The Role of Diet in Influencing the Diversity of Gut Microbiome Related to Lupus Disease Activities: A Systematic Review

Gut microbiome dysbiosis can affect the host immune system. The balance and activity of the gut microbiome, which are influenced by daily diet, might be associated with disease activity in systemic lupus erythematosus (SLE). Therefore, we conducted a systematic review based on the PRISMA guideline to explore the role and types of diet that affects the gut microbiome related to changes in SLE disease activity. All original and full-text English articles in the last ten years were included using predefined keywords according to PEO (population, exposure, and outcome) design in PubMed. The study subjects were carefully analyzed, including lupus-susceptible mice and humans with SLE on various diets. Children and pregnant women populations were excluded. Of 134 studies found, only seven full-text articles had met the inclusion criteria of which only one study conducted in human. This human study showed that dietary polyphenol as dihydrochalcones and flavanones affected the gut microbiome and ameliorated lupus disease activity. On the contrary, dietary flavones increased Blautia (family: Lachnospiraceae), and that often found in active lupus diseases. Furthermore, six studies in lupus-prone mice models showed that resistant starch (RS), retinoic acid (RA) or all-trans retinoic acid (tRA), and acidic water (AW) had influenced the gut microbiome, leading to an improved lupus development. Conversely, the 2018 commercial rodent diet, vitamin A-retinoic acid (VARA), neutral water (NW), and high tryptophan diet had impacted various microbiomes, resulting in increased lupus activity. Interestingly, several diets have the effect of either increasing or decreasing lupus disease activity depending on the microbiome they affect, such as AW associated with Turicibacter spp., which is frequently found in active lupus disease, and tRA in Bacteroidetes associated with renal pathology. To conclude, diet can influence the gut microbiome, which is related to the disease activity process of SLE.


Introduction
Systemic lupus erythematosus (SLE) is an autoimmune disease resulting from a loss of immune tolerance. About 0.3 to 23.7 per 100,000 individuals globally have been diagnosed with SLE yearly. Te prevalence varies from 6.5 to 178.0 per 100,000 population, predominantly in productive-age women and more frequent in adults than children [1,2].
SLE is a unique disease with various atypical manifestations, making it challenging to recognize, prevent, and treat [1,3]. On the other hand, the pathogenesis of SLE is still unclear and multifactorial [4]. Te environmental triggers play an important role in SLE development in genetically susceptible individuals, including hormones (e.g., prolactin and estrogen), drugs (e.g., oral contraceptive and postmenopausal hormone therapy), UV light, infections (e.g., cytomegalovirus and Ebstein-Barr virus), toxins (e.g., silica dust), and cigarette smoking, as well as dietary factors and gut microbiota [5,6].
In the last 20 years, many studies on a diet have been associated with SLE and ofer a promising alternative treatment as it has many advantages in improving the quality of life to the potential for prophylactic efects [7][8][9][10]. Nowadays, the microbiome is a hot topic in research as it infuences the physiology or pathology of the host. Dysbiosis or imbalance of the microbiome is a variation of the gut microbial composition in the shape of loss of benefcial organisms and overgrowth of harmful organisms, leading to loss of microbial diversity. Dysbiosis can afect the regulation of the development and function of the immune system, which may play a role in the development of autoimmune diseases such as SLE [11]. Further dysbiosis can damage the intestinal barrier by penetration of living bacteria or removal of dead bacterial components outside the intestine [12,13]. A study on childbearing-age female lupus-prone mice has shown an increase in Lachnospiraceae and a decrease in Lactobacilli [14]. Of note, the prevalence of human SLE is predominated (99%) in female in their childbearing age; therefore, microbiome disbalance plays a role as a risk factor in SLE development. At the microbiome level, dietary factors are determined by several factors, among others, the type of diet.
At the microbiome level, dietary factors are determined by several factors, among others, the type of diet. One of the roles of diets' pattern or types is its efect on the formation of infammatory or anti-infammatory metabolites [15]. Te correct diet in SLE patients can improve body homeostasis, prevent medication side efects, increase the period of remission, and improve physical and mental well-being [9]. For example, high fber in the Mediterranean diet has been shown to reduce the risk of CVD and infammatory markers, as well as to improve anthropometric profles in SLE patients [16][17][18][19]. Clinical complication and comorbidities resulting from SLE therapy, can also be controlled with a diet; for example, diet with high vitamins, minerals, monounsaturated fatty acid (MUFA), or polyunsaturated fatty acid (PUFA) with moderate energy consumption [20,21]. Inappropriate dietary intake shows worsening SLE disease activity due to changes in the microbiome's composition through increased infammation and the efect of its antigen [14]. A Western diet low in fber, high in sugar and fat, and rich in processed foods can worsen SLE activity by altering the diversity of the gut microbiome and disrupting the intestinal barrier [22,23]. Furthermore, the infuence of SLE treatment on gut microbiome might also play a pivotal role, such as the use of steroids, immunosuppressive drugs, and hydroxychloroquine. Te precise mechanism by which diet infuences the SLE disease process is still not fully elucidated, and there is little literature relating to the infuence of diet on the gut microbiome. Terefore, this review has explored and discussed in more detail the type and the role of diet in infuencing the gut microbiome associated with SLE disease activity. Te results of this study might provide information for future research in nutritional interventions for SLE patients.

