Gut Microbiota in SLE and Lupus Nephritis: Comparison
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Lupus nephritis is a severe manifestation of systemic lupus erythematosus (SLE). It is caused by immune dysregulation and kidney inflammation. In recent findings, gut microbiota potentially acts as primary mediators to enhance immune complex deposition, complement activation, and macrophage infiltration, and led to renal inflammation. Gut inflammation, known as leaky gut, allows pathogenic bacteria to enter the blood stream to form immune complexes which deposit on the kidney. Lymphocytes and macrophages induct a proinflammatory cytokine milieu that leads to kidney inflammation. Accumulating pieces of evidence from the field of gender bias, dietary habit, alcohol, smoking and antibiotic consumption were closely related to dysbiosis of gut microbiota in SLE.

Lupus nephritis is a severe manifestation of systemic lupus erythematosus (SLE). It is caused by immune dysregulation and kidney inflammation. In recent findings, gut microbiota potentially acts as primary mediators to enhance immune complex deposition, complement activation, and macrophage infiltration, and led to renal inflammation. Gut inflammation, known as leaky gut, allows pathogenic bacteria to enter the blood stream to form immune complexes which deposit on the kidney. Lymphocytes and macrophages induct a proinflammatory cytokine milieu that leads to kidney inflammation. Accumulating pieces of evidence from the field of gender bias, dietary habit, alcohol, smoking and antibiotic consumption were closely related to dysbiosis of gut microbiota in SLE. However, little is known about the causes of gut microbiota dysbiosis and the potential pathway that leads to lupus nephritis (LN) flare. In this review, we will bring into deeper insight for the potential link of gut microbiota on immune system with a particular focus on renal inflammation. Moreover, we also discuss the potential novel therapies that regulate gut composition to improve or complement the current treatment of LN.

  • gut microbiota
  • SLE
  • lupus nephritis

1. Introduction

Systemic Lupus Erythematosus (SLE) is an autoimmune disease resulting in multi-organ inflammation with complex clinical manifestation including neuropsychiatric, lupus nephritis and so on. However, the actual cause of SLE is still unknown [1]. Various aetiologies have been postulated which can be categorized into genetic and environmental such as age, gender, ultra-violet exposure, dietary intake, alcohol, and lifestyle behaviour [2]. Lupus nephritis is one of the most severe manifestations of SLE with high mortality rate and 10% of them eventually develop end-stage renal disease within 5 years after diagnosis [3][4].
In a review of medical records of 258 SLE patients in theour centre from 2007 to 2017, majority of the SLE patients were Malay (56.2%) followed by Chinese (38.8%) and Indians (5%) [5]. Renal involvement in theour cohort is high, affecting up to 60% of the patients [6]. Most importantly, patients with LN were found to be at risk of organ damage as almost half of them accrued damage in the duration of follow up of up to 20 years. Although SLE is less common among the Indian population, they are at risk of developing LN (61.1%) [7] and disease damage (66.7%) [6]. Therefore, racial diversity in Malaysia has different organ and system involvement.
Recently, enormous reports highlighted on the association of autoimmune diseases with dysbiosis of gut microbiota [8][9][10][11]. There are trillion of microbes inhabited human gut which dominated by 4 phylum such as Firmicutes, Bacteroidetes, Proteobacteria and Actinobacteria. Every species of gut microbiota plays their own role in modulating immune system, absorption of metabolites, short-chain fatty acid (SCFA) metabolism, and so on. Many factors could alter gut communities such as infant transition, dietary habit, age, gender and antibiotic consumption [12]. Dysbiosis of gut microbiota will affect the intestine membrane permeability, tight junction, mucosal barrier and intestinal metabolites composition. At present, the role of gut microbiota in LN pathogenesis are less understood. Gut dysbiosis has been shown to be associated with SLE while little is known on lupus nephritis [13][14][15].

2. SLE and LN Pathogenesis

B cell dysfunction is still considered as the key factor for immune dysregulation resulting in autoantibodies production in SLE [16]. Other patho-mechanisms of SLE are defective in apoptosis due to ineffective clearance of cell debris during cell death mechanism which exposes nuclear material (nuclear protein, cytoplasmic protein and membrane components) to antigen presenting cells (APCs) [17][18]. Upon the nucleic material being picked up by the APCs, IFN-a was produced and stimulate IL-6 production which [19] act as an immune adjuvant in the maturation of T helper cell [20]. The hyperactivation of T-helper cells will then activate B cells to initiate plasma cells antibodies production. These circulatory immune complexes deposit on kidneys and activate the complementary reaction which led to kidney inflammation, named as lupus nephritis (LN).

