Bioactive Metabolites from Yeasts Presumptively Qualified as Safe as Functional Agents in the Management of Type 2 Diabetes

Abstract

Microbial metabolites offer a multitude of mechanisms for alleviating diabetes, particularly type 2 diabetes (T2D). However, the metabolites of yeasts recognised as safe remain under-explored and are receiving less attention in the treatment of T2D. In addition to the recognised probiotic status of certain yeasts, their genetic feature is responsible for many of the effects observed. Branched and non-branched short-chain fatty acids, bioactive peptides, carotenoids, and polysaccharides (β-glucans, mannans, and peptides derived from them) have vital properties that modulate intestinal permeability, soothe inflammation, and directly influence insulin sensitivity. Their action mechanism ranges from hepatic lipogenesis via the induction of hormone-sensitive lipase and the inhibition of α-glucosidase or DPP-IV to promoting the secretion of GLP-1 (Glucagon-Like Peptide-1) and GIP (Gastric Inhibitory Polypeptide), orchestrating immune modulation, and nourishing the gut microbiota. The richness of the yeast metabolome suggests that a concentrated fermentate could be developed to potentiate the functional effects in vitro in the treatment of T2D. The purpose of this review is to take stock of the current state of knowledge of probiotic yeast metabolites and outline their potential for the treatment of diabetes via the development of food supplements or nutraceuticals.

1. Introduction

Modern dietary habits, combined with an increasing consumption of highly calorific, salty, and fatty processed foods, promote the development of metabolic dysfunctions that underlie chronic diseases. One of the most widespread pathologies to date is type 2 diabetes (T2D), which accounts for around 90% of diabetes cases. It is also the result of hereditary, metabolic, and environmental predispositions [1,2]. The onset of this disease occurs when the pancreatic gland fails to secrete enough insulin, or when the body shows a reduced ability to use the insulin produced. In recent decades, probiotics and their metabolites have been proposed as alternative solutions for improving the management of T2D [3]. Their abilities to modulate the gut microbiota, reduce low-grade inflammation, boost the immune system, and reduce glycaemia and insulin resistance have all been attributed to them [3,4,5]. Although most of the research into anti-diabetic probiotics has focused on lactic acid bacteria, probiotic yeasts and their metabolites represent a particularly interesting but largely underexplored category in the treatment of diabetes [6,7].

A few preclinical studies in rats have demonstrated that the administration of the Saccharomyces boulardii THT 500101 strain moderately improves blood glucose levels, reduces systemic inflammation, normalises the renin-angiotensin II system, and corrects the lipid profile [6,8,9,10]. In addition to Saccharomyces boulardii, the most well-known and commercially available species, this list includes Saccharomyces bayanus, S. pastorianus, Kluyveromyces lactis, Komagataella phaffii, K. pastoris, Schizosaccharomyces pombe, Cyberlindnera jadinii, Hanseniaspora uvarum, Xanthophyllomyces dendrorhous, Ogataea angusta, Limtongozyma cylindracea, Yarrowia lipolytica, and Zygosaccharomyces rouxii [11]. However, their application in the management of diabetes remains very limited or even ineffective, despite the presence in their fermentates of bioactive molecules (organic acids, bioactive peptides, polysaccharides, and carotenoids) known for their ability to alleviate diabetes and/or its complications [12,13,14,15,16]. These metabolites may act as signalling molecules, interpreted by host cells and triggering a cascade of reactions likely to regulate energy metabolism, insulin resistance, and oxidative stress. Therefore, exploring these bioactive compounds could pave the way for a postbiotic approach aimed at formulating food supplements or nutraceuticals that are more stable over time than living cells [17]. The purpose of this review is to take stock of the current state of knowledge of probiotic yeast metabolites and outline their potential for the treatment of diabetes mellitus via the development of food supplements or nutraceuticals

