Prophylactic Aloe Components on Autoimmune Diseases: Barbaloin, Aloe-Emodin, Emodin, and Fermented Butyrate

Akira Yagi, Byung Pal Yu

Akira Yagi, PhD, Faculty of Pharmacy and Pharmaceutical Sciences, Fukuyama University, Hiroshima, Japan
Byung Pal Yu, PhD, Department of Physiology, University of Texas, Health Science Center, San Antonio, Tx, USA

Conflict-of-interest statement: The author(s) declare(s) that there is no conflict of interest regarding the publication of this paper.

Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http: //creativecommons.org/licenses/by-nc/4.0/

Correspondence to: Akira Yagi, PhD, 2-10-1 Hanagaura, Kasuya-machi, Kasuya-gun, Fukuoka-ken, 811-2310, Japan.
Email: akirayagi@nexyzbb.ne.jp
Telephone: +81-92-938-2717
Fax: +81-92-938-2717

Received: February 12, 2018
Revised: February 25, 2018
Accepted: February 26, 2018
Published online: April 21, 2018


The involvement of Aloe plants in the remedy of chronic diseases has been well publicized in the past. In this review paper, we attempted to focus on the major Aloe ingredients on their known efficacy related to the immune modulating activities. Several bioactive phytochemicals present in Aloe barbadensis (vera) are known to relieve rheumatoid arthritis (RA)-related pains by suppressing chronically over-activated inflammatory process. Aloe-emodin has been shown to promote natural killer cell and macrophage phagocytic activities in the tumor, and emodin, an anthraquinone found also in other plants, appeared to have some protective anti-inflammatory effect by showing its inhibition of IL-1β and LPS-stimulated proliferation of RA synoviocytes in a dose-dependent manner under hypoxic condition. Another putative immune modulator we reviewed in this paper is Aloe's butyrate fermented by the dietary Aloe in the gut. Its beneficial effects are based on the host immune metabolism via the activation of intestinal mucosal functions on the suppression of obesity and inflammation. It is hoped that elaboration on butyrate may provide fresh insights as to Aloe's immune modulation and chronic inflammation. Potential efficacious role of barbaloin, Aloe-emodin, emodin and fermented butyrate of Aloe vera needs further scrutiny and evidence-based documentation through carefully designed research.

Key words: Aloe barbadensis; Barbaloin; Aloe-emodin; Emodin; Fermented butyrate; Autoimmune-diseases

© 2018 The Author(s). Published by ACT Publishing Group Ltd. All rights reserved.

Yagi A, Yu BP. Prophylactic Aloe Components on Autoimmune Diseases: Barbaloin, Aloe-Emodin, Emodin, and Fermented Butyrate. Journal of Gastroenterology and Hepatology Research 2018; 7(2): 2535-2541 Available from: URL: http://www.ghrnet.org/index.php/joghr/article/view/2283


Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic, systemic inflammation which primarily effects on synovial joints. A good number of anti-inflammatory or immunomodulatory plant extracts and phytochemicals were studied in the conditions related to RA. One of the good examples in this regard is barbaloin in Aloe barbadensis (A.vera). Barbaloin (Bar), a mixture of barbaloin and isobarbaloin, is metabolized into Aloe-emodin anthrone and Aloe-emodin dianthrone by intestinal bacteria under anaerobic conditions[1]. Bar is inactive as a laxative but activated to Aloe-emodin anthrone to transform to a strong purgative component by a human intestinal anaerobe Eubacterium sp. Bar[2]. Based on "Aloe vera bioassay"[3, 4], International Aloe Science Council has established the quality standard of < 10 mg of Bar showing carcinogenic activity per liter of Aloe vera juice products for safe oral consumption. The intestinal uptake and metabolism of physiologically active Bar and Aloe-emodin was demonstrated using the Caco-2 and everted gut sac model. The % absorption of Bar and Aloe-emodin was ranged from 5.51% to 6.60%, 6.60% to 11.32%, respectively. Up to 18.15% of Bar and 18.11% of Aloe-emodin are absorbed as a glucuronidated or sulfated form. These results suggest that a significant amount is transformed during absorption[5]. Bar content of the leaves of A.barbadensis and A. arborescens were determined by HPLC. Results showed that the Bar content was high in A.arborescens (0.602%) and low in A.barbadensis (0.266%)[6]. For the removal of Bar, various treatments are utilized: the activated charcoal adsorption process and cellulase process for viscosity reduction. Distinct biological and chemical changes are taken place by going through both the charcoal and cellulase processes. The activated charcoal adsorption process that prevents color changes and reduces Bar content can inadvertently cause the loss of some loss of bioactive compounds. In addition, cellulase is routinely used for viscosity reduction. Although it is well known that extracts of Aloe leaf gels can exert significant activities for macrophages and other defensive immunologic cells, unfortunately, the Aloe preparations used for many previous studies poorly defined mixtures, making difficult to pinpoint active ingredients and elucidate the biological pathways involved. The status of bacterial growth on Aloe plant and products needs a careful consideration for the preparation, sanitization, and pasteurization processing, because of their influence on the efficacy of the finalized products. On the microbiology of Aloe vera, one should be cognizant of two sources: endogenous and exogenous microbiota. Exogenous microbiota can be picked up from the environment during industrial processing. Endophytes, endogenous microorganisms include bacteria and fungi living within plant tissues without causing any overt negative effects. It is important to note that endophytic bacteria in Aloe vera gel provided butyric acid in in vitro fermented broth extract[7,8], which will be described in the later section.

This present review focuses on descriptions of the potential efficacious role of barbaloin, Aloe-emodin, emodin, and fermented butyrate of Aloe vera based on what have been documented by previously published data.

