Fulvic Acid Shown As Beneficial in Chronic Inflammatory illnesses

Figure 1

FvA has been indirectly utilized in traditional Indian medicine (“Ayurveda”) for roughly 3000 years [3]. The substance called Shilajit, a tar-like exudate from the Himalayas, contains about 15–20% FvA and is used for medicinal purposes. As per ancient texts, Shilajit can have immune-modulation, antioxidant, diuretic, antihypertensive, and hypoglycaemic effects [3]. In addition, when applied externally, it is claimed to be an antiseptic and analgesic [11].

Reviews on Shilajit indicate that the intake is safe; however, the pharmacological dosing of such molecules remain unknown [3]. Despite such lack of information, Shilajit/FvA is currently available as a nutraceutical to the public [12]. The purpose of this review is to investigate and highlight the current knowledge base regarding FvA and its effects on animals and animal cells.

2. Immunomodulation by FvA

The most adequately researched claim of FvA is its ability to modulate the immune system. However, the outcomes of such studies remain controversial. FvA can be both proinflammatory and anti-inflammatory in animal systems. The available literature regarding the effects of FvA on the immune system is summarized in Figure 2.

Figure 2

2.1. Anti-inflammatory Effects of FvA

Asthma, allergies, and eczema, along with many other disorders, can be associated with overactive immune cells [13]. In these cases, anti-inflammatory drugs are critical for reducing symptoms. Several studies indicate that FvA can act as an anti-inflammatory by reducing the release of proinflammatory mediators from cells. First, Junek et al. show that FvA at 200 μg/mL can reduce tumour necrosis factor alpha (TNF-α) expression after exposure to the endotoxin Lipopolysaccharide (LPS) in differentiated human monocytes (U937) [14].

FvA also is shown to reduce cyclooxygenase 2 (COX2) and prostaglandin E2 (PGE2) secretion after homocysteine stimulation in primary human monocytes [15]. FvA from solubilized sludge (SS-FA) is shown to reduce B-hexosaminidase and histamine release in immunoglobulin-E-sensitized mast cells and basophil cells [16]. This information suggests that FvA can have anti-inflammatory and antiallergy effects. Yamada et al. also show SS-FA decreases TNF-α, interleukin-4 (IL-4), and IL-13 from mast cells.

Unfortunately, in vivo studies into the effects of FvA have been too few and sporadic. A pilot clinical study shows coal-derived FvA (oxifulvic acid) at 4.5% (w/w) reduces wheal and flare size after allergen challenge in humans [17]. The reduction by FvA shows similar results to 1% hydrocortisone. The anti-inflammatory properties of oxifulvic acid are also shown in mice [18]. In the study, mice sensitized with dinitrofluorobenzene on the ear and then again challenged 6 days later see a reduction in swelling with FvA treatment comparable to steroid medication.

A patented isolation procedure yielding carbohydrate-derived fulvic acid (CHD-FvA) mimics the above information almost entirely. In a randomized clinical trial, topical administration of CHD-FvA is shown to significantly reduce eczema rash in humans [19]. However, a burning sensation was also reported in this study. In addition, oral ingestion of CHD-FvA isolated from South Africa at 100 mg/kg can reduce paw edema in rats at levels similar to nonsteroidal anti-inflammatory drugs [20].

Overall, the above studies promise the potential of FvA to treat overactive immune disorders, specifically eczema.

2.2. Proinflammatory Effects of FvA

The immune system is an integral part of human health and has evolved to be a complex organization in which we rely. It provides protection against pathogens and stops tumour growth by initiating the inflammatory response [21, 22]. Interestingly, FvA has been shown to enhance inflammation in animals too. In the same study by Sabi et al. [20], topically applied CHD-FvA can reduce the size of wounds infected with Staphylococcus aureus, thus stopping the progression of the infection.

CHD-FvA is also suggested to reduce the size of wounds infected with antibiotic-resistant pathogens [23]. This suggests a bimodal effect of FvA that not only suppresses immune function but also stimulates it. Essentially, it provides evidence that FvA ensures proper immune function. Schepetkin et al. show that FvA can activate isolated murine macrophages from the peritoneal cavity. Nitric oxide (NO) and reactive oxygen species (ROS) important for killing bacteria and intracellular signalling increase in FvA-treated peritoneal macrophages [24].

They do however indicate cell viability is reduced with 100 μg/mL of FvA, questioning studies by Junek et al. [14]. In addition, Schepetkin et al. also show that IHSS FvA standards and low molecular-weight extracts from Nepal Shilajit can fix the complement system [25]. This gives rise to the thought that FvA can activate the immune system when needed to protect against infection and foreign pathogens.

2.3. Detrimental Immune Effects of FvA

Several studies indicate that FvA may be harmful too. FvA derived from Hungarian lignite can activate humoral immunity and reduce thyroid function in rats [26]. In this study, FvA increases antibody titre against ovalbumin 14 days and 26 days after challenge. They also indicate that lymphocyte diameter increases in rats, a sign of cellular activation [26]. These results are not isolated; Kunavue and Lien show increases in IgG antibodies in weanling pigs after FvA treatment [27].

