Bacteria, yeast, and fungi are microorganisms that together are referred to as gut flora, gut microbiota, or gut microbiome. Gut microbiota is responsible for the basic health in a human being. The gut is inhabited by approximately 100 trillion of these microorganisms, primarily found in the large intestine with a smaller amount in the final part of the small intestine. These gut bacteria thrive on the byproducts of digestion (21). The human body is estimated to have over a thousand different microbial species, which can account for 54.7% to 55% of fecal weight (22).

Gut microbiota contributes significantly to multiple functions ( Table 1 ). It is first an immune system supporter; around 80% of the body’s immune cells live in the gut, where the microbiota helps trigger immune reactions and protect the body from pathogens (23, 24). Second, gut microbiota keeps metabolic health by creating essential vitamins and nutrients. They are involved in the functions of the liver, insulin sensitivity, control of appetite, and weight regulation, and also aid in the bile metabolism beneficial in the digestion of fat (25, 26). Furthermore, a balanced gut microbiota may lower the likelihood of illnesses like type 2 diabetes and other metabolic disorders (27, 28). More and more, the connection between brain and gut health is also being realized. Gut microbiota is responsible for central nervous system function and, perhaps, mood and cognitive status (29–31).

Dysbiosis, however, can lead to pathological states like inflammation and autoimmunity (24, 32). Several studies have presented evidence of deranged gut microbiota and the associated disorder like lupus (33, 34). Therefore, it is well to have sufficient diversity in the gut microbiota for overall health (25).

Research has revealed significant differences in gut flora among healthy and SLE patients. Gut microbiota in healthy individuals is generally rich and diverse, undertaking a range of body functions, including immune regulation and metabolic balance. In contrast, individuals with SLE have reduced diversity of gut microbiota, with a structural and functional disorder known as dysbiosis (35). Studies indicated that SLE patients have some of the populations of bacteria depleted or altered, which initiate inflammatory process development and immune dysregulation. The imbalance is generally the depletion of beneficial bacteria. In a healthy gut, Firmicutes and Bacteroidetes together account for approximately 98% of the bacterial community, low F/B ratio is linked to gut microbiota dysbiosis, once more pointing to microbial imbalance as being key to SLE pathogenesis (33, 36). In Kim et al.’s model, microbial populations were distinct from pre-disease, and lupus-like phenotype development was linked to extreme decreases in the diversity of the gut bacteria (37).

SLE patients are usually characterized by a condition called leaky gut, which is compromised integrity of the intestinal barrier. The compromised integrity permits numerous pathogens, such as microbes, to cross the mucosal layer of the intestine. This invasion is responsible for killing and injuring the intestinal cells, particularly goblet cells and Paneth cells. Both are extremely important to maintain gut integrity: Paneth cells induce defense and control microbes, while goblet cells produce the protective layer of intestinal mucus. The loss of these cells can further exacerbate the intestinal barrier dysfunction, creating a vicious cycle that may contribute to the overall pathology observed in SLE patients (35, 38).

In SLE patients, the gut microenvironment can experience a heightened level of inflammation brought about by the autoimmune nature of the disease. Such an inflammation has the ability to significantly alter the gut bacteria composition and also their function. The changes in the gut microbiota have the potential to influence immune system pathways and become key contributors to SLE pathology. For instance, dysbiosis has the potential to lead to T cell population alterations, which in turn may produce a tipping in the balance towards systemic autoimmunity. Dysregulation will persist to enhance autoreactive T cell activation and lead to disease progression and exacerbation (39).

Changes in the gut microbiota can significantly impact the production of short-chain fatty acids (SCFAs) and other metabolites which in turn modulate systemic inflammation and immunity. SCFAs, including propionate, acetate, and butyrate, strongly modulate inflammation, supporting gut health and immune function. With dysbiosis of the gut microbiota, synthesis of such beneficial metabolites could be reduced, which may promote increased inflammation and compromised immune function. Such disturbance may exacerbate autoimmune conditions like SLE, as defective SCFA generation might be responsible for intestinal wall disruption and modulation of immune signaling pathways, thereby leading to disease pathology (39).

Mounting evidence indicates that the structure of gut microbiota differs drastically in women and men as a result of hormones, lifestyle, and diet (40, 41). Women possess higher levels of some beneficial bacterial species, whereas microbial diversity is higher in men (42, 43). These variations affect sex based immune modulation and disease susceptibility (44).

