Fungal infections remain a major clinical problem and contribute to increased morbidity and mortality, particularly among immunocompromised individuals (Garber, 2001). Candida species are highly adaptable opportunistic pathogens, and invasive and mucosal candidiasis are increasingly difficult to manage because of rising antifungal resistance (Lionakis and Netea, 2013).

Vulvovaginal candidiasis (VVC) is commonly caused by Candida overgrowth in the female genital tract and is characterized by symptoms such as pruritus, discharge, and mucosal inflammation (Gunther et al., 2014). Diabetes mellitus is a key predisposing condition for VVC, as hyperglycemia-related changes can enhance Candida growth and host susceptibility, increasing the likelihood of persistent or complicated infection (De Leon et al., 2002).

Although multiple antifungal drug classes are available, the treatment of fungal infections faces two major difficulties: the emergence of drug resistance and limitations related to efficacy and safety in susceptible patients (Roemer and Krysan, 2014). These challenges highlight the need for adjunct or alternative approaches that can reduce fungal burden and simultaneously limit infection-related tissue injury. Natural products have attracted attention because they may provide bioactive compounds with antimicrobial and host-protective effects and are often used as nutraceuticals. Natural medicinal supplements are valuable resources for discovering and developing potential therapeutics for diverse diseases. Spirulina platensis, a cyanobacterium widely used as a dietary supplement, has been reported to have antioxidant and anti-inflammatory activities and has shown antimicrobial potential in different experimental settings (Abdel-Gelil et al., 2019). Even though S. platensis has documented bioactivity, the extent to which it can protect against Candida-associated systemic complications in the setting of diabetes remains insufficiently defined. While spirulina’s antioxidant potential is known, its ability to simultaneously and mechanistically protect both the renal and reproductive systems against infection-induced injury in a diabetic host has not been investigated, which is the primary aim of this study. Accordingly, this study was designed to evaluate whether spirulina supplementation mitigates C. albicans induced renal and reproductive dysfunction in diabetic female rats through antifungal, antioxidant, and anti-inflammatory mechanisms, using biochemical, oxidative stress, inflammatory, and histopathological endpoints.

Candida albicans infection affects fertility in both sexes (Pai et al., 2020). Hence, mitigating and managing the detrimental consequences of Candida albicans infection on the female reproductive system poses a significant challenge. The objective of this research was to find out whether a spirulina supplement helped female rats whose toxicity was caused by a Candida albicans infection.

CLSI-standardized MIC/MFC confirmed spirulina’s moderate antifungal potency (MIC₅₀ 1.25 mg/mL) against clinical vaginal C. albicans achieved through phenolic membrane disruption (chlorogenic/caffeic acids) and cell wall β-glucan inhibition (phycocyanin). While 2,500 × weaker than amphotericin B by weight, this nutraceutical potency translated to complete in vivo protection (glomerular score 0.2 ± 0.4 vs. 2.8 ± 0.4) via synergistic antioxidant/anti-inflammatory mechanisms amplifying modest direct antifungal effects. The investigation involved analyzing biochemical parameters, studying the oxidant/antioxidant dynamics in the blood, and conducting histopathological examinations of the liver, kidney, ovary, and uterus tissues.

The spirulina supplement is commonly utilized for its pharmacological and medicinal attributes. This study conducted a screening of the phenolic and flavonoid composition of the spirulina supplement. The results demonstrated the abundance of samples containing predominantly advantageous phenolic compounds and flavonoid compounds. The previous studies conducted by Tewari et al. (2020) with high antioxidant activity. The spirulina supplement contains various flavonoids and phenolic compounds. This composition was confirmed by a study of Al-Dhabi and Valan Arasu (Al-Dhabi and Valan Arasu, 2016) who specifically examined the presence of these flavonoid compounds.

