Background
Diabetes mellitus (DM) is a chronic metabolic disorder that constitutes a major public health problem throughout the world. Current estimates indicate that approximately 4% of the global population suffer from DM, a percentage which is expected to reach 5.4% in 2025 [
1]. This disease is a multifactor disorder associated with chronic hyperglycemia and troublesome disruptions in carbohydrate, fat, and protein metabolisms emanating from deficiencies or disruptions in insulin secretion [
2], defects in reactive oxygen species scavenging enzymes [
3], and high oxidative stress impairing pancreatic beta cells [
4,
5]. Hyperglycemia leads to long-term tissue damages and complications, such as liver-kidney dysfunctions, often associated with serious diseases [
6,
7].
The prevalence of type 2 diabetes mellitus is increasing worldwide at alarming rates. Several therapeutic strategies are currently available for the treatment of this chronic metabolic disorder, including the stimulation of endogenous insulin secretion, enhancement of insulin action at the target tissues, inhibition of dietary starch and lipid degradation, and treatment with oral hypoglycemic agents [
8]. The limitations associated with those therapeutic strategies have led to a determined search for more efficient and cost-effective alternatives. This trend has been further intensified by increasing doubts surrounding current dietary and other lifestyle behaviors together with growing interests in functional foods and nutraceuticals [
9]. Complementary and alternative medicine applications have attracted special attention in recent research for they offer new promising opportunities for the development of efficient, side effect-free, and lower cost alternatives to existing synthetic hypoglycemic agents [
10‐
12].
Of particular relevance to this argument, kombucha tea (KT), a traditional drink made from a particular fermentation of sugared black tea (BT) and a symbiosis of yeast species, fungi, and acetic acid bacteria, is commonly consumed throughout the world as a medicinal health-promoting beverage [
13]. Although the beneficial and/or adverse effects of kombucha tea on human health have not been scientifically determined yet, there are several reasons to believe that kombucha may have desirable positive effects on human health. In fact, the metabolic and health effects of several probiotic products are gathering increasing momentum in recent years. A number of currently commercialized food products (e.g. yogurt, cheese, fermented vegetables and kefir) are known to contain live bacteria, or metabolites of bacteria, produced during similar fermentation processes, and are considered as health promoting probiotic foodstuffs [
14,
15]. Moreover, several studies have recently demonstrated that kombucha can reduce cell damage induced by oxidative stress [
16‐
20]. Kombucha has also been reported to constitute a potent therapeutic supplement that improved resistance against cancer, prevented cardiovascular diseases, promoted digestive functions, stimulated the immune system, and reduced inflammatory problems [
17,
21‐
23].
Tea and kombucha are presented in the literature as two very distinct beverages and no correlation has so far been reported between them [
24]. Some of the effects reported for kombucha intakes are, however, very similar to those described for tea [
24]. Nevertheless, while the composition, properties, and effects of tea on chronic and progressive illnesses, such as diabetes, are well documented in the literature [
25], little data are currently available on these issues with regards to kombucha. In fact, most of the data on kombucha tea is anecdotal and further studies are needed to elucidate its putative therapeutic potential, particularly against DM.
In this context, pancreatic lipase, a complex enzyme that plays a key role in lipid metabolism, has often been employed in human and animal model studies involving the evaluation of natural products for potential application as antiobesity and antidiabetic agents [
8]. The inhibition of this enzyme significantly decreases the digestion and uptake of lipids, thereby decreasing the level of postprandial blood glucose in non-insulin-dependent diabetic patients. Pancreatic α-amylase is a key enzyme in the digestive system that catalyses the initial step in the hydrolysis of starch to a mixture of smaller oligosaccharides consisting of maltose, maltotriose, and a number of oligoglucans. These are then acted on by α-glucosidases and further degraded to glucose that enters the blood-stream. The degradation of this dietary starch proceeds rapidly and leads to elevated postprandial hyperglycemia. Inhibitors of pancreatic α-amylase delay carbohydrate digestion, thus reducing glucose absorption rates and lowering postprandial serum glucose levels [
26].