SLE is a disease that primarily targets women, making it one of the known sex-specific autoimmune diseases. The study of gut microbiota in Murphy Roths Large/Lymphoproliferative (MRL/lpr) lupus-prone mice discovered striking sex-dependent differences. The female MRL/lpr mice have lower Lactobacillaceae and higher Lachnospiraceae than the control group. Male MRL/lpr mice do not show any significant differences in gut microbial composition from controls. Likewise, in control groups, female mice have higher abundance of Lactobacillaceae and Streptococcaceae, with lower abundance of Lachnospiraceae and Clostridiaceae than males. In lupus-prone females, reduced abundance of Erysipelotrichaceae and Bifidobacterium, with increased Lachnospiraceae and Bacteroidetes S24–7 abundance, has also been reported (44).

These findings suggest that microbiological dysbioses specific to sex, more precisely the increased prevalence of Lachnospiraceae in females, may account for the earlier onset and greater severity of lupus symptoms. The structure of gut microbiota in female lupus-susceptible mice appears to favor inflammatory processes, which can promote disease onset (44).

Sex hormones, particularly estrogen and testosterone also play a central role in the determination of gut microbiota and SLE susceptibility. Estrogen enhances B cell activation and antibody secretion, leading to increased immune responses, while testosterone exert immunosuppressive effects through inhibition of antibody production. This hormonal effect accounts for sexual characteristics changes in immune function, and the higher susceptibility of women to autoimmune diseases like SLE (45).

It will be crucial to distinguish the interplay of gut microbiota and the sex hormones as it can potentially unlock the mechanisms of higher susceptibility of females to SLE and also unveil novel avenues of therapeutic intervention by manipulation of the gut microbiome for controlling disease course (45).

Through interaction with immune cells and epithelial cells, probiotics participate in the control of immunological response ( Figure 1 ). Probiotics act on epithelial and immune cells in two manners: one is direct probiotic contact with epithelial and immune cells via microbe-associated molecular patterns (MAMPs) such as microbial conserved molecules like surface proteins (SLPs), Lipoteichoic acid (LTA), flagellins, pilins, capsular polysaccharides (CPSs), peptidoglycan (PGN) and lipopolysaccharides (LPS), which may be sensed by host immune receptors to mediate such interactions (53–57). The other is an indirect interaction through the release of metabolites, including SCFAs, which can influence physiological responses through different signaling pathways (58).

Dysbiosis, or gut microbiota disturbance, is a compositional and functional change contributing greatly to the basic pathogenesis of SLE. Dysbiosis destroys the integrity of intestinal barriers, thus making the mucosa permeable to pathological organisms and leading to cell death among small intestinal cells such as Paneth and goblet cells (33, 70, 71). There is evidence in MRL/lpr mice that higher levels of LPS are associated with impaired intestinal barrier function (50). Zonula Occludens-1 (ZO-1) and occludin are two tight junction proteins in the intestinal barrier that are disrupted by LPS. For instance, Guo et al. (72) showed that LPS increases intestinal permeability via induction of expression of TLR4 and CD14 in enterocytes, an event that is mechanistically related to destabilization of tight junctions. These findings demonstrate one way in which LPS could be implicated in gut barrier breakdown in autoimmune conditions, such as lupus (72).

Probiotic-derived metabolites have a protective role in ensuring the intestinal epithelial barrier. They exert their effects either directly by stimulating goblet cell-stimulated mucus secretion such as mucin 2 (MUC2) secretion in colonic epithelial cells that enhances intestinal barrier function and immune response. Probiotic induction of mucin secretion offers not only a shield over the gut lining itself but also immune-modulating effects, therefore overall enhancement of gut health (67, 73, 74), or by interacting with specific receptors, which further stimulate the release of antimicrobial peptides or increase tight junction protein expression (53, 75, 76). For instance, an experiment on the effect of probiotics on the structure of tight junction utilized the marker claudin-7 and observed that Lactobacillus plantarum (L. plantarum) and Akkermansia muciniphila (A. muciniphila) maintain gut barrier integrity and function in a model of SLE (77).