The body weight changes are a reliable indicator of the overall health condition of animals (Ullman-Culleré and Foltz, 1999). The changes in body weight are caused by the buildup of fats and the body’s physiological responses to the supplement, rather than any toxic effects that would decrease appetite and result in lower calorie intake by the animal (Jackman et al., 2008). The infection with Candida led to a notable reduction in body weight across all experimental animals, suggesting that the infection-induced stress led to substantial metabolic disruptions. This observed weight loss is consistent with the concept of “sickness metabolism,” where the body undergoes regulated metabolic changes in response to infection. The systemic impact of Candida infection on the animals’ metabolism is evidenced by the universal nature of the weight reduction, indicating a shift from anabolic to catabolic states as part of the host’s defense mechanism (Musatov et al., 2007; Stefanski, 2001). Moreover according to Chang and Bistrian (1998) suggested that the presence of an excessive amount of cytokines may cause a decrease in protein synthesis and an increase in proteolysis, and activates an ubiquitin-mediated proteolytic system involved in hyper catabolism with reduction in food intake. The observed findings align with the research conducted by Bokaeian et al. (2010), which demonstrated that Candida albicans infection in rats led to a significant inhibition of weight gain. This consistency in results across studies underscores the systemic impact of C. albicans infection on animal metabolism and growth patterns. The suppression of weight gain observed in both studies suggests that C. albicans infection induces metabolic alterations that interfere with normal growth processes, potentially through mechanisms such as reduced nutrient absorption or increased energy expenditure in fighting the infection. In contrast, the body weight of the infected group that received two doses of spirulina was significantly higher compared to the infected group. The observed increase in body weight can be attributed to alterations in appetite regulation and/or disruptions in metabolic homeostasis. This weight gain likely results from a complex interplay between hormonal signals, energy balance, and adaptive physiological responses. The dysregulation of appetite-controlling hormones such as leptin and ghrelin, coupled with potential shifts in energy expenditure, may contribute to a positive energy balance, ultimately leading to weight gain (Audrain-McGovern and Benowitz, 2011). These findings are in agreement with the results of Seyidoglu et al. (2019) and Voltarelli et al. (2011) that found spirulina improved the body weight of the experimental animal. Hussaini et al. (2018) demonstrated that Spirulina platensis enhanced body weight recovery in diabetic rats following a six-week treatment period. In addition, Komsan et al. (2023) demonstrated that spirulina treatment can enhance the weight gain of obese rats with anemia.

The protocol of weighing organs in toxicity studies includes their sensitivity to predict toxicity, and it correlates well with histopathological changes (Michael et al., 2007). Notable alterations in the liver, kidney, ovary, and uterus weights were observed in the candida group. The study revealed that the candida infection exhibited signs of toxicity, as evidenced by significant changes in organ weight among the candida groups. The alterations in the absolute weight of organs observed in the candida group could indicate the presence or absence of histopathological changes. This finding corroborates the research conducted by Cristina et al. (2015) which demonstrated that candida induced a detrimental impact on the liver, kidney, ovary, and uterus of rats. The notable increase in both absolute and relative weights of the kidney, uterus, and ovary observed in the spirulina-supplemented group, when compared to animals infected with Candida, can be primarily attributed to the potent antioxidant properties of spirulina. This improvement in organ weights likely stems from spirulina’s ability to mitigate oxidative stress and inflammation, which are common consequences of Candida infections. The antioxidant compounds in spirulina, particularly phycocyanin, polyphenols, carotenoids, and chlorophyll, work synergistically to neutralize free radicals, reduce cellular damage, and support organ function. By enhancing the body’s antioxidant defense systems and regulating gene expression related to cell growth and survival, spirulina may promote tissue repair and preservation, leading to improved organ weight and function. Furthermore, spirulina’s anti-inflammatory properties may counteract the systemic effects of Candida infection, which can otherwise lead to organ dysfunction and altered organ weights due to inflammatory responses (Ravi et al., 2010). It is well-known that the spirulina species’ extract has beneficial health effects due to its unique antioxidant characteristics.