Considering the increasing concerns over the alarming rates recorded for DM and in light of the promising opportunities that kombucha might open with regards to the alleviation and/or prevention of this troublesome disease, the present study was undertaken to investigate and assess the hypoglycemic and antilipidemic effects of kombucha using a diabetic rat model. It aims to gain principled insights with regards to the biological activities of kombucha towards pancreatic lipase and α-amylase as well as its effects on liver-kidney function, which may provide a starting point for the understanding of the antidiabetic potential of kombucha. For the sake of pertinence, the biological activities of kombucha were compared to those reported for black tea [
27].
Discussion
Although kombucha tea is popular around the world as a beneficial medicinal health-promoting drink, its beneficial and/or adverse effects on human health have not been scientifically determined yet. No previous study has, for instance, so far reported on the systematic investigation and evaluation of the antidiabetic activity of kombucha. To the authors’ knowledge, the present work is the first attempt to investigate the protective effects of kombucha on diabetes and its complications on the functions of the liver, kidney, and pancreas.
Several of the enzymes secreted by the pancreas, namely α-amylase and lipase, are known to break down dietary polysaccharides and lipids into monosaccharides and free fatty acids, which represent some of the major nutrients needed to maintain human health [
36,
37]. Although most of the research so far conducted on diabetes has focused on dyslipidemia as a major risk factor for cardiac, cerebral, and renal complications, several studies have recently showed an impairment of pancreatic exocrine function in type 1 and type 2 diabetes. The analysis of serum/plasma pancreatic enzymes was suggested to provide additional informative parameters for the assessment of the chronicity and progress of the illness as well as of the response to therapy [
38‐
41].
The findings of the present study showed that the administration of kombucha to surviving diabetic rats significantly reduced pancreatic α-amylase activity, which plays a key role in the digestion of carbohydrates. This was indicative of lowered levels of absorbable glucose being formed from the digestion of carbohydrate and leading to reduced levels of blood glucose. The inhibition of pancreatic α-amylase activity in the human digestive tract represents one of the therapeutic approaches commonly used for the control and prevention of postprandial hyperglycemia in non-insulin-dependent diabetic patients through reducing the uptake of glucose released by those enzymes from starch [
42,
43].
To produce kombucha, black tea ingredients and sucrose undergo progressive modifications due to the action of the tea fungus. Several metabolites can be identified in the fermented beverage, including acetic, lactic, gluconic and glucuronic acids, ethanol, glycerol and polyphenols [
20,
44‐
46]. Most of the properties of kombucha are attributed to the polyphenolic composition of the beverage. Tea polyphenolics were previously reported to inhibit and reduce α-amylase activity in the in the saliva and intestines of rats, respectively, which, in turn, were described to lower the hydrolysis of starch to glucose and to reduce the assimilation of glucose [
47].
The present study also showed that the administration of kumbucha to surviving diabetic rats reduced pancreatic lipase activity, a decrease that is responsible for the hydrolysis of non-absorbable dietary triglycerides into absorbable monoglycerides and free fatty acids, which, in turn, leads to the decrease of plasma cholesterol and TG level [
48‐
50]. This represents one of the therapeutic approaches commonly used for the control and prevention of dyslipidemia. Polyphenols were reported to inhibit pancreatic lipase
in vitro. Previous data suggested that the presence of galloyl moieties within polyphenol chemical structures was required for the enhancement of pancreatic lipase inhibition [
51].
Alloxan is a specific toxin that destroys the pancreatic β-cells, provoking a state of primary deficiency in insulin without affecting other types of islets. The diabetic effect of alloxan is due to an excess in the production of reactive oxygen species (ROS). This excess leads to toxicity in pancreatic cells, which, in turn, reduces the synthesis and release of insulin while concurrently affecting other organs, such as liver [
52]. Increased lipid peroxidation products and decreased plasma or tissue concentrations of superoxide dismutase, catalase, and glutathione have been well documented in the literature on alloxan-induced diabetes [
30,
53].