Immune modulation by barbaloin, Aloe-emodin, and emodin in treatment of rheumatoid arthritis (RA)

It has been reported that emodin in Aloe vera latex inhibits various inflammation kinases and signaling pathways in vitro and in vivo conditions as an immunomodulatory agent. The potential immunosuppressive mechanism of emodin may be the suppression of lymphocyte proliferation and influences on cytokines. The putative therapeutic benefits of Aloe vera in treatment of RA and the efficacy of a dietary plant-derived polysaccharide supplement in patients have been reviewed[9]. For the suppression of inflammation, the Aloe vera-mediated reduction of IL-1β was shown to be the consequence of the reduced expression of both pro-IL-1β as well as the most versatile and important NLRP3 inflammasome (more details on inflammasome later) via suppressing the pro-inflammatory signaling transduction pathway. The downregulated expression of the ATP sensor, P2X7R by Aloe vera may contribute to the attenuated IL-1β cytokine secretion. These data could serve as a basis for new therapeutic opportunities on the modulation of inflammasome-mediated responses[10]. Emodin, one of Aloe vera and A. arborescens ingredient, significantly inhibited IL-1β and LPS-stimulated RA synoviocytes in a dose-dependent manner under hypoxic condition. Furthermore, emodin is known to inhibit histone deacetylase (HDAC) as well as suppresses the expression of HDAC1, but not HDAC2 in IL-1β, and LPS-treated synoviocytes under hypoxia. These findings strongly indicate that emodin inhibits pro-inflammatory cytokines and production of vascular endothelial growth factor, and HDAC1 activity in hypoxic RA synoviocytes[11]. Recently, Han et al reported that emodin ameliorated the severity of NLRP3 inflammasome-mediated symptoms in LPS-induced endotoxin mouse models. The anti-inflammatory effect of emodin through attenuation of NLRP3 inflammasome activation was determined as the underlying mechanism. This is the first report providing scientific evidence substantiating the use of emodin in medicine for the treatment of various inflammatory diseases through the regulation of inflammasome activation. This approach may well provide a plausible therapeutic strategy for controlling other related inflammasome-mediated pathological conditions[12].

It is known that Aloe-emodin inhibits dose-dependently inducible nitric oxide synthase (iNOS) mRNA expression and nitric oxide (NO) production at 5-40µM. In addition, the levels of COX-2 mRNA and PGE2 production are also suppressed by 40µM Aloe-emodin. Bar (barbaloin, aloin) also suppresses the production of NO at 5-40µM, while no PGE2 production is affected. These results indicate that aloin and Aloe-emodin may suppress the inflammatory responses by blocking iNOS and COX-2 mRNA expression. Aloe-emodin was shown as a potential key constituent responsible for the anti-inflammatory activity of Aloe. Aloe-emodin suppresses the production of NO, IL-6, and IL-1β in LPS-stimulated RAW264.7 cells with no apparent cytotoxicity[13]. These data indicate that Aloe-emodin is a bioactive component that confers an anti-inflammatory effect through the mechanisms that modulate the pro-inflammatory cytokine production via inhibition of NF-κB, MAPK, and PI3K pathways in LPS-induced RAW264.7 macrophages[14]. IL-1β activation involves reactive multiprotein complexes called inflammasomes. One of the most intensively studied inflammasome complexes is the NLRP3 inflammasome. Its activation requires two signals in that one signal primes the cells, inducing the expression of NLRP3 and pro-IL-1β, while the other signal, leading to the assembly and activation of the complex. The effect of plant-derived natural compounds including Aloe-emodin and emodin was demonstrated on suppressing NLRP3 inflammasome-mediated IL-1β production[15].

RA is a chronic inflammatory disease characterized by synovial hyperplasia. Methotrexate (MTX), an anti-foliate derivative, is used for the treatment of RA, as it exerts anti-proliferative effects on lymphocytes and synovial cells. The effect of Aloe-emodin on the proliferation and apoptosis of MH7A human RA synovial cells was examined by comparing with that of MTX[16]. These results indicate that ≥ 10 µM Aloe-emodin and ≥ 0.05 µM MTX effectively decreased the numbers of viable MH7A cells. In addition, 40µM Aloe-emodin and 1µM MTX induced apoptosis in MH7A cells. Cell cycle analysis revealed that ≥ 20 µM Aloe-emodin induced G2/M phase arrest, whereas ≥ 0.1 µM MTX induced S phase arrest. These observations suggested that Aloe-emodin treatment inhibited the growth of MH7A cells by arresting the cell cycle at a different checkpoint in contrast to MTX treatment. These data support the notion that Aloe-emodin could be used as a potential therapeutic agent for the treatment of RA, and may be used in conjunction with MTX, based on its anti-proliferative effect on synovial cells[16].

The endochondral bone formation is the process by which mesenchymal cells condense into chondrocytes, which are ultimately responsible for new bone formation. Interestingly, the effect of Aloe-emodin on chondrogenic differentiation in clonal mouse chondrogenic ATDC5 cells was demonstrated. Aloe-emodin induced the synthesis of matrix proteoglycans and increased the activity of alkaline phosphatase. Aloe-emodin also enhanced the expressions of chondrogenic marker genes such as collagen II, collagen X, BSP, and RunX2 in a time-dependent manner, and increased the activation of the extracellular signal-regulated kinase (ERK), and enhanced the protein expression of the bone morphogenetic protein (BMP-2) in a time-dependent manner. These results showed that aloe-emodin exhibits chondro-modulating effects via the BMP-2 or ERK signaling pathway[17]. Several publications reported the therapeutic possibility of Aloe-emodin as well in neurodegenerative conditions[18,19].

Amyloid aggregation is linked to a number of neurodegenerative syndromes, the most prevalent one being Alzheimer's disease (AD). The β-amyloid peptides (Aβ) aggregate into oligomers, proto-fibrils, and fibrils and eventually into plaques, which constitute the characteristic hallmark of AD. The in silico and in vitro results provide useful insights for the design of small-molecule, 9, 10-anthraquinone inhibitors of aggregation with therapeutic potential in AD[18]. Aloe-emodin acts as an inhibitor of hemoglobin (Hb) aggregation. Increasing concentration of Aloe-emodin partially reverses the aggregation of the model hemeprotein (hemoglobin).The study serves as baseline for translatory research and development of Aloe-emodin based therapeutics for diseases attributed to protein aggregation[19]. Protein fibrillation is the pathological hallmark of several neurodegenerative diseases such as Alzheimer's and Parkinson diseases. In a case study, the inhibitory activity of barbaloin against insulin fibrillation was investigated. The degradation products of barbaloin formed over weeks of storage, in particular oxidation products, were able to significantly inhibit insulin-fibrillation[20].