Another study revealed that Probiotics such as L. rhamnosus NK210, Lactococcus lactis NK209 (Lc. lactis) and Bifidobacterium longum NK219 (B. longum) has improved tight junction protein levels and inhibited LPS synthesis by gut bacteria. Thereby ameliorating the condition of leaky gut in mice with inflamed intestines (78). Furthermore, Mengchen et al.’s investigation, which examined fecal DNA from experimental groups both before and after probiotic treatment, found that A. muciniphila and L. plantarum considerably changed the gut microbiota’s diversity and structure (77).

Such manipulation of gut microbiota by various probiotic supplements could restore the dysbiotic F/B ratio, which is important both in the prevention and treatment of SLE. It’s highly important to note that balanced gut microbiota is achieved when the F/B ratio is equated, and imbalances occur when this ratio becomes either elevated or diminished. Moreover, various probiotics have different effects on the F/B ratio; therefore, the choice and dosage of probiotics should be proportional to induce balance and eubiosis of gut microbiota (79).

Probiotics reinforce the intestinal barrier by stimulating mucus secretion, maintaining tight junction integrity, and inhibiting lipopolysaccharide translocation. This regulation mitigates leaky gut phenomena, which are key contributors to SLE progression, emphasizing their role in gut-centric therapies.

Inflammation of the gut permits harmful germs to enter the bloodstream and secrete LPS, which stimulates the Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway and enhances pro-inflammatory cytokines and autoantibody production, leading to immune complex generation and deposition in the kidney, which causes organ damage. LPS also activates albumin excretion, which is associated with the aggravation of lupus nephritis (80).

A study of Lactobacillus supplementation in MRL/lpr mice confirmed that it improves the elimination of LPS by inducing intestinal alkaline phosphatase (IAP) activity, which maintains tight junction integrity and barrier function. IAP dephosphorylates LPS and prevents it from binding TLR4, thus inhibiting NF-κB pathway activation, ultimately reducing proinflammatory cytokine release (50). Moreover, SCFA has proven to inhibit the activation of the NF-κB pathway (81). Weakened tight junction increases the intestinal barrier permeability, which enables leaky gut effect, leading to increased levels of anti-Ruminococcus gnavus antibodies (anti-RG) that act on Ruminococcus gnavus (RG) antigens and worsen kidney damage in lupus patients (82).

Kidney disease in New Zealand Black/White F1 hybrid mice (NZBWF1 mice) is characterized by hyperblood pressure, albuminuria, and altered urine creatinine levels, in correlation with anti-dsDNA antibody titers. Probiotic Lactobacillus fermentum CECT5716 (LC40) prevents lupus nephritis caused kidney damage via lowering systemic inflammation and preserving the balance of the gut microbiota and thereby preventing immune complex deposition within the kidneys. LC40 supplementation reduces autoantibody levels and pro-inflammatory cytokines, indicating broader immunomodulatory effects. These results demonstrate its potential as a lupus nephritis adjuvant treatment (83). Furthermore, butyrate has been shown to improve renal disease ( Table 2 ). Through the G-protein-coupled receptor. Butyrate therapy demonstrated effectiveness in reducing kidney damage in lupus-prone mice by boosting the F/B ratio and microbial diversity (84, 85).

An investigation by Kim et al. indicated that the combination treatment between Tacrolimus (Tac) and Lactobacillus acidophilus (L. acidophilus) reduces kidney pathology scores and serum levels of immunoglobulin G2a and anti-dsDNA antibodies (37). Furthermore, it has been shown that A. muciniphila and L. plantarum both lessen kidney damage by lowering proteinuria, creatinine, and urea nitrogen levels (77).

Early on in the inflammatory process, changes in innate immune cells within the intestines have been observed, including mast cells, dendritic cells, neutrophils, and macrophages. These immune cells are recruited due to self-antigens and changes in the composition of commensal bacteria, a process termed dysbiosis. This dysbiosis often leads in turn to colonic barrier dysfunctionalities, a condition notoriously known as “leaky gut” (86, 87). The colonic barrier breakdown thus allows microbial derivation products, whose most common representatives should be considered LPS and Teichoic acid (TA), to begin to translocate into the layer underneath the epithelium, the lamina propria, launching an immune challenge that will express itself through numerous pro-inflammatory cytokines and complex-associated cascades (82, 88).

Chronic inflammation seen in SLE is a result of pro-inflammatory innate immune cells being recruited and activated, leading to the activation of the adaptive immune response, which culminates in autoantibody production. Both the innate and adaptive responses have a central role in the chronic tissue injury and epithelial damage that represent SLE (89, 90).