2. Discovery of Probiotics and Characteristics of Probiotic Yeasts

The European Food Safety Authority (EFSA) has determined that a subset of yeast species known as QPS (Qualified Presumption of Safety) yeasts pose little risk of endangering the health of humans or animals. In the absence of probiotic properties, they may still produce bioactive molecules that can be exploited as postbiotics. The exploration of probiotics has long relied on a “top-down” approach, identifying as beneficial the dominant microorganisms in healthy individuals, notably strains of Bifidobacterium and Lactobacillus [18]. An alternative method, based on the exploration of fermented foods to isolate potentially probiotic micro-organisms, corresponds to the initial approach adopted by Metchnikoff for the isolation and identification of Lactobacillus bulgaricus [19]. Advances in molecular techniques have made it possible to extend this research to species that are difficult to cultivate, such as Faecalibacterium prausnitzii, Akkermansia muciniphila, and Microvirga massiliensis [20,21]. At the same time, bottom–up strategies inspired by drug discovery have emerged, divided into phenotypic and targeted approaches [22]. The former involves evaluating probiotic effects in vitro, ex vivo, and in vivo, as with Lactobacillus rhamnosus JB-1, whose benefits observed in mice have not been confirmed in humans. The second identifies candidates who can produce molecular effectors that modulate important host or microbiota pathways using in silico predictions based on multi-omics data [23,24].

Probiotics are live microorganisms that provide health benefits to humans and animals when consumed in adequate amounts. They enhance the activity of the host’s endogenous microflora, modulate the immune system, support digestion and metabolism, and influence the gut–liver axis [25,26,27]. Yeasts represent a valuable alternative to bacterial probiotics, especially in contexts where antibiotics are frequently used in therapeutic treatments to suppress or eliminate bacterial strains [28]. Their strong resistance to gastric acidity ensures their survival through the stomach and enables them to reach the intestine, where they can colonise effectively thanks to specific surface proteins and glycoproteins [29]. Once established, yeast probiotics exert immunomodulatory effects by stimulating cytokine production and enhancing immune cell activity. They also exhibit antimicrobial action by secreting organic acids, hydrogen peroxide, and antifungal peptides [28]. However, the beneficial effects may be attributed either to the yeast cells themselves or to the various metabolites they produce.

3. Metabolites of QPS Yeasts

Contemporary research reveals a growing interest in the constituents of yeast extract and metabolites secreted by probiotic yeasts in the management of chronic diseases such as T2DM [12]. This approach should be based on concrete scientific evidence, demonstrating that the beneficial effects of probiotics come not only from their living presence but also from the bioactive molecules they produce and release into their environment [30,31]. Several studies have indicated that these compounds can have significant effects on glycaemic control, insulin sensitivity, and systemic inflammation, opening new therapeutic prospects for diabetic patients [32,33,34,35]. Unfortunately, the studies demonstrating the action of the metabolites excreted by yeasts are few and do not make it possible to assess the direct effect on humans, which is why this review will focus on the potential effects of antidiabetic yeast metabolites.

3.1. Metabolite Profile of QPS Yeasts

Yeast metabolism can be likened to the components of a factory, where each stage yields an intermediate product and a final product at the end of the chain, including waste. Each of these products or by-products plays a role in the cell, although they can become harmful depending on their concentration. Their nature also varies according to the metabolic pathway employed, which itself is selected based on several factors, such as the type and concentration of substrate, oxygen availability, temperature, and more [36].

In addition to ethanol abundantly produced by species of the genera Saccharomyces, Pichia, Schizosaccharomyces, Kluyveromyces, Candida, among others, yeasts generate a wide range of metabolites. Food-relevant metabolites are the most extensively documented, including glycerol, succinate, butyrate, acetate, α-ketoglutarate, and malate [36,37]. Except for malate, ethanol, and glycerol, many of these compounds can be utilised by colonocytes as an energy source [38]. Yeasts also synthesise a variety of amino acids via the shikimate pathway and produce numerous volatile organic compounds, such as phenyllactic acid, isoamyl alcohols, ethyl acetate, ethyl butyrate, ethyl isobutyrate, acetaldehyde, 1,1-diethoxyethane, 2-hydroxyisocaproic acid, and limonene [39,40,41]. They also release GABA (γ-aminobutyric acid), shikimic acid (a precursor to phenylalanine, tyrosine, and tryptophan), p-aminobenzoic acid, and tyrosol [42]. Yeasts, particularly Saccharomyces boulardii, produce bioactive peptides involved in regulating carbohydrate metabolism of interest for diabetes management and inhibiting pathogenic microorganisms. In addition to these compounds, certain strains are capable of synthesising polysaccharides and carotenoids, which possess antioxidant properties, modulate inflammation, and stimulate the immune system [12,43].