Roles of butyrate and gut microbiota in compromised immune system and autoimmune diseases

Gut microbiota-derived short-chain fatty acids (SCFAs) regulating T cells

Gut commensal microbes shape the mucosal immune system by regulating the differentiation and expansion of several types of T cell. Treatment of naive T cells under the regulating T cell (Treg)-polarizing conditions with butyrate enhanced histone H3 acetylation in the promoter and conserved non-coding sequence regions of the Foxp3 locus, suggesting a possible mechanism for how microbial-derived butyrate regulates the differentiation of Treg cells. A new insight into the mechanisms by which host-microbe interactions establish immunological homeostasis in the gut was revealed[21]. Treg cells (Tregs) that express the transcription factor Foxp3 are critical for regulating intestinal inflammation. It was shown that SCFAs, fermentation products from gut bacteria regulate the size and function of the colonic Treg pool and protect against colitis in a Ffar2-dependent manner in mice. A class of microbial metabolites underlies adaptive immune microbiota's coadaptation and promotes colonic homeostasis and health[22]. Various factors such as antigens, co-stimulation signals, and cytokines regulate T cell differentiation into functionally specialized effector and Tregs. Other factors such as nutrients and microbial products provide important environmental cues for T cell differentiation. A mounting body of evidence indicates that the microbial metabolites, SCFAs have profound effects on T cells and directly and indirectly regulate their differentiation. A review by Kim et al[23] summarized well about the current understanding of SCFA functions in regulation of peripheral T cell activity on tissue inflammation[23]. Metagenomic shotgun sequencing and a metagenome-wide association study of fecal, dental and salivary samples from a cohort of RA subjects and healthy controls were carried out. Results revealed specific alterations in the gut and oral microbiomes in individuals with RA, suggesting feasible ways of using microbiome profile for prognosis and diagnosis[24]. Another interesting aspect of SCFAs is the inhibition of histone deacetylase (HDAC) in T cells by increasing the acetylation of p70 S6 kinase and phosphorylation rS6, to regulate the mTOR pathway for the generation of Th10, Th1, and IL-10 (+) cells. Butyrate promotes T cell differentiation into both effector and regulatory T cells for boosting either immunity or immune tolerance depending on immunological milieu[25]. The interaction between genetic predisposition and environmental factors are of great significance in the pathogenesis and development of autoimmune diseases (AIDs). Epigenetic modification triggered by environmental factors is an important mechanism that leads to altered gene expression. Studies showed that human microbiota and their metabolites can regulate immune cells and cytokines via epigenetic modifications. SCFAs produced by gut microbiota promote the differentiation of naive T cell into Treg by suppressing HDACs. Dysbiosis and resulting metabolites may cause aberrant immune responses in AIDs via epigenetic modifications, thereby leading to AIDs. The studies aiming at the crosstalk between human dysbiosis and epigenetic modifications and their influences on AIDs will facilitate the understanding and better managing of these debilitating AIDs[26].

Effects and mechanisms underlying oral supplementation with butyrate on experimental murine colitis were evaluated. Butyrate inhibited pro-inflammatory cytokine production in RAW 264.7 cells. Butyrate attenuated both the LPS-induced degradation/phosphorylation of IκBα and DNA binding of NFκB and enhanced histone H13 acetylation. Oral supplementation with butyrate suppressed colitis, even in IL-10-/- mice. Furthermore, butyrate attenuated IκBα phosphorylation and histone H3 deacetylation in the colon. The anti-inflammatory effect of butyrate is IL-10 independent, and butyrate may therefore be a therapeutic agent for colitis[27]. The microbiota in multiple sclerosis patients, an autoimmune disease targeting the myelin sheath of the central nervous system, is characterized by a reduction of bacteria belonging to Clostridium clusters IV and XIV-a, which are potent producers of butyrate through fermentation of indigestible carbohydrates. Oral administration of SCFAs ameliorated the disease severity of systemic autoimmune inflammatory conditions mediated by lymphocytes such as experimental autoimmune encephalitis and collagen-induced arthritis. Amelioration of disease was associated with a reduction of Th1 cells and an increase in regulatory T cell. In contrast, SCFAs contributed to the exaggeration of K/BxN serum transfer arthritis, representing the effector phase of inflammation in rheumatoid arthritis. Further understanding of the effects of microbiota metabolites will lead to prevention of systemic inflammatory disorders[28]. Better understanding is needed for defining roles of individual HDAC isozymes and effects of HDAC inhibitors on bone cells, like osteoblasts, osteoclasts, and osteocytes, in bone remodeling due to pathological bone loss, including periodontitis, rheumatoid arthritis and myeloma bone disease[29]. HDAC inhibitor can regulate bone remodeling by suppressing osteoclasts and promoting osteoblasts. Novel isozyme-specific HDAC inhibitors are critical to elucidate HDAC's role in bone remodeling and communication among bone cells. The adaptive immune response in RA is influenced by an interaction between host genetics and environment, particularly the host microbiome. Chen et al. identified the gut microbiota profile in patients with RA and found decreased species richness (α-diversity) that positively correlated with increased rheumatoid factor levels and disease progression[30]. The rheumatoid factor, C-reactive protein, disease progression and methotrexate treatment correlated with β-diversity found in the gut microbiota of patients with RA, suggesting that these clinical outcomes might play an important role in gut microbiota modulation[31].