Probiotics have been shown to have immunomodulatory effects that are particularly intriguing in relation to controlling the immunological responses in individuals with SLE (88). Numerous metabolic products produced by probiotics may have an impact on immunocompetent cells and the signal pathways that are connected to them in the pathophysiology of SLE ( Figure 2 ) (87). The manner in which probiotics affect both innate and adaptive immune cells, including cytokine production and the modulation of some crucial signal pathways, has been the subject of much research up to this point (82, 87).

Food and medicine have a long history in the natural world, and both share the ability to make a strong influence on health and well-being. Many civilizations have known over the centuries that certain foods, especially herbs and spices, have therapeutic properties as well as nutritional worth. This holistic viewpoint emphasizes how our food choices have a direct effect on our mental and physical well-being (161). Among various dietary components known for their health benefits, ginger stands out as a representative dietary intervention that exerts significant immunomodulatory and anti-inflammatory effects (162). Its bioactive compounds, particularly 6-gingerol, have been shown to impact gut microbiota and enhance the activity of probiotics, thereby improving the regulation of immune responses in SLE.

6-gingerol represents one of the major bioactive ingredients of fresh ginger, being one of the most relevant supplements related to nutrient factors with possible activities of modulation towards immune functions. It possesses well-documented anti-inflammatory and antioxidant properties (163). This compound has lately appeared to be significantly involved also in the enhancement of gut health, especially related to probiotics (164).

The primary way in which 6-gingerol mediates its functions is by promoting probiotic adhesion to intestinal epithelial cells. Research has demonstrated that6-gingerol improves probiotics’ adherence to colonic epithelial cells, particularly those of L. acidophilus and Bifidobacterium bifidum (B. bifidum). in a dose-dependent manner (164). This improved adhesion is crucial because it fosters the colonization of beneficial bacteria, which is necessary for maintaining gut homeostasis and supporting immune modulation which may be beneficial in alleviating conditions such as SLE (164).

Further evidence shows that 6-gingerol can alter gut bacteria diversity and composition to benefit those with inflammatory and immune-related diseases. For instance, 6-gingerol increased the proportion of the phylum Bacteroidetes in high-fat diet-induced obese mice, therefore decreasing the F/B ratio generally related to obesity and inflammation (165).

Based on research by Ali et al, 6-gingerol decreases the development of NETs significantly in lupus models, therefore being protective against the cardinal pathological features associated with lupus-inflammation and autoantibody formation. Furthermore, the study elaborates on the antioxidant properties of 6-gingerol by noting its potential to reduce levels of ROS and recover glutathione to protect cells against oxidative stress and inflammation (162). This effect may be further enhanced in a synergistic manner by probiotics through the reduction of NETs while exhibiting antioxidative properties that lower ROS production and cellular cytotoxicity (92). In another study, 6-gingerol has been found to lower autoantibody levels in a lupus mouse model. The cell-free DNA and myeloperoxidase-DNA (MPO-DNA) complex levels were significantly decreased after treatment, indicating a notable decrease in plasma NET levels. Significant decreases were also noted in primary autoantibodies such as total IgG, anti-β2 glycoprotein I (anti-β2GPI), and anti-dsDNA (162). The findings highlight the synergistic effect of probiotics, which can regulate the amount of autoantibodies along with the 6-gingerol (51).

Moreover, some publications have identified a reduction of inflammatory cytokine levels in SLE patients that might be diminished with the intake of probiotics, highlighting their potential immunomodulatory effects (166). In parallel, an experimental treatment of 6-gingerol on mice induced with lupus showed reductions in the levels of the pro-inflammatory TNF-α and IFN-γ isotypes, pointing to its good effects on SLE’s usual general inflammation aspects (162). These findings suggest that a combined therapeutic strategy involving both probiotics and 6-gingerol may exert complementary or synergistic effects by targeting overlapping inflammatory pathways, thereby offering enhanced clinical benefit in managing SLE.