It is important to note that the metabolomic profile is not fixed; it varies depending on the culture medium in which the microorganism is grown. In the following sections of this manuscript, metabolites with antidiabetic potential are grouped into organic acids (including short-chain fatty acids, branched-chain short-chain fatty acids, and other organic acids), bioactive peptides, and carotenoids, to highlight their relevance in diabetes management.

3.2. Antidiabetic Potential of Yeast-Secreted Metabolites

3.2.1. Branched and Non-Branched Short Chain Fatty Acids

Short-chain fatty acids (SCFAs) are generally produced during in vitro and in vivo fermentation. The microorganisms best studied for this purpose are lactic acid bacteria, although yeasts also produce short-chain fatty acids in modest proportions.

Acetic acid is commonly produced by Saccharomyces and non-Saccharomyces yeasts (Saccharomyces cerevisiae, Zygosaccharomyces bailii, Brettanomyces spp.) and is the product of the conversion of pyruvate to acetate via acetaldehyde [44]. It is the product of numerous microbial fermentations and is a SCFA, recognised for its ability to modulate the gut microbiota [4,6]. Although specific data on its anti-diabetic effects is less well documented than for succinic acid, acetate plays an important role in regulating carbohydrate and lipid metabolism. This molecule, produced mainly by fermentation, improves insulin sensitivity by activating G protein-coupled receptors and regulates gene expression linked to glucose and lipid metabolism by inhibiting histone decarboxylases [45]. It has been shown that acetate consumption in rats is marked by a reduction in accumulation in the liver and adipose tissue, demonstrating that acetate can help correct glucose intolerance and reduce fat accumulation, which are dysfunctions that favour the development of diabetes [46]. Although it does not have a direct effect on blood sugar levels, acetate regulates fat mass reduction and steatosis via the repression of lipogenic genes. In addition, acetate is involved in the specific activation of an enzyme involved in maintaining energy balance in cells, AMPK (AMP-activated protein kinase). This activation is linked to an increase in the AMP/ATP ratio due to the increased formation of acetyl-CoA via short-chain acyl-CoA synthetases (ACSS1 and ACSS2). In turn, phosphorylation of ChREBP (carbohydrate-responsive element-binding protein) by AMPK inhibits its activity, leading to a decrease in transcription of these genes [46]. An analysis using Northern blot techniques revealed that the transcripts of several lipogenic genes in the liver were reduced when acetate was administered [46]. All these phenomena work together to activate the β-oxidation of fatty acids and inhibit hepatic glucose synthesis, thereby improving carbohydrate homeostasis [47]. The mechanisms of action of acetate on energy metabolism, immunity, and intestinal integrity are depicted in Figure 1.

Like short-chain fatty acids (SCFAs), their branched-chain counterparts (BSCFAs) also exhibit similar biological effects. Both serve as energy sources for hepatocytes and colonocytes [48]. Their involvement in carbohydrate and lipid metabolism has been associated with improved insulin sensitivity and enhanced lipid catabolism in adipocytes. Notably, it has been shown that branched short-chain fatty acids, particularly isobutyric acid and isovaleric acid, exert an inhibitory effect on lipolysis induced by isoprenaline (a non-selective beta-adrenergic receptor agonist) in primary rat adipocytes. Interestingly, this inhibition occurs independently of the PI3-kinase and phosphodiesterase three pathways, which are the main regulatory routes of lipolysis. Moreover, BSCFAs promote lipolysis by activating protein kinase A (PKA), which in turn phosphorylates and activates hormone-sensitive lipase [49].

Furthermore, BSCFAs have the capacity to inhibit the activation (phosphorylation) of protein kinase B (PKB), a key serine/threonine kinase involved in the insulin-signalling pathway [50]. Mechanistically, insulin binds to its receptor and initiates a signalling cascade that leads to PKB activation, ultimately facilitating glucose uptake into cells via GLUT4 transporters. By inhibiting this process, BSCFAs may act antagonistically to insulin, thereby preventing glucose entry into rat cells [49,51].