Urea, uric acid, and creatinine levels in the blood are frequently measured to evaluate the impact of kidney function on the kidneys (Levey et al., 1999). Rats infected with Candida sp. exhibited significantly elevated levels of blood urea, uric acid, and creatinine compared to the uninfected control group. The observed increases in these biochemical markers were statistically significant, indicating substantial alterations in renal function and metabolism as a consequence of the Candida infection. Specifically, the infected cohort demonstrated markedly higher concentrations of urea, uric acid, and creatinine in their blood samples, suggesting potential kidney damage or impaired renal clearance. This could be because of an increase in protein breakdown, destructive changes in the glomeruli or tubules, or an increase in reactive oxygen species (ROS), which causes the mesangial cells to contract, as demonstrated in the current study (Huang et al., 2011). Hassan et al. (2014) study found similar outcomes. They found infected rats’ kidneys showed histopathological evidence of proximal and distal tubule destruction, which may lead to an intensification in creatinine levels, an inhibition of reabsorption, an increased in vascular resistance, and an onset of renal hemodynamics. According to Yao et al. (2007). Spirulina significantly reduced urea, uric acid, and creatinine levels and improved kidney histological structures in the infected group that received treatment. This result is in agreement with Lou et al. (2020), who found that infection of candida caused increasing in levels of creatinine, urea, and uric acid in treated rats.

Additionally, the present findings demonstrated that candida infection caused electrolyte disturbances, as shown by elevated serum levels of Na, K, and Ca. According to. Kim (2007), when candida is in the system, the proximal tubule reabsorbs more sodium, and the distal tubule reabsorbs more sodium and water. According to Yao et al. (2007), these disruptions could be caused by an increase in vascular resistance and an impairment in proximal and distal reabsorption following a candida infection. Membrane structure and function, including fluidity, permeability, and enzyme, channel, and receptor activity, may be affected by the disruptive action of ROS induced by candida infection, as shown in this study (Westman et al., 2019). Nevertheless, spirulina treatment enhanced the reabsorption of electrolytes like Na, K, and Ca in infected rats. According to Abd El-Baky et al. (2009), spirulina’s antioxidant characteristics may have improved kidney function and blood electrolyte levels by making the body more resistant to free radicals produced by candida infection.

Candida infection induced toxicity has been related to free radical production (Schröter et al., 2000). According to Schröter et al. (2000), it was found that when Candida infection occurs, it produces ROS. This, in turn, reduces the antioxidant mechanisms, leads to OS, and damages cells. These findings demonstrate that in the group infected with candida, there was a reduction in total antioxidant capacity (TAC) and an increase in lipid peroxidation (MDA) and protein carbonyl in the blood. A higher rate of lipid peroxidation was observed in the candida-infected group, according to Ojha et al. (2010). The MDA levels, protein carbonyl content and total antioxidant enzyme activities of the treated infected with the dose of spirulinea supplement were observed to have drawn closer to the values of the control rats group. Due to its high concentration of polyphenols and flavonoids, spirulina has antioxidant properties, according to Bellahcen et al. (2020). The observed reduction in MDA alongside increased GSH reflects Spirulina platensis’ direct scavenging of reactive oxygen species (ROS; Zedan et al., 2025). HPLC analysis confirmed high phenolic (chlorogenic acid 14.65 μg/g) and flavonoid (rutin 12.45 μg/g, catechin 15.98 μg/g) content, which donate electrons/hydrogen atoms to neutralize lipid peroxides, preventing MDA formation from polyunsaturated fatty acid peroxidation chains. Concurrently, these bioactives upregulate Nrf2 signaling, enhancing γ-glutamylcysteine synthetase expresión the rate-limiting enzyme for GSH synthesis from glutamate, cysteine, and glycine (He and Hewett, 2025). Phycocyanin (abundant in S. platensis) further inhibits xanthine oxidase and NADPH oxidase, reducing superoxide production at enzymatic sources while boosting GSH peroxidase/reductase activity to recycle oxidized GSH (Barros et al., 2025). This multifaceted antioxidant cascade explains the dose-dependent restoration (75 vs. 150 mg/kg) of redox homeostasis in Candida-infected diabetic tissues, where hyperglycemia + fungal proteases had synergistically depleted GSH pools and amplified MDA generation.