In addition to their ability to balance cytokine production, probiotics enhance the activity of Treg cells (125). Perhaps 6-gingerol may work in collaboration with probiotics by additionally enhancing Treg proliferation and activity, hence autoimmune flares and symptoms and enhancing SLE symptoms (167). Interestingly, 6-gingerol also was found to suppress the NF-κB pathway, thereby lessening the inflammatory cytokine output (168). This increases the effectiveness of probiotics in inhibiting this route, which may provide a promising treatment for autoimmune conditions like SLE (147).

In summary, the synergistic effect of 6-gingerol in combination with probiotics offers a potential direction of study in managing SLE. Through their collective capacity for modulating the immune system and lessening inflammation, these therapies hold the potential to be utilized as adjunctive therapies in SLE management.

While nutritional components like ginger regulate gut health and immunity through the natural consumption of foods, nutritional supplements like vitamin D are major regulators of immune activity and balance of gut microbiota. Vitamin D deficiency is observed in SLE patients and also reported to be linked with disease activity. Vitamin D has an important function in inhibiting inflammation and enhancing immune tolerance in SLE by functioning in collaboration with probiotics and immune cells. Many studies have reported that large percentages of SLE patients have low levels of vitamin D, and in some studies, as much as 73.3% insufficiency and 23.3% frank deficiency (169). The effects of corticosteroid medication, increased sunscreen use, and decreased sun exposure are also contributing reasons for this insufficiency (170). It is mostly observed that higher disease activity scores are equivalent to low levels of vitamin D, and therefore low levels can be implicated in worsening symptoms and overall poor health outcomes in these patients (169). Indeed, vitamin D levels were reported to inversely relate to the SLE Disease Activity Index, in which low levels of vitamin D were indicative of greater disease severity (169). Deficiency in vitamin D may also worsen the systemic symptoms, such as fatigue, that are experienced by most SLE patients (171).

In recent studies, consideration has been given to an interaction existing between vitamin D and gut microbiota. Vitamin D particularly modulates the intestinal microbiome by improving the growth of bacteria, usually regarded as beneficial or through enhancement of antimicrobial properties of gut epithelium. Vitamin D may also act through VDR to lower microbial dysbiosis and improve intestinal barrier function with a rise in SCFA production by commensal bacteria. These changes not only improve gut health but also enhance immune function by regulating intestinal inflammation (172–174). 1,25-dihydroxyvitamin D₃ (1,25-(OH)₂-VitD₃) is the active form of vitamin D₃, which is known for its immunomodulatory effect. Research showed that it can interact with the VDR receptor, enhancing its action. VDR is present on several immune cells’ surfaces, including B lymphocytes, macrophages, T cells, and dendritic cells enhancing the immune modulatory effect (175).

In SLE, there is a general overactivation of T helper cells, with the Th17 cells especially contributing much to inflammation. Indeed, active vitamin D was shown to suppress Th17 cell differentiation and activity, hence diminishing their contribution to the inflammatory response characteristic of SLE. In contrast, 1,25-(OH)2-VitD3 enhanced Tregs’ T cell differentiation-required for maintenance of immune tolerance and resistance to autoimmunity (176, 177). probiotics also restrict production of Th17, yet concurrently it promotes proliferation of Tregs (120, 125). This might provide insight into the different aspects that demonstrate potential synergic actions of probiotics with vitamin D supplementation on each.

Other studies cite the ability of 1,25-(OH)2-VitD3 to reduce autoantibodies such as anti-dsDNA by acting negatively on B cells through suppression of its growth and apoptosis induction of the autoreactive B cells (178). Long-term observational data further correlate Vitamin D sufficiency with reduced autoantibody titers such as anti-dsDNA and disease activity (179). 1,25(OH)2D3 has been shown to suppress mitogen-stimulated IgG production in peripheral blood mononuclear cells from both healthy individuals and inactive SLE patients, indicating a direct inhibitory effect on IgG synthesis (180). Long-term observational data further correlate Vitamin D sufficiency with reduced autoantibody titers and disease activity. probiotics have been shown to lower the serum levels of Antinuclear Antibodies (ANA) (51). This activity cites a hopeful role for 1,25-(OH)2-VitD3 and probiotics as a therapy for autoimmune diseases.

Furthermore, vitamin D also showed significant inhibition of NF-κB pathways (181), and a regulatory effect regarding cytokine production, thus it inhibits proinflammatory cytokines in SLE pathogenesis, including IFN-γ, IL-17, IL-23, IL-6, and TNF-α (182–184), while stimulating anti-inflammatory cytokine production like IL-10 and TGF-β (185, 186). Similarly to probiotics, which are also able to enhance anti-inflammatory cytokines and decrease pro-inflammatory cytokines, probiotics are also believed to block the NF-κB pathway, showing possibilities for a synergistic approach with vitamin D to further reduce inflammation in SLE (51, 147, 166).