Protective role of intestinal microbiota in gout, amyotrophic lateral sclerosis, Alzheimer's disease and Parkinson's disease

1. NLRP3 inflammasome in gout:

Recent studies have implicated IL-1β as a key regulatory pro-inflammatory cytokine in gout, by promoting a neutrophil influx into the synovium and joint fluid, which is the pathological hallmark of an acute inflammatory attack. This IL-1-dependent innate inflammatory phenotype, which is observed in a number of diseases in addition to gout, is now understood to rely on the formation of the macromolecular NLRP3 inflammasome complex in sensing to the MSU (monosodium urate) "danger signal". Current understanding of the NLRP3 inflammasome and its critical role in MSU-crystal induced inflammatory gout attacks was highlighted by Kingsbury et al[32]. Butyrate exhibit its anti-inflammatory effects mainly through the underlying mechanisms of inhibition of HDACs. The additional suppression action of butyrate was reported on MSU-induced cytokine production and its inhibition of specific HDAC. These novel HDAC inhibitors could even improve the efficacy as well as reducing adverse effects[33]. More recently, Vieira et al[34] reported that the effects of a high-fiber diet and acetate generated from the metabolism of fiber by gut microbiota, promote resolution of neutrophilic inflammation in an experimental model of gout in mice. It was also found that acetate is effective, even when given after injection of MSU crystals at the peak of the inflammatory response and induced caspase-dependent apoptosis of neutrophils that accounted for the resolution of inflammation[34].

2. Butyrate as a therapeutic agent for restoring Amyotrophic lateral sclerosis (ALS) –related dysbiosis:

ALS is a serious neurodegenerative disease characterized by the progressive loss of motor neurons. It was shown recently by Zhang et al[35] that G93A transgenic mice fed with butyrate, intestinal microbiota homeostasis was restored, gut integrity was improved, and lifespan was prolonged compared with those in control mice. At the cellular level, abnormal Paneth cells-specialized intestinal epithelial cells that regulate the host-bacterial interactions-were significantly deceased in the ALS mice treated with butyrate. In both ALS mice and cultured human intestinal epithelial cells, butyrate treatment decreased aggregation of the G93A superoxide dismutase 1 mutated protein. These findings highlight the complex role of the gut microbiome and intestinal epithelium in the progression of ALS and present butyrate as a therapeutic potential for restoring ALS-related dysbiosis[35].

3. The role of SCFAs in Alzheimer's disease (AD)-type β-amyloid (A β) aggregation:

The presence of the individual differences in the human gut microbiota may lead to interpersonal variation to benefit from the protective effects of dietary fiber and polyphenols in AD. Such findings provide critical information for developing probiotics to help prevent and/or treat of AD[36]. Multiple complementary assays were used to investigate individual SCFAs for their responsive effects in interfering with the assembly of Aβ 1-40 and 1-42 peptides into soluble neurotoxic Aβ aggregates. It has been proposed recently that intestinal microbiota may help protect against AD, in part, by supporting the generation of selective SCFAs interferes with the formation of toxic soluble Aβ aggregates[37]. Aggregation of proteins that is an aspect of the physiological process is considered as the major causative culprit underlying pathophysiology of several maladies including diabetes mellitus, Huntington's disease and AD. Aloe-emodin and emodin, which are active components of Aloe vera and A. arborescens, act as inhibitors of hemoglobin aggregation[18,19]. Combination of Aloe-emodin and emodin together with butyrate fermented in Aloe vera show intriguing insights into the design of small molecule inhibitors of aggregation with therapeutic potential for AD.

4. The contribution of SCFAs to gastrointestinal dysmotility in Parkinson's disease (PD):

Investigation of anti-parkinsonian effect of Aloe vera revealed the possibility of Aloe vera's efficacy on haloperidol-induced experimental animal model, suggesting Aloe vera could serve as a good alternative in improving to dysmotility of PD[38]. α-Synuclein (α-Syn) damage and its deposition cause neurodegeneration in the brain resulting in PD. The abnormal α-Syn accumulation has been identified in the biopsies within colon and rectum of PD patients. Colonization of α-Syn-overexpressing mice with microbiota from PD-affected patients enhances physical impairments compared to microbiota transplants from healthy human donors. α-Syn is considered a major culprit in PD pathophysiology[39]. Recent evidence suggests that α-Syn may play a role in transcription regulation, possibly by modulating the acetylation of histones. As turn out, increased α-Syn expression led to reduced levels of acetylated histone 3 in dopaminergic neuronal cells. Importantly, treatment with sodium butyrate rescued wild-type α-Syn-induced DNA damage, possibly via upregulation of genes involved in DNA repair. These findings provide novel insights into the mechanisms associated with α-Syn neurotoxicity in DNA repair[40]. Patients with PD frequently have gastrointestinal symptoms (e.g. constipation) and exhibit the PD-typical pathologic histology in the enteric nervous system. Recent reports show the association between PD and the abundance of certain gut microbiota. Alterations in gut microbiota might be accompanied by altered concentrations of SCFAs. The reduction in fecal SCFA concentrations might induce alterations in the enteric nervous system, contributing to gastrointestinal dysmotility in PD[41].

Importance of gut microbial Metabolites butyrate and host immune responses

Gut butyrate has been suggested to promote the development of the intestinal barrier. The molecular mechanisms underlying this interesting butyrate's action on the intestinal barrier were demonstrated by the regulation of the assembly of tight junctions involving the activation of the AMP-activated protein kinase[42]. The effects of butyrate on colonic mucus glycoprotein (mucin) synthesis have been assessed using tissue from colonic resection samples. The marked increase in mucin synthesis by butyrate suggests its important role affecting the rate of mucin synthesis in vitro and may also explain the therapeutic effect of butyrate in colitis[43].