No significant increase is found in lymphocyte, monocyte, or granulocyte numbers in the blood however. Unfortunately, Kunavue and Lien do not mention the location and isolation procedure of the FvA used. Such discordant effects seem to result from variances in therapeutic dosages and/or the origin of FvA in the study. Thereby, it is an absolute must to establish safe dosing for FvA depending on its source in order to treat/prevent immune-modulatory disorders.

3. Oxidative Stress

Oxidative stress is closely linked to chronic inflammatory diseases [28]. Oxidative stress is described as an imbalance of highly reactive oxygen species (ROS) compared to antioxidants [29]. When the cellular equilibrium shifts towards higher ROS, endogenous antioxidants like glutathione (GSH) and superoxide dismutase (SOD) are outmatched. This leads to cellular dysfunction, lipid peroxidation, and possible cell death [30]. The effects of FvA on the oxidative state in cells and animals are summarized in Figure 3

Figure 3

3.1. Antioxidant Capabilities of FvA

FvA has been shown to sequester superoxide radicals and other ROS outside of the cell [31]. Inside the cell though, FvA can uncouple the electron transport chain in liver mitochondria, which is associated with lowering ROS production [32]. In addition, the most promising in vivo study regarding the antioxidant ability of FvA is the reduction of oxidative stress markers after isoproterenol (ISO) induced myocardial damage in rats.

Shikalgar and Naikwade show that FvA at 300 mg/kg/day for 4 weeks decreases lipid peroxidation and myocardial damage markers after ISO and significantly increases GSH, SOD, and catalase (CAT) levels [33]. Another study confirms this information in fish. After feeding FvA for 60 days, a decrease in lipid peroxidation and an increase in the expression of SOD, CAT, and glutathione peroxidase (GPx) are seen [34].

3.2. Oxidant Capabilities of FvA

Just like in inflammation, FvA can also cause oxidative damage instead of preventing it. FvA increases oxidative stress when exposed to isolated cartilage cells from 12-day-old embryonic chicks [35]. This study contrasts ones showing a decrease in lipid peroxidation and further suggests FvA as a causative factor in Kashin-Beck disease. An underlying factor for elevated oxidative stress is that FvA can increase cellular respiration rates at extended exposure in rat mitochondria, which may lead to the production of more oxygen radicals [30].

FvA has been shown to increase oxidative markers like hydrogen peroxide and nitric oxide and induce apoptosis in hepatic cancer cell lines [36]. Similarly, FvA can increase smooth muscle contractions, which can be linked to oxidative damage [37].

4. Gut Health

The gut forms the interphase of the outside world, the microbiome, and the host. Sufficient evidence shows that poor gut health can lead to inflammation and disease [38]. In agriculture, FvA has been shown to influence the soil microbe composition and be able to conjugate itself to various minerals, aiding in the uptake in plants [39, 40]. As a result, FvA is suggested to improve the gut flora, nutrient absorption, and heal adverse disorders related to the gut. Below is the available content regarding FvA effects on gut health and summarized in Figure 4.

Figure 4

4.1. Shifting the Microbiota

In regard to the microbiota, very little information is available in animals. A study by Gao et al. show that FvA at 1.5% (w/w) can modulate the gut microflora in loach (Paramisgurnus dabryanus) fish [34]. After 60 days of feeding, the abundance of Proteobacteria phyla decreases and Firmicute levels increase in the intestine. In addition, 10 bacteria genera were influenced by FvA treatment. Bacteria of note include an increase in Variovorax, Lactococcus, and Lactobacillus and a decrease in Serratia and Acinetobacter.

This is the only study investigating the effect of FvA on the microbiome.

4.2. Enhancing Nutrient Absorption

Gao et al. [34] also show FvA increases the activity of digestive enzymes like lysozyme, proteases, and acid/alkaline phosphatases in fish. This is strengthened in part by an intensive study investigating nutrient digestibility in pigs [27]. FvA supplemented at 200 ppm in fed improved phosphorus and ash digestion but interestingly had no effect on fat and protein digestibility, contrasting data found in loach.

FvA is shown to influence the bioavailability of heavy metals in animal models as well. FvA can increase the absorption of copper in porcine oviductal epithelial cells and simultaneously reduces its toxicity [41]. In addition to nutrients, FvA has been shown to mediate drug delivery in rats too [42]. Carbamazepine (CBZ) a common anticonvulsant has a low bioavailability, but when conjugated to FvA, absorption across an everted rat intestinal sac increases along with concentrations of CBZ in the blood plasma.

FvA has been shown to increase absorption of nutrients and drugs; thus, a concern is the absorption of pollutants and toxins into the blood. However, in a study by Qiang et al., FvA does not increase the absorption of perfluorooctanesulfonate (PFOS) in carp, a conclusion based on the amount of PFOS in the feces of fish compared to controls [43].

4.3. Improve Gut Disorders

A preliminary clinical study exists which investigates the efficacy of probiotics in combination with FvA in gastrointestinal (GI) disorders [44]. Unfortunately though, all groups including ones with FvA see no improvement in Gastrointestinal Quality of Life Index (GIQLI) and Visual Analogue Scale (VAS) scores for GI symptoms. This study does showcase the safety of FvA intake over a 12-week period. Even though FvA is not shown to have an effect in the previous study, FvA isolated from Shilajit shows promise to be antiulcerogenic during several battery tests in albino rats [45].

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