Probiotics exert anti-inflammatory and immunomodulating effects and can therefore also act synergistically with vitamin D. Probiotics can enhance vitamin D receptor (VDR) protein expression, improving active vitamin D absorption, which acts in turn to potentiate immune response regulation (187). Research has demonstrated that probiotics such as LGG and L. plantarum enhanced the expression of VDR protein and L. plantarum alone increased VDR transcriptional activity in Human Colorectal Carcinoma Cell Line 116 (HCT116) cells. Furthermore, while probiotics had no effect on VDR (-/-) mice, they were demonstrated to provide physiological and histologic protection against Salmonella-induced colitis in VDR (+/+) animals (187). Recent evidence suggests that vitamin D-probiotics co-supplementation might increase VDR expression and improve the anti-inflammatory action of these compounds (188). Co-supplementation is a novel approach for the therapy of SLE and other autoimmune disorders. Through the utilization of vitamin D’s immune-modulatory effect and the ability of probiotics to enhance VDR signaling and gastrointestinal health, this treatment may deliver synergistic benefits over current treatments.

In conclusion, Vitamin D may have a multirole in immune function regulation, creating anti-inflammatory effects and supporting general health. Its interaction with gut microbiota and synergistic action with probiotics make it a very promising adjunctive therapy for autoimmune diseases, including SLE.

Probiotic application in immunosuppressed patients is extremely important due to their compromised immune protection. Systemic infection is among the serious hazards because live probiotic bacteria (e.g., Lactobacillus or Saccharomyces) may translocate across the gut barrier and induce septicemia, fungemia, or endocarditis. While rare, these infections are improperly recorded in immunocompromised individuals, particularly central venous catheter patients or those with severe intestinal permeability, emphasizing the need for strain-specific risk assessments (193, 206). Imbalance of flora is another concern, probiotics unintentionally can trigger overgrowth of commensal or pathogenic bacteria in an uncontrolled gut environment. For example, immunocompromised patients on chemotherapy or antibiotics experience reduced microbial diversity and are susceptible to probiotic-induced disturbances, e.g., overgrowth of Chloridoids difficile or fungal domination (193).

Immune overactivation poses a theoretical yet significant risk. Probiotics modulate dendritic cell function and cytokine release (e.g., IL-6, IFN-γ), possibly exacerbating autoimmune or inflammatory disease in predisposed hosts. BAFF and APRIL pathways are particularly concerning, as overexpression initiated by probiotic metabolites like bacterial DNA or exopolysaccharides has been linked with autoantibody production and lupus-like syndromes (193, 207). Finally, metabolic disturbances, though inadequately reported, represent a theoretical risk. Probiotic strains with urease activity or D-lactate production could theoretically contribute to hyperammonemia or metabolic acidosis in patients with hepatic or renal impairment (193). While evidence is limited, these risks underscore the necessity for rigorous monitoring and personalized probiotic strategies in immunosuppressed populations.

Sex-specific probiotic efficacy differences may arise due to the interaction of probiotics with sex hormone signaling, most notably estrogen. L.reuteri was seen to improve the secretion and expression of intestinal hormones, including estrogen receptor-beta (ER-β), which can improve anti-inflammatory effects by promoting IL-10 levels and Treg differentiation. These are especially relevant in females, in whom estrogen signaling boosts probiotic-induced immune modulation (208).

Further, animal studies demonstrate sex-dependent differences in response to L. reuteri therapy. In mice, L. reuteri supplementation increases beneficial bacteria and immune cell populations more significantly in females compared to males, which is probably explained by the immunomodulatory actions of estrogen. This agrees with the observation that probiotic effects may be more potent in females, and sex must be considered as a biological variable when conducting research and therapy with probiotics (209).