Lin et al[44] recently reviewed the findings on the mechanisms underlying the interaction between microbiota and products with host immunity and regulating imbalanced gut microbiota (dysbiosis) which often lead to autoimmune disorders, like inflammatory bowel disease, type-1 diabetes and systemic immune syndromes such as RA[44]. SCFAs were shown to directly activate G-protein-coupled-receptors, and inhibit HDACs, and also serve as energy substrates. Butyrate, acting as a HDAC inhibitor and ligands for G-protein-coupled receptors, is considered as a crucial signaling molecule affecting host immune responses[45]. The immunological data in the literature strongly implicate a close association between gut microbiota and RA. It became increasingly clear that gut microbiota contributes to the pathogenesis of RA via multiple molecular mechanisms. A better understanding of the dynamic nature of the interaction between gut microbiota and their host will help greatly in establishing a highly individualized management RA patient[46].The protective effects of SCFAs on bone mass are associated with inhibition of osteoclast differentiation and bone resorption in vitro and in vivo, while bone formation is not affected. Mechanistically, propionate and butyrate induce metabolic reprogramming of osteoclasts resulting in enhanced glycolysis at the expense of oxidative phosphorylation, thereby downregulating essential osteoclast genes such as TRAF6 and NFATc1. These data pinpoint SCFAs as potent regulators of osteoclast metabolism and bone homeostasis[47].

Putative anti-inflammatory action of Aloe vera supplementation

In our previous study, we found that the inner gel of Aloe vera facilitates fermentation with endophytic bacteria in bacterial growth promotion, and butyrate was identified by GC/MSD analysis from ether extract of the gel fermentation broth[8]. Furthermore, the prebiotic activity of Aloe vera juice (AVJ) with Lactobacillus fermentum was experimented in in vitro fermentation. Acetic, propionic and lactic acids were identified from the fermentation medium. The prebiotic activity of AVJ can be identified by the participation of SCFAs during 24h-incubation with L. fermentum. An innovative concept of symbiosis is perspective for future intestinal health claims to target health and possible anti-inflammatory effects of AVJ supplementation[7]. It is interesting to speculate that such a rather simple dietary intervention might have the prophylactic effect on inflammatory diseases and autoimmunity.

The potential benefits, the antioxidant effects and the antibacterial effects on food-borne pathogens of Aloe vera fermentation supernatant, were evaluated in vitro. The Aloe vera fermentation supernatant fermented by Lactobacillus plantanum HM218749.1 had very strong scavenging capacities of the DPPH (86%), O2*/- (85%), *OH (76%), and Fe2+ chelation (82%) and reducing powers (242.5 mg/L), and the inhibiting zones for Salmonella spp. and Escherichia spp. The antioxidant and antibacterial effects on food-borne pathogens of Aloe vera fermentation supernatant were evaluated in vitro. Moreover, the low concentration of Aloe vera fermentation supernatant had significantly reduced the production of IL-1β, TNF-α, and IL-6 in both mRNA and protein levels (p < 0.001). Therefore, the Aloe vera fermentation supernatants indicate its potential use as functional beverage, foods to guard human intestinal health and preventing chronic diseases. The anti-inflammatory effects of the Aloe vera fermentation supernatant were evaluated[48]. In fermentation study by endophytic bacteria in Aloe vera gel, the anti-inflammatory activity of the fermented supernatant containing butyrate was identified. The finding of anti-inflammatory as well as anti-oxidant activities of butyrate in the fermented supernatant may help explain the known beneficial effects of butyrate in intestinal colon and on colitis[49].

Gut microbial dysbiosis is linked to aberrant immune responses, which are often accompanied by the abnormal production of inflammatory cytokines. As part of the Human Functional Genomics Project (HFGP): Genomics, gut microbiome, and host-environment shape human immune-cytokine responses, Schirmer et al investigated how differences in composition and function of gut microbial communities may contribute to inter-individual variation in cytokine responses to microbial stimulation in healthy humans. Microbiome-cytokine interaction patterns that are stimulus specific, cytokine-specific, and cytokine and stimulus-specific were aimed at understanding the interplay between microbial, genetic, and environmental factors in the regulation of the immune response in humans. Many previous studies provided a comprehensive resource on how immune response vectors are determined by environmental, genetic, and microbial factors. The impact of host environmental factors, host genetics, and the gut microbiome on stimulus-induced cytokine responses was assessed in complementary studies of the HFGP[50]. Accumulating data provide the basis for future clinical studies aiming to elucidate the potential preventive and therapeutic roles of butyrate in human health.


The present review provides that Aloe vera gel containing Aloe components: barbaloin, Aloe-emodin, emodin and fermented butyrate are fully expected as prophylactic immune-stimulants on auto-immune diseases. Aloe vera inhibited the expression of pro-IL-1β, NLRP3, and caspase-1 as well as that of the P2X7 receptor in the LPS-induced primary macrophages. Furthermore, LPS-induced activation of signaling pathways, such as NF-κB, p38, JNK, and ERK, was inhibited by Aloe vera in these cells[9]. Chronic inflammation of rheumatoid arthritis is promoted by pro-inflammatory cytokines and closely linked to angiogenesis.

Barbaloin is inactive as a laxative itself but is activated to Aloe-emodin anthrone, a genuine purgative component by Eubacterium sp. strain BAR[2], and Aloe-emodin was produced from the oxidation of Aloe-emodin anthrone. Aloe-emodin on chondrogenic differentiation in clonal mouse chondrogenic ATDC5 cells showed that Aloe-emodin enhanced the expressions of chondrogenic marker genes such as collagen, collagen X, BSP and RunX2 in a time-dependent manner. Aloe-emodin may have potential future applications for the treatment of growth disorder and new bone formation[15]. Furthermore, Aloe-emodin acts as an anti-aggregatory agent to thermally aggregated hemoglobin. The development of Aloe-emodin based therapeutics for diseases attributed to protein aggregation is expected[19].

Emodin, an active constituent of oriental herbs, which is widely used to treat allergy and inflammation, provided the scientific basis for the anti-inflammasome effects of the substantiating traditional claim[12].

Microbiota and products thereof: short-chain fatty acids and quorum sensing signal molecule, are indispensable for shaping the development and function of host innate immune system, thereby exerting the multifaceted impact on gut health. Butyrate was found to be anti-inflammatory mainly through the suppression of NF-κB, be capable of altering the composition of the mucus layer by inducing mucin synthesis and of exerting anti-cancer activities. Multiple beneficial effects of butyrate at an intestinal and extra-intestinal level have been demonstrated and the mechanisms of action of butyrate are different and many of these involve an epigenetic regulation of gene expression through the inhibition of histone deacetylase[51].