3.2.2. Other Organic Acids

Yeasts produce, in addition to SCFAs and BSCFAs, other organic acids, among which succinic and malic acids stand out for their influence on carbohydrate and lipid metabolism. Several studies have underlined the significant role these acids may play in diabetic patients and their associated comorbidities.

An investigation by Ives et al. [52] examined the impact of succinic acid on lipid profiles and insulin resistance in rats rendered obese by a high-fat diet. The authors reported a marked reduction in adipose tissue mass and a decline in the mitochondrial respiratory capacity in oxidative muscle. Paradoxically, a supplementation with succinic acid at 0.75 mg/mL (equivalent to 6.35 mM) led to an increase in the fasting blood glucose in these animals. This finding contrasts with that of Yuxuan Yang et al. [53], who observed that a 40 mM succinate supplementation lowered the fasting glycaemia and improved glucose tolerance. These discrepancies suggest that succinic acid’s effects on glycaemic control are complex and may hinge on its concentration (with improvements in insulin tolerance noted from around 5 mM) as well as on the experimental setting. Indeed, in Ives et al.’s study, no enhancement of the glucose tolerance or insulin sensitivity was detected, indicating that the reduction in fat mass does not necessarily translate into better carbohydrate metabolism [52]. Nevertheless, Yang et al. also found that succinate improved the lipid profile by reducing plasma triglycerides, total cholesterol, and LDL-C, while raising HDL-C levels [53].

The biological action of succinic acid is mediated through the cell-surface receptor SUCNR1 (GPR91), a metabolic sensor expressed in various tissues, including the liver, white adipose tissue, and retina. Upon binding to SUCNR1, succinic acid triggers the p38 MAPK- and PI3K/AKT-signalling cascades, both of which are pivotal for adipocyte differentiation and the maintenance of energy homeostasis [53]. One notable outcome of this pathway activation is the browning of white adipose depots, a process marked by enhanced thermogenesis and elevated energy expenditure [54]. A schematic representation of this mechanism of action is shown in Figure 2.

By contrast, malic acid has been evaluated in the context of xerostomia, a common complication of T2D, via topical application. In a controlled trial involving 52 type 2 diabetic patients, a 1% malic acid formulation applied for four weeks led to a significant increase in unstimulated salivary flow. However, to date, the literature offers no evidence regarding malic acid’s potential to modulate energy metabolism in individuals with T2D [55].

3.2.3. Bioactive Peptides

Bioactive peptides produced from yeast have a wide range of biological functions, including antioxidant, hypotensive, and antimicrobial effects. They are mainly obtained by yeast fermentation, a process in which yeast extracts are used as substrates, and proteolytic enzymes from microorganisms fragment the proteins to generate functional peptides [56].

A study by Aquino et al. [12] on the effect of bioactive peptides extracted from the yeast Saccharomyces cerevisiae highlighted a multitude of beneficial effects in regulating the metabolism of people with diabetes. These include their ability to inhibit enzymes linked to glucose metabolism, such as α-glucosidase and dipeptidyl peptidase IV (DPP-IV). Glycosylation had a differentiating effect on the activity, with peptides carrying mannose in their primary chain being more effective at inhibiting α-glucosidase, whereas non-glycosylated peptides preferentially inhibited DPP-IV. In addition, the impact of these peptides on the gene expression related to glucose metabolism was assessed using mouse jejunum organoids. The results indicated a down-regulation of genes associated with carbohydrate catabolism and glucose uptake, as well as an increased expression of incretin hormones, such as glucose-dependent insulinotropic peptide (GIP) and relevant glucagon-like peptide 1 (GLP-1) [12]. A Cyclo-His-Pro-rich hydrolysate, produced by enzymatic hydrolysis (neutrase, alkalase, protamex, flavourzyme, ficin at 50 °C, W/O 1/100), significantly lowered the blood glucose levels after an oral glucose tolerance test in male ICR mice for up to 120 min [57].

Unlike some anti-diabetic agents, inhibitory peptides have the advantage of not causing hypoglycaemia and are thought to have a direct effect on pancreatic β cells, stimulating their differentiation and proliferation. A meta-analysis conducted by Zhou et al. [58] showed that DPP-IV inhibitors were associated with a significantly lower risk of hypoglycaemia compared with conventional sulphonylureas in type 2 diabetic subjects. Among the outstanding features of these peptides is their ability to neutralise free radicals and prevent lipid peroxidation, which helps to alleviate oxidative stress in the body, thereby reducing chronic inflammation and the dysregulation of oxidative mediators that impair pancreatic β-cell function. They also play an antimicrobial role.