Search Strategy and Study Selection.
Tis systematic review was conducted according to the PRISMA guideline. Te literature source search was carried out using electronic data of PubMed until the end of August 2021. Te keyword was searched according to PEO (population, exposure, and outcome) design; the population was the microbiome in patients with systemic lupus erythematosus, the exposure refers to dietary factors, and the outcome was in the form of SLE disease activity. Te keywords had been linked using the Boolean operator, as follows: (((diet) OR (dietary factor) OR (nutrition) OR (dietary intervention) OR (carbohydrate) OR (protein) OR (vitamin) OR (fber) OR (mineral)) AND ((microbiome) OR (gut microbiome) OR (gut microbiota) OR (microbiota)) AND ((lupus) OR (SLE) OR (systemic lupus erythematosus) OR (human lupus))). In addition, we included all original full-text research articles in English within the last ten years, and as subjects were human and mice models of SLE.
Interventions in the form of diets that infuence the gut microbiome targeting changes in SLE disease activity were included with no restrictions, especially on types of diet. Outcomes were measured by the changes in the gut microbiome and identifed changes in the SLE disease process. A benefcial efect existed when dietary intake afecting the gut microbiome might ameliorate lupus disease activity. On the other hand, an adverse efect occurred when diet infuencing the gut microbiome worsens SLE activity. Te exclusion criteria of the articles were children and pregnant women. Articles found with relevant titles were reviewed for abstracts, and then a full-text review was conducted.

Data Extraction and Quality Assessment.
Te full texts from included articles were extracted into a table, consisting of collected various data on authors, year, research design, population, exposure, target phyla/genera/families/other, indicators for assessing SLE activity, and study results. Te assessment of the quality of the articles was carried out using Joanna Briggs Institute's critical appraisal tools from the Faculty of Health and Medical Sciences of the University of Adelaide to determine the clarity and focus of the discussion on the research, the validity of the methods used, and the importance and usefulness of the research result [24]. Several questions were given that had to be flled in with "Yes," "No," "Unclear," or "Not applicable" answers.

Study Selection.
A qualitative synthesis was conducted with a critical appraisal frst. In total, 134 articles were found in the PubMed database. However, only seven articles were relevant to our study, including six experimental studies using lupus-prone mice models and only 1 study using human SLE ( Figure 1) [14,[25][26][27][28][29][30]. Te other articles (n � 127) were excluded due to review study design (n � 59), comment articles (n � 3), opinion (n � 1), paediatric population (n � 3), and pregnant women population (n � 1). Te other articles (n � 60) were irrelevant or of-topic because they did not answer research questions, discussed other diseases, or used other terminology of lupus related to wolf or Canis lupus familiaris.

