Le modèle standard supersymétrique minimal (MSSM) est probablement une des théories de nouvelle physique les plus étudiées. Dans la plupart des études phénoménologiques, on fait l'hypothèse de la violation minimale de la saveur dans laquelle toutes les interactions violant la saveur sont directement liées à la matrice CKM du modèle Standard. Cependant, si la supersymétrie est plongée dans des cadres plus larges tels que les théories dites de Grande Unification, de nouvelles sources de violation de la saveur peuvent apparaitre. Les termes correspondant dans le lagrangien sont directement liés au choix du mécanisme de brisure de la supersymétrie. Or, à l'heure actuelle, aucun consensus n’existe quant au choix exact du mécanisme de brisure de la SUSY. Plusieurs mécanismes ont été évoqués récemment (entre autre, par le co-directeur de la thèse), qui pourraient conduire à des signatures prometteuses au LHC pour différents scénarios et domaines de paramètre. Le projet est donc idéalement situé à la frontière entre le 'model building' et des aspects plus phénoménologiques. Pour cette raison, le thésard sera naturellement amené à interagir de manière active avec le groupe de phénoménologie de physique des particules du LAPTh ainsi qu'avec les groupes de physique des particules du LAPP (ATLAS, LHCb..), laboratoire expérimental partageant le même bâtiment que le LAPTh. De plus, des collaborations sur le plan national, en particulier avec le LPSC de Grenoble, ainsi que sur le plan international, avec les universités de Würzburg et Münster (Allemagne) et le nouvel institut de physique de NATAL (Brésil) sont également envisagées. / The Minimal Supersymmetric Standard Model (MSSM) is probably the best studied of all new physics theories. In most phenomenological studies, one assumes the hypothesis of minimal flavour violation, where all flavour-violating interactions are related to the CKM-matrix (as it is the case in the standard model). However, if supersymmetry is embedded in larger frameworks such as grand unified theories (GUT), new sources of flavour violation can appear. The corresponding terms in the Lagrangian are directly related to the mechanism of supersymmetry breaking, for which at present no theoretical consensus exists. Several processes have recently been evoked (among others by the co-director of the proposed thesis), which might lead to promising signatures at the LHC if non-minimal flavour violation is realized. These studies, however, included flavour-violating terms directly at the electroweak scale without taking into account their possible origin at some high scale. The main goal of the project is to extend the previous work in order to take into account the link between the electroweak and the GUT scale. This will allow to put constraints on parameters describing supersymmetry breaking using constraints imposed at the electroweak scale. A second goal is the analysis of relevant processes with the help of current Monte-Carlo simulation tools in order to study the background and thus clarify the observability at LHC for different scenarios and regions of parameters space. So, the project is ideally situated at the frontier between model building and more phenomenological aspects. For this reason the project naturally includes interactions with the local particle physics phenomenology group at LAPTh as well as with the the neighbouring experimental groups (e.g. ATLAS, LHCb) at LAPP. Moreover, collaborations on the national, in particular with the LPSC Grenoble, and international level, e.g. with the University of Würzburg (Germany), the University of Münster (Germany) and the newly created International Institute of Physics in Natal (Brasil) are envisaged.

Our gut microbiota is involved in human development, nutrition, and the pathogenesis of gut disorders, but has more recently been implicated as a possible mechanism in the pathophysiology of several brain disorders, including disorders of mood and affect, such as depression. Researchers have referred to this dynamic, bidirectional signaling pathway between the gut and the brain as the “gut-brain axis.” However, most research on this axis has been limited to rodent studies, and there has been little insight into the mechanism behind it. I propose that the kynurenine pathway, where tryptophan is converted to kynurenine, is a compelling mechanism mediating the gut microbiota’s influence on depression. Kynurenine is a metabolite associated with depression, and this pathway has been shown to be manipulated through probiotic (Lactobacillus reuteri) consumption. I propose to study a probiotic intervention in humans, which would assess tryptophan metabolism along the kynurenine pathway by measuring metabolites downstream of this pathway. Urine, feces and blood samples would be collected from two groups, control and probiotic treatment, on day zero and day thirty. Colonic biopsies would be obtained on day thirty, and various analyses would be run to measure metabolite concentrations from the collected samples. The results from this study will help clarify a mechanistic connection between gut microbes and depression via the kynurenine pathway. Additionally, findings could indicate that a probiotic intervention has the ability to influence depressive behavior via a two-pronged approach originating from the kynurenine pathway.