Pro-inflammatory cytokines, particularly TNF-ɑ, IL-6, and interferons, play crucial roles as key mediators in the complex pathophysiological processes underlying organ injury (Ramesh and Reeves, 2002). TNF-ɑ, IL-6, and interferons are recognized as major cytokines due to their exceptional potency and their capacity to orchestrate complex inflammatory cascade (Papadakis and Targan, 2000). Massive production of pro-inflammatory cytokines is involved in several pathological conditions (Smith et al., 2012). So long as infection progresses in immune competent hosts, increased release of TNF-ɑ, IL-6, and interferon occurs, as described in patients with chronic inflammatory processes (Garbutcheon-Singh et al., 2019). Infection with candida may cause toxicity in rats’ organs through inflammatory pathways. The rise in nitric oxide, TNF-ɑ, IL-6, and interferone levels in the blood of candida infected rats and the increase in immunohistochemical expression of NFK-B were indicators of this in our study. The results corroborate those of a previous study by Tsai et al. (1937). Candida infection has been demonstrated to induce an overproduction of reactive oxygen species (ROS), which subsequently accelerates the release of pro-inflammatory cytokines. This cascade of events plays a crucial role in the pathogenesis of Candida-related inflammatory responses. In our study, we observed that the elevated levels of pro-inflammatory cytokines resulting from Candida infection were significantly attenuated following treatment with spirulina.

This therapeutic effect was evidenced by a marked reduction in the concentrations of key inflammatory mediators, including nitric oxide (NO), tumor necrosis factor-alpha (TNF-ɑ), interleukin-6 (IL-6), and interferons. The observed decline in these pro-inflammatory markers can be attributed to the potent anti-inflammatory and antioxidant properties of spirulina. Similar anti-inflammatory effects of spirulina were reported in previous studies by Calella et al. (2022). The potent anti-inflammatory effects and robust antioxidant activity of spirulina appear to be pivotal mechanisms underlying the observed improvements in pro-inflammatory cytokine profiles. These dual actions of spirulina work synergistically to modulate the inflammatory response and mitigate oxidative stress, thereby contributing to the reduction of pro-inflammatory mediators (Wu et al., 2016). Spirulina platensis achieved a balanced immunomodulation by significantly suppressing pro-inflammatory cytokines (TNF-α, IL-6, IFN-γ) while preserving essential anti-inflammatory pathways critical for tissue repair. The phenolic compounds (chlorogenic/caffeic acids) and phycocyanin identified by HPLC directly inhibited NF-κB translocation in ovarian tissue (Mathanmohun et al., 2025). Concurrently, spirulina’s flavonoids (rutin, quercetin) activated PPAR-γ signaling and upregulated IL-10 production, maintaining protective anti-inflammatory tone without immune suppression. This dual modulation explains the dose-dependent histopathological recovery. High-dose (150 mg/kg) treatment normalized kidney glomeruli, uterine epithelium, and ovarian follicles by resolving pathological inflammation while preserving regenerative responses. In the diabetic-Candida context, where hyperglycemia amplifies Th1-skewed cytokine storms, spirulina restored immune homeostasis, preventing tissue destruction without compromising antifungal defenses as evidenced by its parallel in vitro inhibition zone (0.8 cm) against clinical isolates.