3. Gut Microbiota Dysbiosis of SLE

Gut microbiota as gut commensals in host gastrointestinal tract especially significant in immune modulatory. During the autoimmune disease condition, the symbiotic relationship is broken due to various factor such as dietary habit that change microbiota diversity. The decrease of microbial diversity was found in autoimmune diseases such as SLE and inflammatory bowel disease (IBD), presented by reduce commensal bacteria (Firmicutes and Bacteroidetes) and increase of detrimental bacteria (Proteobacteria and Actinobacteria) [21]. Homeostasis of gut microbiota maintain the function of dietary metabolism of the general host, formation of protective barrier, tight junction expression and immunology regulation [22]. Microbiota involves in dietary metabolism of digested protein, carbohydrate and dietary fibre. There are 100 trillion bacteria that form gut microbial community in general human population, where the composition could be easily influenced by age, gender, genotype and food intake [23][24]. In healthy human gut, the majority of the bacteria (98%) is dominated by two major phylum which are Bacteroidetes and Firmicutes [25]. Firmicutes responsive in fatty acids and carbohydrates absorption whereas Bacteroidetes correspond to polysaccharides absorption [26]. Alteration of gut microbiota expresses as Firmicutes/Bacteroidetes ratio potentially act as the measurement for pathological condition in SLE patients which cause systemic inflammation. The decreased ratio of F/B microbiome in SLE patients occur either by the reduction in Firmicutes or increase abundance of Bacteroidetes. The lower F/B ratio in SLE patients was proven by a Spanish cross-sectional study, which compared gut microbiota of SLE patients in remission with sex-matched health control [27]. However, the gut microbiota was found to be reduced in microbial diversity and complexity in lupus patients and lupus-like mice [28][29]. Furthermore, SCFA (butyrate) and tryptophan, as indispensable role in activating B cell and generate autoantibodies which initiate autoimmune intolerance [29][30]. In human study, SCFA was found in fecal level of lupus patient with low Firmicutes to Bacteroidetes (F/B) ratio suggesting the potential link of gut absorption function with microbes [31]. However, the effect of F/B ratio also show significant in other autoimmune disease such as IBD and rheumatoid arthritis [32]. Hence, it is necessary to identify the exact mechanism on how the gut microbiota promote SLE and LN pathogenesis in human studies.

3.1. Dietary Habits

Transgenic mice TLR7.1 Tg mice was closely resemble to the TLR7-pDC-IFN axis in SLE patients. In TLR7.1 Tg mice study suggest resistant starch (RS) rich diet producing SCFA, suppress the enrichment of L. reuteri, by decreased pDCs and interferon pathways to reduce lupus symptoms [33]. Hence, the evidence manifest that RS rich diet could suppress interferon pathway from gut pathobiont which particularly important in human SLE pathogenesis. Interestingly, high level of fecal kynurenic acid as one of the common tryptophan metabolites, have been identified in SLE patients from a China report [34]. High tryptophan diet exerts proinflammatory effect to triple congenic (TC) lupus-prone mice which exhibit altered microbial communities with elevated level of Lactobacillus spp. and Bacteroides dorei. In contrast, low tryptophan diet in TC mice improved lupus feature such as Tregs functionality which was similar to germ-free B6 mice [30]. The expression of CD25 on Treg cells was increased in TC mice after low tryptophan diet while high tryptophan diet demonstrate increased expression on Th 17, B cell and plasma cells [30]. From the findings above, gut microbiota could initiate immune response in SLE through tryptophan degradation. Hence, in order to shape immune tolerance gut environment, dietary habits such as low tryptophan, high fibre and resistant rich diet were essential to maintain normal gut function. Metabolite profile can be the potential measurement on microbial activity in mediate SLE.

3.2. Gender

Despite female preponderance of 9:1 ratio, many studies showed that males with renal involvement have higher mortality rate and more severe disease manifestation [2][35]. Gender bias was a significant factor in affecting predominant of SLE and severity of LN. SLE affects predominant woman of childbearing age indicating hormonal factor could be the predisposing factor for SLE. Immunoregulatory function of oestrogen were range from various immune cells of innate immunity to adaptive immunity [36]. The IFN-stimulated genes were highly stimulated to secrete proinflammatory cytokines after in vivo treatment of 17β-oestradiol with PBMCs from SLE patients and healthy controls [37]. Furthermore, oestrogen was related to renal disease exacerbation. The female MRL/lpr mice develop severe glomerular damage after consumption of a synthetic 17β-oestradiol, which was 17α-ethinyl oestradiol [38]. Higher oestradiol and lower plasma testosterone in female reduce T-regulatory cells (Tregs) ability to express FoxP3 which is postulated to cause SLE [39]. The protective effect from male hormone associated with gut microbiota generally inhibit disease development in early life of male BWF1 lupus model [40]. Interestingly, the gut microbiota was also significantly different in both genders. Early development of lupus in the female and castrated males BWF1 mice strongly suggest the influence of sex hormones. However, male patients were more prevalent in developing higher disease activity and renal related autoimmune disease [41]. Whether composition gut microbiota influence this effect is still unknown.

3.3. Geographical Factor

SLE patients in Northeast China were found to have different gut microbiota profiles compared to Spain and a Southern China cohort. The intestinal microflora of Northeast China was significantly increased in phylum Proteobacteria, family Enterobacterlaceae and family_XI_o_Clostridiales and decreased in family Prevotellaceae. On the other hand, Spain and Southern China patients did not have any changes in family Enterobacterlaceae and family_XI_o_Clostridiales. Although the exact mechanism to the changes of microflora in Northeast China still need deeper exploration, rwesearchers cannot deny the possibility of gut microbes in SLE patients were influenced by geographical regions [42]. Analysis from 1995 to 2010 in 41 study centres showed that prevalence of LN patients increased with decreasing latitude from the north to the south part of China [43]. More research is needed to explain the relationship between geographical factors with gut microbiota of LN and SLE patients.