Study Characteristics and Outcomes.
Te only study with human SLE found in the literature search was a case-control study, including female SLE patients without active disease at the time of sampling. Furthermore, they were not taking antibiotics, glucocorticoids, immunosuppressive drugs, monoclonal antibodies, or other immunotherapy.
Additionally, antimalarial drugs and non-steroidal antiinfammatory drugs were used regularly by 18 of the 20 participants [25].
Variations of diet composition in this study focused on polyphenols (dihydrochalcones, favanones, and favone), vitamin A (RA/tRA and VARA), resistant starch (RS), high tryptophan diet, pH water (acidic water/AW and neutral water/NW), and 2018 commercial rodent diet or isofavonerichsoy-based diet (2018 diet). Due to dietary intervention, gut microbiota had changed signifcantly in composition, quality, and quantity. Microbiota was analyzed in all studies, using DNA taken from fecal or gut samples. Te main characteristics of the studies about diet that afect the gut microbiome related to SLE disease activity are summarized in Table 1.
An adverse efect occurred when diet afected the gut microbiome, resulting in increased SLE activity as indicated by the intake of polyphenols in the form of favones in SLE patients that afect Blautia. In SLE mice models, the VARA and 2018 diet had an adverse efect on Lachnospiraceae in MRL/lpr mice. Interestingly, VARA in MRL/lpr mice and SNF1 mice fed NW at the prenephritic stage had an adverse efect on Rikenellaceae. Te SNF1 mice fed NW also had an adverse efect on Pedobacter kwangyangensis and Flavobacterium antarcticum at the prenephritic stage. Also, AW-fed SNF1 mice in the nephritic stage on Turicibacter spp. and L. reuteri. Moreover, high tryptophan diet in TC mice had an adverse efect on L. reuteri, L. johnsonii, Bacteroides dorei, Prevotella, and Prevotellaceae, and tRA diet in Balb/c mice treated with pristane-afected   International Journal of Microbiology 5

Discussion
Only a few studies, seven qualifed in this systematic review, have been identifed to fll in the gaps, since the relationship between the diet-gutmicrobiome-autoimmune diseases is relatively recent. Tis systematic review has proven that certain diets may infuence the microbial profle and afect disease activity in SLE patients or experimental lupus-prone mice. Diet and immunity have complex interrelationships. Nutritional needs and metabolism, as well as physiological responses to food, are infuenced by immunity [15]. Te microbiome, designated as microorganisms and their ecosystems in the intestine, must be in a balanced number and location. Infammation or autoimmune disease development can occur when the balance is not reached [12].