Mechanistically, probiotics can interact with SLE pathophysiology in various ways by gender. In females, estrogen dominance enhances gut permeability via claudin-2 upregulation, a process counteracted by probiotics like L. rhamnosus GG, which strengthen tight junctions and reduce bacterial translocation (210, 211). Conversely, probiotics that metabolize estrogen (e.g., L. plantarum) could lower systemic estrogen levels, indirectly dampening B-cell hyperactivity (77). In men, testosterone’s immunosuppressive effects might synergize with probiotics to suppress autoimmunity, but this is not yet investigated in SLE models (212). Despite these insights, most clinical trials fail to stratify outcomes by sex, obscuring gender-specific mechanisms. Addressing this gap is critical, as personalized probiotic strategies could optimize therapeutic benefits while mitigating risks in SLE management (51).

Most investigations of probiotic effectiveness in SLE underscore the importance of optimum dose maximization for immune modification. Optimum concentrations of 10^7 CFU/mL for L. rhamnosus and 10^5 CFU/mL for L. delbrueckii have been determined from an ex vivo experiment conducted with peripheral blood mononuclear cells (PBMCs) in SLE patients. Both of these probiotics, in those dosages, enhanced regulatory T cell-related gene expression and lowered proinflammatory cytokines as markers of high immunomodulatory activity (146).

Survival of probiotic bacteria through the gastrointestinal tract is crucial to their functionality because they must survive harmful conditions of gastric pH, bile salts, and digestive enzymes to maintain viability and functionality (213, 214). Formulation with protective measures, such as the use of encapsulation techniques using polymeric materials, shields the probiotics from stresses, allowing them to survive and target specifically in the intestine (215, 216). For example, alginate hydrogels find widespread use on the basis of acid insolubility and ability to form protective microcapsules that confer probiotic stability and controlled release (215).

Probiotic delivery systems can be broadly classified into conventional and non-conventional systems. The conventional drug delivery systems include beads, capsules, and tablets, with the oral route being the most used for convenience, economy, minimal risk of infection, and good patient compliance (213, 217). Technological innovation in formulation has witnessed the advent of microencapsulation and nano-encapsulation techniques, where there is precise control over particle size and surface chemistry, further promoting probiotic viability and enabling targeted delivery within the gastrointestinal tract (216). Methods like electrospun alginate nanofibers have been found to provide improved protection for probiotics against gastric conditions and improved survival rates compared to non-encapsulated ones (216).

In addition, other administration routes such as nasal, transdermal, vaginal, and rectal are investigated to potentially enhance therapeutic effects and maximize clinical efficacy of probiotics beyond oral delivery (218). These alternative routes may help overcome some limitations of oral delivery, such as degradation in the GI tract, and offer new opportunities for probiotic therapies.

In SLE animal models, 6-gingerol, has been administered at about 10 mg/kg intraperitoneally three times per week from week 4 of treatment. For example, in TLR7 agonist-induced lupus mouse model, delayed treatment with 6-gingerol from week 4 and for 2 weeks greatly reduced plasma NET levels, autoantibody formation (e.g., anti-dsDNA and anti-β2GPI antibodies), and thrombosis but not total leukocytes or spleen size (162). Other studies using oral gavage reported doses ranging from 100 to 250 mg/kg daily in mice, which effectively reduced lupus-related inflammation and symptoms without observed toxicity (219, 220). While no direct clinical trials provide data on optimal human dosing of 6-gingerol for SLE, ginger extracts are generally regarded as safe, with human doses up to 2 grams daily (approximately 25 mg/kg for a 70 kg adult) showing good tolerability in other contexts (219). Translating findings from mice to humans would require careful dose scaling and clinical validation to establish safety and efficacy in SLE patients.

For vitamin D supplementation in SLE patients with deficiency (serum 25-hydroxyvitamin D < 20 ng/mL), clinical practice guidelines are typically vitamin D3–8000 IU daily for 8 weeks and then maintenance on 2000 IU daily. For vitamin D insufficiency (21–29 ng/mL), the dosing is 8000 IU daily for 4 weeks followed by an identical maintenance regimen (221). Importantly, this dosing strategy has been found safe, with no reported incidents of hypercalcemia (221, 222). The benefits include improved SLEDAI scores and reductions in inflammatory markers, supporting the necessity of long-term vitamin D supplementation, ideally lasting at least 6 to 12 months, to achieve maximal therapeutic benefits in SLE patients (221–223).

