][29][30][31][32][33][34][35][36][37][38][39][40], and two both [41,42].…”

Section: Characterization Of the Selected Studiesmentioning

confidence: 99%

Let’s review the gut microbiota in systemic lupus erythematosus

Almada-Correia

Costa-Reis

Guerreiro

et al. 2022

Exploration of Medicine

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Systemic lupus erythematosus (SLE) is a chronic, immune-mediated disease associated with significant morbidity and mortality. New evidence suggests that diet, gut microbiota, intestinal permeability, and endotoxemia may modulate chronic inflammation and disease activity in SLE. This review focus on what is known about the gut microbiota in lupus mouse models and SLE patients and the possible mechanisms that connect the gut microbiota with SLE. It included 29 studies (12 animal studies, 15 human studies, and 2 included data on both), with variable results regarding alpha and beta-diversity and gut microbiota composition between lupus-mouse models and SLE patients. Ruminococcus (R.) gnavus was significantly increased in lupus nephritis (LN) in one study, but this was not corroborated by others. Despite the different results, mechanistic lupus mouse model studies have shown that gut microbiota can modulate disease activity. Interestingly, pathobiont translocation in monocolonized and autoimmune-prone mice induced autoantibodies and caused mortality, which could be prevented by a vaccine targeting the pathobiont. Moreover, studies on fecal transplants and diet on different lupus mouse models showed an effect on disease activity. In SLE patients, a higher adherence to the Mediterranean diet was associated with lower disease activity, which may be explained by the connection between diet and gut microbiota. Although gut dysbiosis has been observed in SLE patients and lupus mouse models, it remains to clarify if it is a cause or a consequence of the disease or its treatments. Further studies with larger and well-characterized populations will undoubtedly contribute to deciphering the role of gut microbiota in SLE development, progression, and outcome.

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Phenotypic Drift in Lupus-Prone MRL/lpr Mice: Potential Roles of MicroRNAs and Gut Microbiota

Cited by 8 publications

References 30 publications

Lactobacillus spp. act in synergy to attenuate splenomegaly and lymphadenopathy in lupus-prone MRL/lpr mice

Lactobacillus spp. act in synergy to attenuate splenomegaly and lymphadenopathy in lupus-prone MRL/lpr mice

Prolonged Antibiotic Use in a Preclinical Model of Gulf War Chronic Multisymptom-Illness Causes Renal Fibrosis-like Pathology via Increased micro-RNA 21-Induced PTEN Inhibition That Is Correlated with Low Host Lachnospiraceae Abundance

Let’s review the gut microbiota in systemic lupus erythematosus

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