Chronic hyperglycemia and dyslipidemia are associated with a variety of metabolic disorders in human and animal diabetic patients [
54,
55], causing oxidative stress, depleting the activity of the antioxidative defense system, and resulting in elevated levels of ROS [
30,
43]. Oxidative environments might cause the damage of cells and tissues in the liver and kidney [
5], which is observed in the increased levels of AST, ALT, and GGT activities (indices of liver dysfunction) and of urea and creatinine (indices of kidney dysfunction). As far as the present study is concerned, the findings showed that kombucha proved remarkably efficient in the decrease of the liver and kidney dysfunction indices in surviving diabetic rats, namely the AST, ALT, and GGT activities and the urea and creatinine levels. This supplement could, therefore, be considered as a potential strong candidate for future industrial application as a therapeutic agent against liver and kidney toxicity.
Several recent studies have provided ample support for the strong candidacy of kombucha for application as an antioxidant agent for the alleviation of oxidative stress and free radicals as well as the enhancement of enzymatic defenses. Bhattacharya
et al. have, for instance, showed that murine hepatocytes treated with KT prevented the disruption of mitochondrial membrane potential and blocked the activation of mitochondria-dependent apoptotic signaling pathways, thus displaying a significant reduction of tertiary butyl hydroperoxide-induced ROS generation and a considerable attenuation of malonaldehyde levels [
20]. The inhibition of radical species could, therefore, be one of the mechanisms involved in the efficient hepatoprotective and curative properties of KT. These findings are, in fact, in good agreement with the results previously reported by Murugesan
et al. showing that KT has the potential to revert the CCl
4-induced hepatotoxicity back through the production of antioxidant molecules during fermentation [
17]. The presence of glucaric acid and its derivatives, as potent detoxifying agents, could also be considered as another reason for the hepatoprotective effects of KT [
19].
Furthermore, Gharib
et al. showed that, owing to its antioxidant potential, KT can ameliorate trichloroethylene-induced kidney damage by preventing lipid peroxidation and ROS species formation [
16]. The nephroprotective effects kombucha were also attributed to organic acids (e.g. acetic and glucuronic acids) which are known to facilitate the detoxification process through conjugation with toxins, which they then solubilise and eliminate from the body [
56].
Kombucha polyphenols may, therefore, prevent the damage and death of pancreatic β-cells, and/or stimulate the regeneration of this type of cells in diabetic rats. Coskun
et al. have reported that the administration of polyphenols, such as quercetin and epicatechin, to surviving diabetic rats protects the architecture of pancreatic β-cells, preserves the secretion of insulin, and stimulates the regeneration of this type of cells [
57]. The administration of an antioxidant-rich beverage, such as kombucha, to diabetic rats would, therefore, presumably decrease the ROS-mediated toxicity in pancreatic β-cells [
35]. The ability of kombucha to reduce the blood glucose level could also be attributed to its ability to modulate the immune system [
18], leading to the decrease of β-cell damages. It is worth noting that the findings indicated that the curative effects achieved with the administration of KT were more pronounced than those reported for BT, which could presumably be attributed to the large amounts of polyphenols and flavonoids present in KT as compared to black tea [
20]. In fact, further studies on the mechanisms and modes of action of kombucha are needed to fully appreciate its values and limitations.
Competing interests
The authors declare that they have no competing interests.
Authors’ contributions
All authors participated in the conception, set up, and carrying out of the study, as well as in the handling and interpretation of its findings, and the writing and reviewing of its text. AA and KH have equally contributed to this work and undertook data analysis. DE, MB and KH contributed to the interpretation of the data. BJ helped in the writing and reviewing process. FA contributed in the design of the study and the discussion of the data. EA and AE supervised the work. All authors have read and approved of the final manuscript.