Promising results have shown that certain peptides excreted during yeast fermentation can delay the proliferation of pathogenic microorganisms by disrupting the wall stability or binding to sites essential to the survival of fungi and bacteria; the best known are mycocins, extracellular proteins or glycoproteins with an inhibitory effect against species close to the yeast that produces them. These antimicrobial peptides are effective at pH 4–7 against several pathogenic species, such as Bacillus subtilis, Escherichia coli, Klebsiella aerogenes, and Staphylococcus aureus. Their mode of action varies according to their charge. Cationic peptides bind to the anionic components of membranes, causing them to rupture, while anionic peptides cross the membrane, form pores, and lead to uncontrolled exchange between the intra- and extracellular compartments [59,60]. Branco et al. [61] showed that GAPDH fragments alter the plasma and vacuolar membranes of Hanseniaspora guilliermondii, lowering the intracellular pH from 6.5 to 5.4 in 20 min. In addition, S. cerevisiae K1 toxin creates channels that imbalance H⁺ and K⁺ fluxes, leading to cell death [62].

3.2.4. Carotenoids

Carotenoids represent a broad class of naturally occurring pigments found not only in fruits and vegetables but also synthesised by fungi, including yeasts [63,64]. Chemically, these compounds are hydrocarbons divided into two main classes: carotenes, which are non-oxygenated and non-polar, and xanthophylls, which are oxygenated and polar [65]. A distinctive feature of yeast strains capable of carotenoid production is the pigmentation of their colonies, ranging in colour from pale orange to deep red. Among the carotenoids most widely recognised for their biological activity are β-carotene, γ-carotene, astaxanthin, torulene, and torularhodin (native yeasts), lycopene, canthaxanthin, and zeaxanthin (engineered yeasts) (see Table 1). These compounds are associated with a range of health-supporting properties, particularly in relation to the prevention of cancer and cardiovascular diseases, as well as complications linked to diabetes mellitus. Their beneficial effects have been attributed to various mechanisms, including the enhancement of insulin sensitivity and the attenuation of oxidative and inflammatory stress [36,66].

Few investigations have reported an inverse association between the plasma levels of certain carotenoids, such as lycopene and β-carotene, and fasting insulin concentrations or the presence of metabolic syndrome [36,67]. Furthermore, astaxanthin has demonstrated the capacity to improve glucose tolerance and markedly increase insulin responsiveness. The biological mechanisms underpinning these effects are multifactorial. Carotenoids exert protective effects on pancreatic β-cells by mitigating inflammation and neutralising reactive oxygen species that contribute to oxidative injury. In murine models, the administration of astaxanthin was shown to suppress the upregulation of oxidative enzymes. Astaxanthin exhibits particularly potent antioxidant properties, reportedly surpassing those of lutein, β-carotene, and zeaxanthin [68]. Astaxanthin has also been shown to protect pancreatic β-cells from glucotoxic damage and to modulate the expression of key inflammatory proteins, including Nuclear Factor kappa B (NF-κB), Cyclo-oxygenase-2 (COX-2), Intercellular Adhesion Molecule-1 (ICAM-1), and inducible Nitric Oxide Synthase (iNOS) molecules known to sustain inflammatory cascades, nociception, and oxidative stress. In addition, it reduces the levels of pro-inflammatory cytokines, such as TNF-α, IL-6, and IL-1β. This cytokine downregulation supports the anti-inflammatory response observed in the brain, particularly within the cerebral cortex of diabetic rats [69,70]. These carotenoids are of particular interest for their role in mitigating or preventing complications of diabetes, including nephropathy, retinopathy, and neurological dysfunction. Although little is currently known about the in vitro biological activity of torularhodin, it has found practical use as a natural pigment in the agri-food sector.

Table 1. Yeast carotenoids, antidiabetic properties, and action mechanisms.