Diet Tat Afects the Gut Microbiome and Its Association
with Ameliorating SLE Disease Activity. In SLE, dysbiosis occurs as loss of benefcial organisms, overgrowth of harmful organisms, and loss of microbial diversity [31]. Intake of polyphenols with dihydrochalcones from the regular diet, exclusively apple, in female SLE patients is positively associated with Bifdobacterium [25]. Tis genus has antiinfammatory properties, and one of its strains, B. infantis, has an immunoregulatory efect on lymphocytes, epithelial cells, and dendritic cells [32]. In SLE patients, Bifdobacterium can maintain the balance of Tregs, T17, and T1 as well as prevent the overactivation of CD4+ lymphocytes [33]. Bifdobacterium, an SCFA-producing bacterium, as a probiotic, can maintain the gut and the balance of gastrointestinal microbiota through changes in intestinal pH, produce antimicrobial substances, compete for nutrients, and reduce intestinal lipopolysaccharide levels [33,34]. Diet with favanones (mainly from oranges and their products) in SLE patients and RA diet in MRL/lpr mice have shown a positive relationship with Lactobacillus, which was decreased in MRL/lpr lupus-prone mice. Tis relationship negatively correlates with lupus disease parameters (lymphadenopathy and glomerulonephritis) and relieves infammatory fares in lupus patients [14,25]. Tis protective mechanism, produced by lactic acid-producing bacteria, Lactobacilli, may occur due to increased immunoregulation by dendritic cells, such as increased Treg balance costimulatory molecules [35]. In addition, there is an increase in the production of anti-infammatory cytokines (IL-10) which can inhibit the production of IFN-c-induced autoantibodies and clinical nephritis [35,36].
A decrease in Clostridiales (class: Clostridia; phylum: Firmicutes) occurred in TLR7.1Tg lupus-prone mice and could be increased by resistant starch (RS) diet [26]. Clostridiales can ferment RS into short-chain fatty acids (SCFAs), thereby inhibiting the pathogenesis of lupus by decreasing IFN-I signalling and pDC. SCFAs also improve the integrity of the epithelial barrier, thereby reducing translocation and growth of lupus-prone bacteria such as L. reuteri, especially in mesenteric lymph node complex (MLN), liver, and spleen [26,37]. Fermentation sites mainly occur in the distal jejunum, cecum, and proximal colon with SCFA metabolites such as acetate, propionate, and butyrate [38].
Resistant starch (RS) is a type of fber that can suppress lupus-related pathogenesis and mortality and consists of a carbohydrate source in the form of plant oligosaccharides and polysaccharides that cannot be digested in the small intestine [26]. Dietary patterns associated with high fber intakes, such as vegetables, fruit, and whole grains, have been found in the Mediterranean diet (Med Diet) [16,39]. A good prognosis is shown in SLE patients with Med Diet, as evidenced by an excellent anthropometric profle, a reduced risk of CVD, and infammatory markers. Te decrease in SLEDAI scores was also shown to be associated with the consumption of fruits, vegetables, olive oil, sofrito, nuts, fsh, and nuts, as well as the abstinence from red meat, meat products, sweet foods, and pastries in the Med Diet component, enabling the contribution of the gut microbiota [16].
An increase in the order Clostridiales and the genus Clostridium has been demonstrated by pristane-induced lupus mice, given tRA (all-trans-retinoic acid) at week two after pristane injection. Although the administration of tRA in the progressive phase of lupus can increase the infltration of infammatory cells in the tissues, it shows the immunosuppressant function in the kidneys by reducing glomerulonephritis [29].
Te presence of the Erysipelotrichaceae family, which belongs to the Firmicutes phylum, in MRL/lpr lupus mice depends on gender. Tere is a decrease in female mice, inversely proportional to male mice [14]. Interestingly, this Erysipelotrichaceae family is increased signifcantly in female SLE patients [40]. Treatment using vitamin A in the form of RA and VARA can lower the level of Erysipelotrichaceae [14]. Furthermore, increased infammation in the intestine is directly proportional to Erysipelotrichaceae [41].
In the prenephritic 12-week-old SNF1 mice, AW recipients can enhance several microbiomes such as members of Lactobacillus (L. hayakitensis, L. intermedius, L. siliginis, and L. equi), Christensenellaceae, and Clostridiales such as Ruminococcus gnavus, Peptoniphilus coxii, Caloramator mitchellensis, and Peptoniphilus methioninivorax. Tese changes have implications for the increase in the Firmicutes phylum and contribute to improving the Firmicutes/Bacteroidetes ratio previously decreased in SLE.
Several phyla, such as cyanobacteria member Trichodesmium hildebrandti, Proteobacteria member Hydrocarboniphaga daqingensis, and Bacteroidetes member Polaribacter butkevichii, are also increased in AW-fed prenephritic stage SNF1 mice [30]. Although the mechanism of involvement of the gut microbiome is not precisely known, the rate of disease progression such as nephritis severity (measured by grading proteinuria and proinfammatory cytokines), are lower levels in AW recipients than in NW-recipients mice. Te production of autoantibodies against DNA (e.g., total serum IgG anti-dsDNA, IgG2a, and IgM) or against nucleohistone complex (e.g., IgG2 and IgM) are at lower levels in AW recipients than in recipient NW, the potential for immune cell infltration and glomerular necrosis is also low.