The microbial populations in the gastrointestinal tracts of poultry play an important role in normal digestive processes and in maintaining animal health. The purpose of this study was to evaluate the effects of probiotics, prebiotics and synbiotics on the growth parameters, gut ecosystem, histology and immune function. In this study, four experiments one in vitro and three in vivo were conducted using specific pathogen free (SPF) and Hubbard broiler chickens. The first experiment was designed to determine the influence of inulin as an effective prebiotic on lactic acid bacteria (LAB) strains, and to screen LAB for selection as a source of chicken probiotic. Eight strains of LAB were isolated from chicken caeca and three strains from the Plymouth University culture collection were screened for potential probiotic properties for growth in inulin from Jerusalem artichoke (Helianthus tuberosus) and commercial inulin (Frutafit® HD, Netherlands). Lactobacillus animalis JCM 8692 strain isolated from chicken caeca showed the highest auto-aggregation and co-aggregation ability, resistance to acidity and bile salts, strong suppression of pathogens and ability to adhere to epithelial cells compared with other isolated strains. The second experiment was conducted to investigate the influence of commercial inulin and Jerusalem artichoke tubers as prebiotic supplementation on the diversity of the caecal microflora, jejunum histology and immune organ of SPF chickens. This investigation has found that inulin which was extracted from JA had a similar result when compared with commercial inulin and could be a suitable candidate for an inulin source in broiler diets. The third experiment was conducted to investigate the influence of Bactocell® (PRO1) and Lb. animalis (PRO2) as probiotic supplements on broiler chickens. EPEF was significantly increased in probiotic1 and probiotic2 compared with control (311.03, 309.87 and 260.06) respectively. Both types of probiotics supported the growth of chicks healthy and could be a suitable candidate as a source of probiotic in broiler diet. The fourth experiment was conducted to investigate the influence of dietary supplementation of a probiotic (Lb. animalis), a prebiotic JA tuber and a combination of both (Synbiotic) in broiler chickens. Growth performance was improved in all additive supplementation compared with the control group. EPEF was increased in probiotic, prebiotic and synbiotic compared with control (290.8±11.8, 300.9±3.86, 322.1±7.09 and 262.3±5.94) respectively. Beneficial bacteria in the guts of chicks fed probiotic, prebiotic and synbiotic was increased compared with chicks fed control diet. The diversity of microbial population in the gastrointestinal tract of chickens improved due to additives. The intestinal villus lengths and microvilli density was improved in all additives supplementation in comparison with control. Overall, it was concluded that probiotic, prebiotic and synbiotics can positively affect production performance and can improve the gut health.

Puberty is a critical period of development characterized by rapid physiological changes and significant brain reorganizing and remodeling. These rapid changes render the developing brain particularly vulnerable to stress and immune challenge. In mice, exposure to an immune challenge (lipopolysaccharide; LPS) during puberty causes enduring effects on stress reactivity, cognitive functioning, and depression- and anxiety-like behaviors later in life. However, the mechanisms underlying these effects are unknown. The gut microbiome can profoundly influence the immune system. There is also close bidirectional communication between the gut microbiome and the central nervous system (CNS) through neural, endocrine and immune signaling pathways, which can alter brain chemistry and emotional behaviour. Thus, we hypothesized that altering microbial composition during puberty could mitigate acute immune responses and prevent enduring outcomes later in life. The current thesis examined the effect of gut manipulation with probiotics during puberty on LPS-induced immune responses and enduring anxiety- and depression-like behaviours, and stress-reactivity in adulthood, in male and female CD1 mice (Article 1). Next, we examined age and sex differences in gut microbial composition before and after exposure to an immune challenge. We also examined the effects of consuming a single strain probiotic bacterium (Lactobacillus Reuteri) during puberty on the immune response and the long-term changes in memory, anxiety-like behavior, and stress reactivity in adulthood (Article 2). Lastly, we examined how microbial colonization between pubertal and adult mice can alter acute peripheral and central inflammatory responses to LPS (Article 3). The current dissertation has addressed sex-specific vulnerabilities to an immune challenge during pubertal development and the moderating influence of the gut microbiome. These studies have demonstrated that manipulating the gut microbiome during puberty can mitigate acute immune responses and prevent enduring neurobehavioural outcomes later in life.