In moving from laboratory findings to clinical applications, one critical bottleneck is the limited effectiveness of direct administration of therapeutic agents such as probiotics, 6-gingerol, and vitamin D. Probiotics often face harsh gastric conditions, including low pH and bile salts, which drastically reduce their viability before they reach the intestine—the primary site of action (213, 214). Similarly, 6-gingerol suffers from poor water solubility, instability in physiological fluids, and rapid metabolism, all contributing to low oral bioavailability (224). Vitamin D, being lipophilic, is vulnerable to degradation and exhibits variable absorption depending on fat intake and individual metabolic status (225).

These limitations highlight the need for advanced delivery systems such as nano-encapsulation, nano-emulsions, or self-microemulsifying drug delivery systems (SMEDDS) that can protect these compounds from degradation (226–228), enhance mucosal absorption, and enable targeted delivery. Such strategies are essential to overcome pharmacokinetic barriers, improve therapeutic consistency, and enhance patient outcomes in SLE treatment.

Microbiota profiling is a useful path to the personalization of treatment strategies for SLE patients. 16S rRNA gene sequencing and metagenomics are some of the high-throughput sequencing technologies with the ability to identify patient-specific dysbiosis signatures. For example, increased Lachnospiraceae or reduced Lactobacillus species can guide the selection of specific probiotic strains (229, 230). Furthermore, unsupervised gut microbiota-based clustering of SLE patients recognized patient subgroups that associated with immune phenotypes and disease activity, which justified the use of microbiota patterns to predict response to therapy (229). Moreover, associating microbiota patterns with cytokine levels, autoantibody profiles, and clinical phenotypes can forecast response to therapies like 6-gingerol or vitamin D (231, 232). This precision medicine approach potentially enables clinicians to individualize treatment regimens through the selection of the best strain, dose, and combination therapies to maximize efficacy and minimize toxicity.

Pharmacokinetic (PK) and pharmacodynamic (PD) studies are needed to determine how combination treatments such as probiotics, vitamin D, and 6-gingerol interact together in the body to impact both efficacy and safety for treating SLE (233). Currently, there is a significant gap in such studies for these combinations, which hinders the optimization of dosing regimens, prediction of drug interactions, and understanding synergistic or antagonist effects of the agents. As SLE’s immune dysregulation is so complex and with the very real possibility of herb-drug and supplement-drug interactions, PK/PD studies are imperative (233). These studies help to determine the absorption, distribution, metabolism, and excretion profiles of combination agents, characterize their immunomodulatory effects and kinetics in terms of drug concentrations, identify any undesirable effects or toxicities arising from combination use, and inform personalized treatment approaches according to patient-specific factors and disease activity. Without this vital pharmacological data, clinical use of these combinations is largely empirical and could pose safety risks (233, 234).

Effective real-world monitoring of disease activity, flare, and relapse in SLE is at the core of disease management and therapy adjustment, including adjustment of new combination therapies. Modern clinical practice is aimed at frequent measurement of disease activity using validated measures like the SLE Disease Activity Index (SLEDAI) or the British Isles Lupus Assessment Group (BILAG) scores. These are adjusted based on disease severity and patient status (235, 236). Biomarker monitoring is likewise a cornerstone of disease management, including measurement of complement levels (C3, C4), anti-double stranded DNA antibodies, erythrocyte sedimentation rate (ESR), and IFN-α levels (236–239). Sensitive tests like digital ELISA have been found to be helpful in identifying low-level disease activity and even in pre-dicting imminent flares (240). Routine laboratory studies, including complete blood counts, urinalysis, and metabolic panels, are recommended every 3 to 6 months or more frequently during active disease to screen for organ involvement or complications (237, 241). Physicians individualize the frequency of visits based on disease activity, ranging from frequent visits in the context of active lupus nephritis to less frequent follow-up in stable disease, enabling individualized care (241). Emerging biomarkers such as IFNα levels may further improve flare prediction and help guide therapy adjustments, potentially enhancing the management of complex combination therapies (237, 238, 240).

The implementation of sensitive biomarker tests and accredited clinical indices in routine practice is pivotal towards accurate disease monitoring as well as effective therapeutic management. However, an evident lack of real-world evidence in terms of how such monitoring procedures can be applied specifically for combination probiotic, vitamin D, and 6-gingerol therapy in SLE does exist. This shortfall highlights the necessity for future observational registries and studies to evaluate the safety, efficacy, and optimal monitoring practices in these novel combination therapies.