Diet Infuences the Gut Microbiome and Is Associated with
Worsening Disease Activity in SLE. Te higher levels of Lachnospiraceae are a characteristic of gut microbiota changes in lupus-susceptible MRL/lpr and B6/lpr mice at specifc points during lupus progression. In female SLE patients, genus Blautia (family: Lachnospiraceae) was positively associated with favone intake, of which the main contributors were oranges and their products. However, favone-rich foods must be present in a combined whole diet to predict the proportion of Blautia [25]. Studies in SLE   International Journal of Microbiology patients with active lupus disease have shown increased levels of Blautia [43]. Retinol mixed with retinyl palmitate, VARA, signifcantly increased levels of Lachnospiraceae and correspondingly increased lupus disease parameters such as lymphadenopathy and renal pathology in MRL/lpr mice [14]. Te 2018 commercial rodent diet, which contains phytoestrogenic isofavone-richsoy-based chow diet, also increases Lachnospiraceae related to glomerulonephritis and more severe lupus disease in MRL/lpr mice [28]. EFFECT

International Journal of Microbiology
Phytoestrogens are estrogen-like substances of plant origin and can produce either good or bad efects on the development of SLE, depending on the estrogen receptor they afect [44]. Proinfammatory efect is associated with increased estrogen receptor alpha (ERα) in lupus-prone models [45]. Te diference in fber sources between the 2018 diet with RD diet and 7013 diets is thought to be the cause of the diference in the abundance of Lachnospiraceae, where the 2018 diet used a mixture of soluble and insoluble fber derived from plants. [28]. As part of the XIVa cluster of Clostridia, Lachnospiraceae (including Blautia) can promote the accumulation of mucosal Treg cells, anti-infammatory, and maintain intestinal health through butyrate [46]. However, Fas lpr mutations can lead to impaired butyrate-associated T cell apoptosis, so the infammation in MRL/lpr and B6/lpr mice cannot be controlled by Lachnospiraceae, leading to increased SLE disease activity [14,47].
Another lupus-enriched family in MRL/lpr mice was Rikenellaceae (phylum: Bacteroidetes), further enhanced by the VARA diet and associated with more rapid lupus progression [14]. Tis was also demonstrated by NW in the prenephritic stage of SNF1 mice [30]. An increase in Pedobacter kwangyangensis and Flavobacterium antarcticum species (phylum: Bacteroidetes) has been shown at the prenephritic stage of NW-recipient SNF1 mice [30]. A signifcant increase in the phylum Bacteroidetes that contributes to a decrease in the Firmicutes/Bacteroidetes ratio is associated with several infammatory diseases [48,49]. In autoimmune diseases, the development of infammation and the outcome of the disease can be infuenced by the balance of microorganisms; therefore, disease progression in pH water recipients may be gut microbiome-dependent [50]. Tis is evidenced by the suppression of disease progression, including low autoantibody level and proteinuria in NW recipients who have been given the cecum microbiota of AW recipients orally through microbiota manipulation [30].
Turicibacter spp., as a part of the family Erysipelotrichaceae, is positively associated with administering acidic water (AW) in the nephritic stage of SNF 1 lupus-prone mice [30]. In MRL/lpr mice, this genus is included in the top ten genera with the highest level and is a biomarker in the GF + SLE group [51,52].
An increase in L. reuteri is also demonstrated in AW-fed nephritic stage SNF1 mice and high tryptophan diet in TC mice [26,30]. Environmental and genetic infuences play a signifcant role in the response of L. reuteri. Despite its potential as a probiotic through its anti-infammatory and Treg-inducing properties, the increased growth of L. reuteri has the potential for translocation, which may induce the pathogenesis of lupus related to organ pathology and pDC/ IFN triggering properties [27,37].
A high tryptophan diet in TC mice can also increase L. johnsonii, where these taxa have been thought to increase after developing autoimmunity that can exacerbate lupus. In diferent lupus-susceptible mouse models, the efect of Lactobacillus spp. abundance will also be diferent as in TLR7.1Tg and TC mice; the more Lactobacillus spp., the worse the activity of SLE disease [27]. An increase in the abundance of Bacteroides dorei, Prevotella, and Prevotellaceae (phylum Bacteroidetes) has also occurred in TC mice with a high tryptophan diet [26]. Te formation of indole derivative metabolites from tryptophan can be carried out by Gram-negative bacteria such as Bacteroides spp., which can negatively afect TC mouse immune cells [26,53,54]. On the other hand, tryptophan can be converted to kynurenine by indoleamine 2,3-dioxygenase (IDO) and is regulated by IFN-1, a cytokine that is increased in SLE patients. Tis increased conversion can lower serotonin levels in serum, leading to a severe SLE phenotype with elevated anti-dsDNA antibodies and nephritis as demonstrated in TC mice [26,55]. Sources of tryptophan are highprotein foods such as eggs, meat, fsh, beans, nuts, and cheese [53].
In pristane-treated Balb/c mice, to demonstrate the phenotypes of lupus, administration of tRA at week ten after pristane injection has resulted in an increase in Bacteroidetes associated with worsening glomerular pathological scores and proteinuria [29]. In addition, there is also a decrease in Firmicutes, which contributed to a decrease in the Firmicutes/Bacteroidetes ratio, as happened in SLE patients compared to healthy controls [29,56]. Tis suggests that the tRA diet can positively and negatively afect SLE activity depending on the administration time. Te worsening efect of diet on various microbiomes is depicted in Figure 3.