Alterations in composition and function of human gut microbiota can affect physiological processes and are known to be associated with many diseases including inflammatory bowel disease, hypertension, asthma and colon cancer. Complex interactions between gut microbiota, environmental toxins, nutrients and host genetics may result in an increased permeability of the gut, which is closely linked to the presence of adverse metabolic conditions. As a consequence, translocation of bacterial DNA into the blood circulation increases in patients with obesity. Obesity is a growing health problem worldwide and often paired with severe secondary complications, such as type 2 diabetes or cardiovascular problems. A main feature of disease progression is a chronic low-grade inflammation of adipose tissue which contributes to the development and aggravation of insulin resistance and many of the underlying mechanisms are still unknown. Although data from mice studies suggest that the presence of bacterial components in adipose tissue can support these processes, human studies on this subject are lacking. In my thesis entitled ``Bacterial translocation to adipose tissue in metabolic diseas'' I provide evidence supporting the initial hypothesis, namely that bacterial DNA is present in adipose tissue, even after stringent controlling for contaminants. To this end, I established a wet lab routine protocol to eliminate contamination as well as a bioinformatics pipeline accounting for contamination by subtracting negative controls. Briefly, this included the use of lab ware and reagents UV-treated for at least 90 minutes, the use of breath protection, extra-long gloves and single-use lab coats as well as working under a sterile laminar flood hood in a clean lab free of any PCR products. The bioinformatics pipeline employed commonly used 16S rRNA gene analysis tools including qiime2, phyloseq and DESeq2 as well as decontam, a novel tool to extract negative controls. Observed quantity of bacterial DNA was in the range of 1 to 10 pg/µg total isolated genomic DNA, which is equivalent to about 0.01 to 0.7% of bacterial cells per human cell. The highest quantity was present in subcutaneous adipose tissue, followed by mesenteric adipose tissue. Bacterial amount correlated with adipose tissue macrophages and PPARG expression in omental and with IL1B and TNF expression in subcutaneous adipose tissue. Mesenteric adipose tissue showed the highest diversity of the observed genera. The most commonly observed phyla in all tissues were Proteobacteria and Firmicutes, which is in line with previously published data on blood bacterial DNA. Still, many genera were predominantly found in specific tissues, e.g. Enterobacter in subcutaneous and Acinetobacter in omental adipose tissue. I further showed that the distribution of observed features could partially be explained by markers of insulin resistance (HOMA-IR, HbA1c) and inflammation (IL-6, TNFa, macrophages) and that certain genera, such as Rhodoferax or Lactobacillus are associated with type 2 diabetes status. In first functional approaches I demonstrated that concentrations of bacterial DNA in the observed range are sufficient to stimulate an inflammatory response in immortalized subcutaneous adipocytes derived from a healthy donor. The effect was most prominent after four hours of treatment and increased in a dose-dependent matter. One of the aims in the present study was to determine levels of gut leakage by measuring zonulin, the most commonly used biomarker for intestinal permeability in humans, and analyze possible associations with adipose tissue bacterial signature. As there are few well-conducted studies on circulating zonulin levels in patients with metabolic diseases, I first performed a correlation study in the available and metabolically well-characterized Sorbs cohort. Circulating zonulin correlated significantly positive with BMI, fasting glucose, triglycerides and cholesterol and negatively with HOMA-IS, high density lipoprotein and circulating adiponectin levels. Albeit these strong correlations with markers of glucose and lipid metabolism supported previously reported findings, the results pointed to some inconsistencies. As zonulin is reported to be pre-haptoglobin 2 (preHP2), and about 15% percent of a typical western European population are homozygous for haptoglobin 1, they should not express zonulin at all. I confirmed in the Sorbs cohort previously reported distributions of haptoglobin genotypes and showed that the target of the only commercially available zonulin ELISA kit was not related to haptoglobin genotype, therefore presumably not measuring zonulin/ preHP2. Subsequently, I