Although immunity influenced by hereditability and the environment is well-known, but how these factors synergize to influence immune function is not well characterized. Autoimmune diseases present an especially relevant context to study the intersection of these factors. Extensive genomic and epidemiological studies suggest that autoimmunity results from the coincident interaction of an environmental trigger with a genetically predisposed individual.


1. Hattori M, Kanda T, Shu YZ, Akao T Kobashi K, Namba T. Metabolism of barbaloin by intestinal bacteria Chem Pharm Bull. 1988; 36(11): 4462-4466.

2. Akao T, Che QM, Kobashi K, Hattori M, Namba T. A purgative action of barbaloin is induced by Eubacterium sp. strain BAR, a human intestinal anaerobe, capable of transforming barbaloin to Aloe-emodin anthrone. Biol Pharm Bull. 1996; 19(1): 136-138.[PMID: 8820926]

3. Beland FA. Division of biochemical toxicology FDA, U.S. Food & Drug Administration. 1 November 2016: Accomplishment #1; Aloe vera Bioassay; Aloin-Goblet cell/mucosal hyperplasia

4. Boudreau MD, Mellick PW, Olson GR, Felton RP, Thron BT, Beland FA. Clear evidence of carcinogenic activity by a whole-leaf extract of A.barbadensis M. (A.vera) in F344/N Rats. Toxicol Sci. 2013; 131(1): 26-39. [PMID: 22968693]: [DOI: 10.1093/toxsci/kfs275]

5. Park MY, Kwon HJ, Sung MK. Intestinal absorption of aloin, Aloe-emodin, and Aloesin; A comparative study using two in vitro absorption models Nutrition Research and Practice 2009; 3(1): 9-14. [DOI: 10.4162/nrp.2009.3.1.9]

6. Li JY, Wang TX, Chen ZG, Hu ZH.Relationship between leaf structure and aloin content in six sp. of Aloe leaves. Acta Botanica Sinica 2003; 45(5): 594-600.

7. Al-Madboly L, Kabbash A, El-Aasr M, Yagi A. Symbiotic effect of Aloe vera juice on the growth of Lactobacillus fermentum and L.helveticus isolates in vitro J. of GHR 2017; 6(3): 2365-2369.[DOI: 10.17554/j.issn.2224-3992.2017.06.709]

8. Yagi A, Kabbash A, Al-Madboly L. Short-chain fatty acids from fermentation by endophytic bacteria in Aloe vera leaf rind and gel J. of GHR 2016; 5(4): 2122-2124.[DOI: 10.17554/j.issn.2224-3992.2016.05.658]

9. Yagi A. Putative prophylaxes of Aloe vera latex and inner gel as immunomodulator J. of GHR 2015; 4(5): 1585-1598. [DOI: 10.17554.j.issn.2224-3992.2015.04.50]

10. Budai MM, Varg A, Milesz S, Tozser J, Benko S. Aloe vera downregulates LPS-mediated inflammatory cytokine production and expression of NLRP3 inflammasome in human macrophages Molecular Immunology 2013; 56(4): 473-479.[DOI: 10.1016/j.molimm.2013.05.005]

11. Ha MK, Song YH, Jeong SJ, Lee HJ, Jung JH, Kim B, Song HS, Huh JE, Kim SH. Emodin inhibits proinflammatory responses and inactivates histone deacetylase 1 in hypoxic rheumatoid synoviocytes Biol. Pharm. Bull. 2011; 34(9): 1432-437. [PMID: 21881229]

12. Han JW, Shim DW, Shin WY, Heo KH, Kwak SB, Sim EJ, Sim EJ, Jeong JH, Kang TB, Lee KH. Anti-inflammatory effect of emodin via attenuation of NLRP3 inflammasome activation Int J Mol Sci. 2015; 16(4): 8102-8109. [PMID: 25867480]: [DOI: 10.3390/ijms.16048102]

13. Park MY, Kwon HJ, Sung MK. Evaluation of aloin and Aloe-emodin as anti-inflammatory agents in Aloe by using murine macrophages Biosci. Biotechnol. Biochem. 2009; 73(4): 828-832. [DOI: 10.1271/bbb.80714]

14. Hu B, Zhang H, Meng X, Wang F, Wang P. Aloe-emodin from rhubarb (Rheum rhabarbarum ) inhibits lipopolysaccharide-induced inflammatory responses in RAW264.7 macrophages J. of Ethnopharmacology 2014; 153(3): 846-853. [DOI: 10.1016/j.jep.2014.03.059]

15. Tozser J and Benko S. Natural compounds as regulators of NLRP3 inflammasome-mediated IL-1β production Mediators of Inflammation 2016; Article ID 5460302, 16 pages [DOI: 10.1155/2016/5460302]

16. Hashiguchi M, Suzuki K, Kaneko K, Nagaoka I. Effect of Aloe-emodin on the proliferation and apoptosis of human synovial MH7a cells; a comparison with methotrexate Mol. Med.Rep. 2017; 4398-4404; [PMID: 28487948]: [DOI.org/10.3892/mmr.2017.6541]

17. Yang M, Li L, Heo SM, Soh Y. Aloe-emodin induces chondrogenic differentiation of ATDC5 cells via MAP kinase and BMP-2 signaling pathways Biomol Ther (Seoul) 2016; 24(4): 395-401. [PMID: 27359340] [DOI: 10.4062/biomolther.2016.020]

18. Convertino M, Pellarin R, Catto M, Carotti A, Caflisch A. 9,10-Anthraquinone hinders β-aggregation: how does a small molecule interface with Aβ–peptide amyloid fibrillation? Protein Sci. 2009; 18(4): 792-800. [PMID: 19309732] [DOI: 10.1002/pro.87]

19. Furkan M, Alam MT, Rizvi A, Khan K, Ali A, Shamsuzzaman, Naeem A. Aloe-emodin, an anthraquinone from Aloe vera acts as anti-aggregatory agent to the thermally aggregated hemoglobin Spectrochimica Acta Part A: Mol Biomolecular Spectroscopy. 2017; 179: 188-193 [PMID: 28242448] [DOI: 10.1016/j.saa.2017.02.014]