Diet and Metabolic Function of the Microbiome.
In addition to microbial composition, diet can also impact the metabolic function of the microbiome. In the gut microbiome of MRL/lpr mice treated with RA, there is a change in genes in carbohydrate metabolism (glycoxylate, galactose, and dicarboxylate). In contrast, there is a decrease in galactose metabolism and glycolysis and an increase in glycoxylate and dicarboxylate metabolism in lupus disease [14]. Te metabolism of amino acids such as histidine, phenylalanine, tyrosine, and tryptophan can also be afected by RA treatment, so these metabolic changes indicate weakening of lupus symptoms [14]. On the other hand, through metagenomic prediction of microbial metabolic function, there is a decrease in genetic information processing and nucleotide metabolism as well as signifcant increases in membrane transport, signal transduction, cell motility, and sporulation genes which can be exacerbated by VARA treatment and worsening disease [14].
Diet is not the only defnite factor that infuences the course of SLE disease related to changes in the microbiome. Another factor that must be considered is the use of drugs in SLE patients. Te decrease in Firmicutes and Enterococcaceae occurred with hydroxychloroquine (HCQ), both shortterm/high-dose and long-term [57][58][59]. As an antiinfammatory and immunosuppressive agent, glucocorticoid therapy is not only capable of reducing cytokine production but also has the potential to stabilize the gut microbiome, which is characterized by a decrease in Bacteroidetes with an increase in Lactobacillus, Streptococcus, and Bifdobacterium [60]. However, in the human study, there has been no further discussion of the efects of antimalarial drugs and non-steroidalanti-infammatory drugs on microbiome activity.
Te limitation of this systematic review is that most research subjects have used animal-prone lupus models with varied types and genders, and only one study has included SLE patients. In addition, all eligible studies did not use uniform tools to measure lupus disease activity. However, SLE development might be seen through lupus disease parameters such as antibody responses, organ pathology, gut leakiness or bacterial translocation, microbiota manipulation or transfer, and change in microbiome metabolic functions. Interestingly, even dysbiosis itself has become a parameter of SLE activity [61]. Moreover, this study only focused on the efect of diet on microbiome activity in SLE patients without considering the current treatment. Further studies exploring factors related to the axis of diet-microbiome-SLE disease activity are of greatly needed. Moreover, considering the drugs interaction involving microbiome in SLE therapy maybe enhance the quality of life of SLE patients.

Conclusions
Te nutrient-gut microbiome relationship has a signifcant role in the pathology of systemic lupus erythematosus (SLE). Resistant starch (RS) diet from fbrous foods can be fermented by the gut microbiome into several types and amounts of shortchain fatty acids (SCFAs) and have a benefcial efect on SLE outcomes in lupus-prone mice models. Moreover, polyphenols, especially from apples and oranges, can increase benefcial microorganisms in SLE patients. Tese fndings suggested a new therapeutic approach through dietary intervention to treat autoimmune diseases.

Data Availability
Te data used to support the fndings of this study are included within the article.

Conflicts of Interest
Te authors declare that there are no conficts of interest regarding the publication of this paper.