identified properdin as a possible target by employing mass spectrometry approaches. Properdin is structurally related to haptoglobin, as both proteins belong to the mannose-associated serine protease family, however further experiments are needed to validate a possible functional resemblance. In regard to bacterial translocation two adipose tissue depots were of notable interest due to their close proximity to the gastrointestinal tract. Mesenteric adipose tissue is located around the small intestine and the adipose tissue of the appendices epiploicae, small chunks of fat also called epiploic adipose tissue, are directly attached to the colon. After a thorough literature research I could also assert that both adipose tissues were rarely analyzed in the context of obesity. Therefore they were extensively investigated by measuring gene expression of adipo(cyto)kines, circulating inflammatory markers and analyzing adipocyte size and adipose tissue macrophages. Furthermore, a ``multiomics'' characterization was conducted and by analyzing transcriptome and methylome data I could identify epiploic adipose tissue as a tissue of interest in regard to type 2 diabetes and insulin resistance, which was further confirmed by untargeted proteomics data. Contrary to initial assumptions, I observed only a slight increase in translocation of bacterial DNA and no increased inflammation, as measured by tissue specific TNF and IL6 expression as well as adipose tissue macrophage infiltration. However, both transcriptome and proteome profiles allowed a clear discrimination of patients with and without insulin resistance which was most distinct in epiploic adipose tissue. Compared to other fat depots, epiploic adipose tissue exhibited a discriminable metabolic profile whereas mesenteric adipose tissue was more similar to omental-visceral adipose tissue. Most strikingly, epiploic adipose tissue showed a strong increase in leptin expression and, in general, the upregulation of various metabolic pathways involved in sugar, amino acid or sphingolipid metabolism. In accord with the leaky gut hypothesis high expression of lipopolysaccharide binding protein and various pathways involved in chemokine signaling were observed. In summary, I did not observe an increase in bacterial DNA or adipose tissue macrophages, but demonstrated elevated inflammatory signals such as increased chemokine or IL-8 signaling which are linked with an overall increase of metabolic processes and an increased expression of various adipokines. Epiploic adipose tissue might have a watch dog function by being the first adipose tissue sensing and forwarding certain (microbial) stimuli from the large intestine to the host. In the last part of my thesis I addressed a possible role of the HLA genomic region on the development of type 2 diabetes. The influence of HLA genetics on type 2 diabetes has been under debate for several decades, since HLA was recognized to largely contribute to type 1 diabetes heritability. However, studies remained inconclusive due to lacking cohorts with sample sizes providing sufficient statistical power for association analyses. More recently, animal studies suggested MHC class II proteins as crucial factors mediating adipose tissue inflammation and insulin resistance. The sample size of the leaky gut cohort was insufficient to determine any correlation between HLA class II genotypes and the presence or type of bacteria in adipose tissue due to the high variability in the observed genomic region. Yet, I had access to three large population-based cohorts which allowed me to analyze associations between HLA class II alleles and type 2 diabetes. Therefore HLA genotypes of the LIFE-Adult (N=4649), LIFE-Heart (N=4815) and Sorbs (N=949) cohort were imputed from SNP genotyping data and analyzed for association with type 2 diabetes. In a meta-analysis including all three cohorts, I identified a protective effect for the well-established type 1 diabetes protective haplotype DRB1*15:01~DQA1*01:02~DQB1*06:02 and confirmed DRB1*07:01~DQA1*02:01~DQB1*03:03 as a risk haplotype in non-insulin treated diabetes. These results suggest that the genetic foundation of both type 1 and 2 diabetes shares common elements involving the HLA class II locus. In conclusion, to the best of my knowledge, I provide in my work the first contaminant-aware identification of bacterial DNA in human adipose tissue and highlight the importance of analyzing novel adipose tissue depots by showing that fat of the appendices epiploicae, previously only considered to have a cushioning function, is metabolically active and possibly involved in the development of insulin resistance.