20. Lobbens ES, Fodera V, Nyberg NT, Andersen K, Jager AK, Jorgensen L, van de Weert M. The inhibitory effect of natural products on protein fibrillation may be caused by degradation products-A study using aloin and insulin PLOS ONE 2016; 11(2); e0149148. [DOI: 10.1371/journal.pone.0149148]

21. Furusawa Y, Obata Y, Fukuda S, Endo TA, Nakato G, Takahishi D, Nakanishi Y, Uetake C, Kato K, Kato T, Takahashi M, Fukuda NN, Murakami S, Miyauchi E, Hino S, Atarashi K, Onawa S, Fujimura Y, Lockett T, Clarke JM, Topping DL, Tomita M, Hori S, Ohara O, Morita T, Koseki H, Kikuchi J, Honda K, Hase K, Ohno H. Commensal microbe-derived butyrate induces the differentiation of colonic regulatory T cells. Nature 2013; 504(7480): 446-450. [PMID: 24226770]: [DOI: 10.1038/nature 12721]

22. Smith PM, Howitt MR, Panikov N, Michaud M, Gallini CA, Bohlooly-YM, Glicman JN, Garrett WS. The microbial metabolites, short chain fatty acids, regulate colonic Treg cell homeostasis. Science 2013; 341(6145): 569-673. [PMID: 23828891]: [DOI: 10.1126/science.1241165]

23. Kim CH, Park J, Kim M. Gut microbiota-derived short-chain fatty acids, T cells, and inflammation Immune Netw. 2014; 14(6): 277-188. [PMID: 25550694]: [DOI: 10.4110/in.2014.14.6.277]

24. Zhang X, Zhang D, Jia H, Feng Q, Wang D, Liang D, Wu X, Li J, Tang L, Li Y, Lan Z, Chen B, Li Y, Zhong H, Xie H, Jie Z, Chen W, Tang S, Xu X, Wang X, Cai X, Liu S, Xia Y, Li J, Qiao X, Al-Aama JY, Chen H, Wang L, Wu QJ, Zhang J, Zheng W, Li Y, Zhang M, Luo G, Xue W, Xiao L, Li J, Chen W, Xu X, Yin Y, Yang H, Wang H, Kristiansen K, Liu L, Li T, Huang Q, Li Y, Wang J. The oral and gut microbiomes are perturbed in rheumatoid arthritis and partly normalized after treatment Nat Med. 2015; 21(8): 895-905 [PMID: 26214836]: [DOI: 10.1038/nm.3914]

25. Park J, Kim M, Kang SG, Jannasch AH, Cooper B, Patterson J, Kim CH. Short-chain fatty acids induce both effector and regulatory T cells by suppression of histone deacetylases and regulation of the mTOR-S6K pathway Mucosal Immunol. 2015; 8(1): 80-93.[PMID: 24917457]: [DOI: 10.1038/mi.2014.44]

26. Chen B, Sun L, Zhang X. Integration of microbiome and epigenome to decipher the pathogenesis of autoimmune diseases J. of Autoimmunity 2017; 83: 31-42 [DOI.org/10.1016/j.aut.2017.03.009]

27. Lee C, Kim BG, Kim JH, Chun JH, Chun J, Im JP, Kim JS. Sodium butyrate inhibits the NF-κB signaling pathway and histone deacetylation, and attenuates experimental colitis in an IL-10 independent manner International Immunopharmacology 2017; 51: 47-56 [DOI: 10.1016/j.intimp.2017.07.023]

28. Mizuno M, Noto D, Kaga N, Chiba A, Miyake S. The dual role of short fatty acid chains in the pathogenesis of autoimmune disease models PLOS ONE 2017; 12(2): e0173032. [DOI: 10.1371/journal.pone.0173032]

29. Cantley MD, Zannettino CAN, Bartold PM, Fairlie DP, Haynes DR. Histone deacetylase (HDAC) in physiological and pathological bone remodeling Bone 2017; 95: 162-174. [DOI: 10.1016/j.bone.2016.11.028]

30. Chen J, Wright K, Davis JM, Jeraldo P, Marietta EV, Murray J, Nelson H, Matterson EL, Taneja V. An expansion of rare linage intestinal microbes characterizes rheumatoid arthritis Genome Medicine 2016; 8: 43 [DOI: 10.1186/s13073-016-0299-7]

31. de Olivela GLV, Leite AZ, Higuchi BS, Gonzaga MI, Mariano S. Intestinal dysbiosis and probiotic applications in autoimmune diseases Immunology 2017; 152: 1-12.[PMID: 28556916]: [DOI: 10.1111/imm.12765]

32. Kingsbury SR, Conaghan PG, McDermott MF. The role of the NLRP3 inflammasome in gout J. of Inflammation Research 2011; 3: 39-49. [DOI: 10.2147/jir.s11339]

33. Cleophas MC, Crisan TO, Lemmers H, Toenhake-Dijkstra H, Fossati G, Jansen TL, Dinarello CA, Netea MG, Joosten LA. Suppression of monosodium urate crystal-induced cytokine production by butyrate is mediated by the inhibition of class I histone deacetylases Ann Rheum Dis. 2016; 75(3): 593-600. [PMID: 25589513]: [DOI: 10.1136/annrheumdis-2014-2062258]

34. Vieira AT, Calvao I, Macia LM, Sernaglia EM, Vinolo MAR, Carcia CC, Tavares LP, Amaral FA, Sousa LP, Martins FS, Mackay CR, Teixeira MM. Dietary fiber and the short-chain fatty acid acetate promote resolution of neutrophilic inflammation in a model of gout in mice J. of Leukocyte Biology. 2017; 101(1): 275-284. [PMID: 27496979]: [DOI: 10.1189/jlb.3a1015-453RRR]

35. Zhang TG, Wu S, Yi J, Xia Y, Jin D, Zhou J, Sun J. Target intestinal microbiota to alleviate disease progression in Amyotrophic Lateral Sclerosis Clinical Therapeutics 2017; 39(2): 322-336. [DOI: 10.1016/j.clinthera.2016.12.014].