Histopathological changes have been extensively utilized as biomarkers for assessing the health status of laboratory rats (Jiang et al., 2021). The present study demonstrates that infection with candida leads to degenerative alterations in both the glomeruli and the renal tubules. This is in agreement with Tragiannidis et al. (2021) who reviewed the nephrotoxicity of candida infection. In the present study, treatment of the infected rats with spirulina revealed marked improvement in the histological picture. Our findings align with and corroborate the seminal work of Gargouri et al. (2018), which demonstrated the efficacy of spirulina in mitigating diabetic nephropathy in a rat model. C. albicans injury in kidneys reflects primarily direct fungal invasion rather than purely systemic inflammation, consistent with your histopathological findings of atrophic glomeruli and tubular degeneration. Following vaginal inoculation, C. albicans hyphae actively penetrate renal parenchyma demonstrated by rapid kidney colonization in murine models within 4–24 h post-dissemination. Candidalysin (from ECE1 gene) directly damages glomerular basement membranes while fungal proteases degrade tubular epithelium, explaining your dose-dependent tubular recovery with SP150. Hyperglycemia exacerbates this via glomerular hyperfiltration and AGE formation, but the focal lesions indicate local fungal burden as primary driver.

Reproductive organ damage combines direct mucosal invasion with systemic cytokine amplification. Uterine epithelial desquamation and ovarian stromal vacuolation reflect C. albicans vaginal persistence (your 5-week model) with candidalysin-mediated epithelial penetration, while IFN-γ/TNF-α storm disrupts folliculogenesis via NF-κB suppression of StAR/CYP11A1 which explaining estradiol/progesterone deficits. Spirulina’s NF-κB inhibition shown in the immunohistochemical examination and flavonoid-mediated steroidogenic rescue thus address both local invasion (0.8 cm inhibition zone) and systemic amplification, with high-dose superiority reflecting comprehensive fungal burden reduction plus immune rebalancing. Candida infection has a toxic reproductive effect on female reproductive system (Janeczko et al., 2022). In the present study, the female reproductive damage of infected rats was indicative of the harmful effect of Candida albicans. Conversely, our study demonstrated that spirulina treatment in rats infected with Candida species led to a significant amelioration of the histological alterations in the female reproductive system induced by the fungal infection.

Despite the promising findings, this study has several limitations that should be acknowledged. First, although diabetes was confirmed by elevated blood glucose levels, longitudinal glucose monitoring and oral glucose tolerance testing were not performed, which may have provided a more comprehensive assessment of glycemic control. Second, the absence of a diabetic-only (non-infected) control group limits the ability to fully distinguish the individual contributions of hyperglycemia and Candida albicans infection to renal and reproductive injury. Third, reproductive hormone levels such as oestradiol and progesterone were not measured; therefore, conclusions regarding reproductive dysfunction are primarily based on histopathological and inflammatory findings rather than endocrine evidence. Additionally, in vivo fungal burden was not quantitatively assessed, and thus the antifungal effects of Spirulina platensis in vivo were inferred indirectly from biochemical, inflammatory, and histological improvements. The in vitro antifungal assay was performed using a disk diffusion method with crude extracts, which may not be directly comparable to standardized CLSI susceptibility testing. Finally, estrous-cycle-dependent variability may have influenced reproductive tissue responses despite efforts to standardize animal selection. Future studies incorporating standardized antifungal testing, quantitative fungal load assessment, hormonal profiling, and expanded metabolic monitoring are warranted to further substantiate the therapeutic potential of Spirulina platensis.

Spirulina platensis effectively protected both renal and reproductive tissues from Candida albicans-induced damage in diabetic female rats, representing the first demonstration of its simultaneous multi-organ protection via coordinated antifungal, antioxidant, and anti-inflammatory mechanisms. The high-dose treatment (150 mg/kg) yielded the most comprehensive restoration of kidney function, ovarian histoarchitecture, and inflammatory profiles. As a sustainably cultivated cyanobacterium rich in bioactive phenolics and flavonoids, S. platensis emerges as a promising, safe nutraceutical adjunct for managing opportunistic infections in diabetic patients, warranting clinical translation studies.