The human gut microbiome is home to many hundreds of different microbes which play a crucial role in human physiology. For most of them, little is known about how their genetic diversity translates into functional traits and how they interact with their host, which is to some extent due to the lack of isolate genomes. Cultivation-free metagenomic approaches yield extensive amounts of bacterial genetic data, and recently developed algorithms allow strain-level resolution and reconstruction of bacterial genomes from metagenomes, yet bacterial within-species diversity and transmission dynamics after fecal microbiota transplantation remain largely unexplored over cohorts and using these technological advances. To investigate bacterial within-species diversity I first undertook large-scale exploratory studies to characterize the population-level genomic makeup of the two key human gut microbes Eubacterium rectale and Akkermansia muciniphila , leveraging many hundreds of bacterial draft genomes reconstructed from short-read shotgun metagenomics datasets from all around the planet. For E. rectale , I extended previous observations about clustering of subspecies with geography, which suggested isolation by distance and the putative ancestral loss of four distinct motility operons, rendering a subspecies specifically found in Europe immotile. For A. muciniphila, I found that there are several closely related but undescribed Akkermansia spp. in the human gut that are all likely human-specific but are differentially associated with host body mass index, showcasing metabolic differences and distinct co-abundance patterns with putative cognate phages . For both species, I discovered distinct subspecies-level genetic variation in structural polysaccharide synthesis operons. Next, utilizing a complementary strain-resolved approach to track strains between individuals, I undertook a fecal microbiota transplantation (FMT) meta-analysis integrating 24 distinct clinical metagenomic datasets. I found that patients with an infectious disease or those who underwent antibiotic treatment displayed increased donor strain uptake and that some bacterial clades engraft more consistently than others. Furthermore, I developed a machine-learning framework that allows optimizing microbial parameters - such as bacterial richness - in the recipient after FMT based on donor microbiome features, representing first steps towards making a rational donor choice. Taken together, in my work I extended the strain-level understanding of human gut commensals and showcased that genomes from metagenomes can be suitable to conduct large-scale bacterial population genetics studies on other understudied human gut commensals. I further confirmed that strain-resolved metagenomics allows tracking of strains and thus inference of strain engraftment characteristics in an FMT meta-analysis, revealing important differences in engraftment over cohorts and species and paving the way towards better designed FMTs. I believe that my work is an important contribution to the field of microbiome research, showcasing the power of shotgun metagenomics, modern algorithms and large-scale data analysis to reveal previously unattainable insights about the human gut microbiome.

In the gastrointestinal (GI) tract, goblet cells are the major source of mucins, the main structural components of the mucus layer, which functions as the front line of innate defense. The GI tract contains trillions of commensal microbes, and these microbes can manipulate mucin production by activating different signalling cascades initiated by pattern recognition receptors (PRRs), including bacterial sensing Toll-like receptors (TLRs). In addition, sterile α motif pointed domain-containing ETS transcription factor (SPDEF) is a transcription factor that modulates goblet cell differentiation and positively regulates mucin production. During helminth infections, due to the co-existence of parasites and microbiota in close proximity of goblet cells in the gut, it is likely that helminth-microbiota interactions play an important role in mucin production. Indeed, goblet cell hyperplasia and increased mucin production are observed in many enteric helminth infections, including Trichuris muris, and these processes play key roles in host infection clearance. However, it should be noted that the role of microbiota within this axis is not yet understood. Here, we hypothesize T. muris-induced altered microbiota modulates goblet cell differentiation and mucin production via SPDEF-mediated transcriptional regulation and TLR2 signalling. C57BL/6 mice were gavaged with ~300 T. muris eggs. Mice were sacrificed 36 days post-infection. Microbiota from these T. muris-infected and non-infected mice were transferred into two groups of germ-free (GF) mice. Microbiota analysis revealed that treatments in both experiments (infection with T. muris and microbiota transfer from T. muris-infected mice into GF mice) significantly account for the among-sample variations in the composition of the gut microbiota between groups (p <= 0.001). In GF mice, transfer of T. muris-infected microbiota significantly increased goblet cell numbers and TLR2 expression as well as upregulated Muc2 expression compared to MSc Thesis –Yousefi Y; McMaster University – Medical Sciences v GF mice with non-infected microbiota. Antibiotic-treated (ABX-treated) TLR2 knockout (KO) mice after receiving microbiota from T. muris-infected mice showed significantly decreased expression of Muc2 and Muc5ac compared to ABX-treated wild-type (WT) mice receiving the same microbiota. To investigate whether SPDEF is a driving factor for Muc2 production in response to T. muris microbiota stimulation, we next transferred T. muris-infected microbiota into antibiotic-treated SPDEF KO and WT mice. We observed a slight, though not significant, the influence of SPDEF on the stimulation of mucin production by T. muris microbiota. These findings reveal important interactions among parasites, resident microbiota, and host in relation to goblet cell response in the gut. In addition, this study provides new information on TLR2-based innate signalling in the regulation of goblet cell biology and mucin productio / Thesis / Master of Science (MSc)