3.4. Concomitant Medication

Kidney involvement affects 60% of SLE patients which require treatment with non-specific immunosuppressive such as glucocorticoid. The effect of glucocorticoid on gut microbiota was shown by M. Guo et al., 2020. In this study, the gut microbiota of two human SLE groups (with or without glucocorticoid) and healthy human control were compared. Glucocorticoid treatment had almost similar gut microbial community with healthy human control [44]. They have increased Firmicutes to Bacteroidetes ratio indicating enrichment of Firmicutes and depletion of Bacteroidetes, including Lactococcus, Streptococcus, and Bifidobacterium. Those genera activate anti-inflammatory mechanism such as glycan metabolism, SCFA production, tight junction and mucosal stimulation thus restoring the gut function of SLE patients. Unfortunately the glucocorticoid has adverse effects for SLE patients on cardiovascular, optical disease, psychiatric disorders [44] and increase risk of infection [45]. Treatment with Hydroxychloroquine (HCQ) was found to reduce infection risk as shown in C57BL/6J mice [45]. The ratio for Firmicutes/Bacteroidetes decrease in C57BL/6J mice after 7 days high dose of HCQ suggesting the inflammatory influenced by alteration of gut diversity and gut membrane integrity [46].

4. Potential Initiation of LN by Gut Microbiota

4.1. Microbes Metabolite Host Axis

There were numerous studies establishing the effect of certain types of diet with gut microbiota species in lupus nephritis. Diet with low fibre promotes immune dysregulation resulting in deposition of immune complex in kidney glomeruli as observed in the control C57BL/6J mice. In contrast, the lupus symptoms were significantly attenuated in mice lacking Lyn tyrosine kinase (Lyn−/− mice) that were fed with high fibre diet. The link between high fibre diet and immune modulatory in mice could suggest a similar possibility in humans as well [47]. The non-digestible carbohydrate, fibre will be fermented into SCFA [33]. Most of the SCFA exist in gut are acetate, propionate and butyrate [48]. Immunoregulatory function of SCFA were range from anti-inflammatory, T cell and epigenetic pathway. Bacteroides and Negativicutes produce propionate through the succinate pathway [49]. However, butyrate was mainly produced by phylum Firmicutes via acetate CoA-transferase pathway [49]. Dysbiosis of gut microbes in SLE was associated with the SCFAs production by increase of SCFAs in fecal level and reduce F/B ratio [48]. However, butyrate has been demonstrated to attenuate kidney disease via G-protein coupled receptor [50]. Butyrate was essential to maintain gut homeostasis by activate PPAR-γ-signalling, consequently suppress inducible nitric oxide synthase (iNOS) synthesis and prevent overgrowth of nitrate dependent microbes in gut [30]. Study using butyrate treatment in lupus-prone mice showed it could ameliorate kidney damage by increasing F/B ratio and microbial diversity [29]. In NZB/W mice, treatment with histone deacetylate 6 inhibitor showed significant reduction in lupus nephritis symptoms by inhibiting B cell activation pathway [51]. Therefore, the significant relationship between SCFA and histone deacetylate (HDAC) provide insight of SCFA as an immunomodulator for LN. Hence, microbial metabolite was significant in immune regulation between diet and gut microbiota [50].

4.2. Sex Microbes Axis

The link of sex hormones, such as oestrogen and androgen with X and Y chromosome can be used to explain sex bias on disease predominant and severity. Oestrogen associates in female upregulated X-linked genes, ERα, preferably activate Th2 immune response and autoreactive B cell [41][52]. In a study of TGP treatment on SLE mice, ERα in B cell contribute to glomerulonephritis while TGP treatment on SLE mice able to reverse the pathogenic condition [52]. However, there were higher chance for a men to develop chronic lupus nephritis with androgen through programmed cell death pathway in kidney [41]. The anti-dsDNA antibodies in male mice was elevated with the presence of Y chromosome with Tlr7 gene expression and develop LN [53]. However, upregulation of the related epigenetic was due to gut dysbiosis [54]. Female lupus mice were found to have higher levels of Lachnospiraceae whereas male lupus mice have higher Bifidobacterium in the gut [55]. In addition, Lactobacillus treatment resulted in significant improvement in the renal inflammation and worked only in female and castrated male lupus mice [4]. Post Lactobacillus treatment, castrated lupus mice showed significant decrease in IgG2a and IgA while increase TGFβ and IL-10, which reduce the LN pathology. These findings could suggest the correlation between different gut microbiota with different gender and hormonal profiles with immune responses. Level of serum creatinine and haematuria was significantly higher in male SLE patients compared to female SLE patients of similar age, race and disease durations [56]. Hence, female contain higher risk in SLE when compare with males. In addition, males consist of higher risk in renal damage.

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