36. Ho L, Faith J, Ono K, Pashinetti GM. Protective roles of intestinal microbiota in Alzheimer's disease through mechanisms involving short-chain fatty acids and phenolic acids The J. of the Alzheimer's Association 2016; 12(7): 224-225. [DOI: 10.1016/j.jalz.2016.06.402]

37. Ho L, Ono K, Tsuji M, Mazzola P, Singh R, Pasinetti GM. Protective roles of intestinal microbiota-derived short-chain fatty acids in Alzheimer's disease-type beta-amyloid neuropathological mechanisms Expert Review of Neurotherapeutics 2018; 18(1): 83-90. [DOI: 10.1080/14737175.2018.1400909]

38. Bagewadi HG, Afzal Khan AK. Investigation of antiparkinsonian effect of Aloe vera on haloperidol induced experimental animal model Indian J. Pharm. Biol. Res. 2015; 3(1): 108-113

39. Sampson TR, Debelius JW, Thron T, Jannsen S, Shastri GG, Ilian ZE, Challis C, Schretter CE, Rocha S, Gradinaru V, Chesselet MF, Keshavarzian A, Shannon KM, Krajmalnik-Brown R, Wittung-Stafsede P, Knight R, Mazmanian SK. Gut microbiota regulate motor deficits and neuro-inflammation in a model of Parkinson's disease Cell. 2016; 167(6): 1469-1480.e12. [PMID: 27912057]: [DOI: 10.1016/j.cell.2016.11.018]

40. Paiva I, Pinho R, Pavlou MA, Hennion M, Wales P, Schutz AL, Rajput A, Szego EM, Kerimoglu C, Gerhardt E, Rego AC, Fischer A, Bonn S, Outeiro TF. Sodium butyrate rescues dopaminergic cells from α-synuclein-induced transcriptional deregulation and DNA damage Human Molecular Genetics 2017; 26(12): 2231-2246 [DOI: 10.1093/hmg/ddx114]

41. Unger MM, Spiegel J, Dillman KU, Grundmann D, Philippeit H, Burmann J, Fassbender K, Schwiertz A, Schafer KH. Short chain fatty acids and gut microbiota differ between pat]:[ients with Parkinson's disease and age-matched control Parkinsonism Relat Disord 2016; 32: 66-72 [PMID: 27591074DOI: 10.1016/j.parkreldis.2016.08.019]

42. Peng L, Li ZR, Green RS, Holzman IR, Lin J. Butyrate enhances the intestinal barrier by facilitating tight junction assembly via activation of AMP-activated protein kinase in Caco-2 cell monolayers J Nutr. 2009; 139(9): 1619-1625 [PMID: 19625695]: [DOI: 10.3945/jn.109.104638]

43. Finnie IA, Dwarakanath AD, Taylor BA, Rhodes JM. Colonic mucin synthesis is increased by sodium butyrate Gut. 1995; 36(1): 93-99. [PMID: 6890244]:

44. Lin L, Zhang J. Role of intestinal microbiota and metabolites on gut homoeostasis and human diseases. BMCImmunol. 2017; 18(1): 2. [PMID: 28061847]: [DOI: 10.1186/s12865-016-0187-3]

45. Koh A, De Vadder F, Kovatcheva-Datchary P, Backhed F. From dietary fiber to host physiology: Short chain fatty acids as key bacterial metabolites Cell. 2016; 165(86): 1332-1345. [PMID: 27259147]: [DOI: 10.1016/j.cell.2016.05.041]

46. Wu X, He B, Liu J, Feng H, Ma Y, Li D, Guo B, Liang C, Dang L, Wang L, Tian J, Zhu H, Xiao L, Lu C, Lu A, Zhang G. Molecular insight into gut microbiota and rheumatoid arthritis Int J Mol Sci. 2016; 17(3): 431 [PMID: 27011180]: [DOI: 10.3390/ijms17030431]

47. Lucas S, Omata Y, Hofmann J, Bottcher M, IIjazovic A, Sarter K, Albrecht O, Schulz O, Krishnacoumar B, Kronke G, Herrmann M, Mougiakakos D, Strowig T, Schett G, Zaiss MM. Short-chain fatty acids regulate systemic bone mass and protect from pathological bone loss Nature Communications 2018; 9: 55 [DOI: 10.1038/s41467-017-02490-4]

48. Jiang M, Deng K, Jiang C, Fu M, Guo C, Wang X, Wang X, Meng F, Yang S, Deng K, Chen T, Xin H. Evaluation of the anti-oxidative, antibacterial, and anti-inflammatory effects of the Aloe fermentation supplement containing Lactobacillus plantanum HM218749.1 Mediators of Inflammation 2016; (2016): Article ID 2945650, 8 pages. [DOI: 10.1155/2016/2945650]

49. Al-Madboly LA, Kabbash A, Yassin AM,, Yagi A. Dietary cancer prevention with butyrate fermented by Aloe vera gel endophytic microbiota J. of GHR 2017; 6(2): 2312-2317 [DOI: 10.17554/j.issn.2224-3992.2017.06.698]

50. Schirmer M, Smeekens SP, Vlamakis H, Jaeger M, Oosting M, Franzosa EA, Ter Host R, Jansen T, Jacobs L, Bonder MJ, Kurilshikov A, Fu J, Joosten LAB, Zhernakova A, Huttenhower C, Wijmenga C, Netea MG, Xavier RJ. Linking the human gut microbiome to inflammatory cytokine production capacity Cell 2016; 167(4): 1126-1136.e8. [PMID: 27814509]: [DOI: 10.1016/j.cell.2016.10.020]

51. Yagi A, Al-Madboly L, Kabbash A, El-Aasr M. Dietary Aloe vera gel and microbiota interactions: Influence of butyrate and insulin sensitivity J of GHR. 2017; 6(4): 2376-2383 [DOI: 10.17554/j.issn.2224-39992.2017.06.721]


  • There are currently no refbacks.

Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 License.