Woody breast (WB) is a meat quality problem that has caused significant economic losses for the poultry industry. Ross × Ross 708 chicks were randomly assigned to a 3 (diet) × 2 (cocci challenge) × 2 (sex) factorial arrangement of treatments. The three diets included the control diet (corn-soybean meal basal diet), antibiotic diet (basal diet + 6.075 mg bacitracin /kg feed), and probiotic diet (basal diet + 2.2 × 108 CFU Bacillus subtilis PB6 /kg feed). Birds in the cocci challenge treatment group received 20 × the live cocci vaccine as an inoculum on d 14. Growth performance and WB score were measured to understand the effects of management factors (diet and coccidiosis) on broiler growth and WB development. Results indicated that dietary bacitracin and Eimeria spp. increased WB incidence, body weight, and growth rate. Bacillus subtilis increased WB incidence in male broilers without affecting body weight and growth rate. The association of the development of the internal organs and skeletal muscle with WB myopathy incidence in broilers were evaluated. The digestion organs (proventriculus and gizzard) and the skeletal muscles (drumsticks, thighs, and wings) developed at lower rates in birds with WB. In addition, the effects of the dietary and challenge interventions on the gut microbiota diversity and composition associated with WB in broilers were investigated. Results showed that cocci challenge altered gut microbiota composition and various biosynthetic pathways. Maintaining a healthy gut ecosystem is critical for the reduction of WB incidence in broilers. Gene expression related to oxidative stress, gut barrier function, and inflammation in jejunal mucus was investigated. Results showed that WB is related to decreased mucin expression (MUC6) in mucus, indicating a correlation between WB incidence and a lessening of the secretion of gel-forming mucin. In conclusion, dietary antibiotic and probiotic and challenge intervention strategies increased WB incidence, and microbiota composition and gut health gene expression differed in broilers exhibiting WB myopathy.

Despite the association of the human gut microbiome and various diseases, a systematic definition of what constitutes a healthy human gut microbiome has not been established. This is crucial for microbiome research as it provides a basis for evaluating whether a given microbiome sample may deviate from the homeostasis state and is thus prone to the development of chronic diseases. This work aims to propose one such definition by using species/strain-resolved Genome-scale (GEM) models of metabolism. More specifically, we have constructed sample-specific GEMs from 30 healthy subjects using the taxonomic profiling of fecal metagenomic samples. We then computationally simulated these GEMs under a relevant diet (a supplemented typical Western diet) to determine which microbes in each sample contribute to the production of 17 key metabolites curated from literature and reported to be produced and secreted by the gut microbiota of healthy subjects. Beyond this pilot study, we plan to expand our analyses by creating samples-specific GEMs for a large-scale database of all publicly available metagenomic data from healthy subjects (~2,500 samples so far). We will additionally identify a core set of microbial species/strains that are necessary to perform all essential functions of a healthy microbiome. Taken together, this project offers a new paradigm to establish a healthy baseline microbiome definition by identifying generalized and personalized microbial blueprints that could serve as viable markers of health.

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. / Ph. D. / Systemic lupus erythematosus (SLE) is a multi-system autoimmune disease with no known cure. SLE affects over 5 million people worldwide, especially women of childbearing age. Lupus nephritis is a manifestation of SLE occurring in the kidney which affects more than 50% of SLE patients and is a major cause of morbidity and mortality in SLE. Current treatments for lupus nephritis are primarily nonselective immunosuppressants, which can cause a higher incidence of severe infections. There is an imperative need for the development of new therapeutic strategies against SLE. Our research team was the first to describe the dynamics of gut microbiota in a mouse model of SLE. My dissertation research studying the role of gut microbiota in the pathogenesis of lupus-like disease in mice showed that there were both pathogenic and beneficial bacteria co-existing in the gut microbiota of lupus-prone mice. My studies revealed not only the effects of different bacteria on lupus pathogenesis, but also the immunological mechanisms by which they exert the effects. The results suggest that modulation of the gut microbiota through diet, probiotics, and/or prebiotics to selectively enhance the abundance and activity of beneficial bacteria may be an attractive strategy for disease prevention and treatment of SLE patients. Nevertheless, studies on human samples and clinical trials are required to confirm the translational application of this strategy.