Carotenoid	Producing Yeast	Class	Antidiabetic Properties	Reference
β-Carotene	Rhodotorula glutinis, Sporobolomyces roseus	Carotene	≈22% reduction in T2D risk, enhanced insulin sensitivity, antioxidant defence	[36]
γ-Carotene	Sporobolomyces spp., Sporidiobolus spp.	Carotene	Antioxidant properties, cardiovascular protection in diabetic individuals	[71]
Astaxanthin	Xanthophyllomyces dendrorhous	Xanthophyll	Improved glucose tolerance, reduced HbA1c, enhanced insulin responsiveness	[71]
Torularhodin	Sporidiobolus pararoseus, Rhodotorula spp.	Xanthophyll	Improved lipid metabolism, reduced hepatic inflammation, enhanced insulin sensitivity	[72]
Torulene	Sporidiobolus pararoseus, Rhodotorula glutinis	Carotene	Protection against hyperglycaemia-induced oxidative stress, superior antioxidant activity	[73]
Lycopene	Candida utilis (engineered), Saccharomyces cerevisiae (engineered)	Carotene	Reduced blood glucose, improved lipid profile, protection against diabetic complications	[74]
Canthaxanthin	Saccharomyces cerevisiae (engineered)	Xanthophyll	Oxidative stress tolerance, anti-inflammatory properties	[75]
Zeaxanthin	Saccharomyces cerevisiae (engineered)	Xanthophyll	Protection of diabetic retina, improved visual function	[75]

Table 1. Yeast carotenoids, antidiabetic properties, and action mechanisms.

Carotenoid	Producing Yeast	Class	Antidiabetic Properties	Reference
β-Carotene	Rhodotorula glutinis, Sporobolomyces roseus	Carotene	≈22% reduction in T2D risk, enhanced insulin sensitivity, antioxidant defence	[36]
γ-Carotene	Sporobolomyces spp., Sporidiobolus spp.	Carotene	Antioxidant properties, cardiovascular protection in diabetic individuals	[71]
Astaxanthin	Xanthophyllomyces dendrorhous	Xanthophyll	Improved glucose tolerance, reduced HbA1c, enhanced insulin responsiveness	[71]
Torularhodin	Sporidiobolus pararoseus, Rhodotorula spp.	Xanthophyll	Improved lipid metabolism, reduced hepatic inflammation, enhanced insulin sensitivity	[72]
Torulene	Sporidiobolus pararoseus, Rhodotorula glutinis	Carotene	Protection against hyperglycaemia-induced oxidative stress, superior antioxidant activity	[73]
Lycopene	Candida utilis (engineered), Saccharomyces cerevisiae (engineered)	Carotene	Reduced blood glucose, improved lipid profile, protection against diabetic complications	[74]
Canthaxanthin	Saccharomyces cerevisiae (engineered)	Xanthophyll	Oxidative stress tolerance, anti-inflammatory properties	[75]
Zeaxanthin	Saccharomyces cerevisiae (engineered)	Xanthophyll	Protection of diabetic retina, improved visual function	[75]

3.2.5. Polysaccharides

The yeast cell is a natural source of complex polysaccharides, namely mannan oligosaccharides and β-d-glucan, which possess biological properties. Supplementation of these polymers in the diet induces the modulation of energy metabolism, immune response, hormonal balance, and the gastrointestinal tract [7,76].

The aforementioned effects are partly supported by a meta-analysis including three review studies and 273 participants, which demonstrated that the intake of S. cerevisiae hydrolysate (Stetikal^® (Quito, Ecuador), Lipigo^® (Barcelona, Spain)) induced a generalised weight loss, with a reduction in abdominal circumference and fat mass [77]. The administration of β-glucans (30 mg/kg/d, for 28 d) in type 2 diabetic rats resulted in a reduction in several biochemical markers, such as glycaemia, triglycerides, and alanine aminotransferase by 30, 32, and 41%, respectively [76]. In a randomised, placebo-controlled, phase I pilot study, supplementation with yeast β-glucan (2.5 g/d) significantly reduced the insulin resistance and TNFα after 8 and 4 weeks, respectively, in the treated group, with an increase in bile acid levels, of which tauroursodeoxycholic acid accounted for the majority, without any close link with gut microbiota or SCFAs [7]. In fact, the increase in intestinal bile acid levels is strongly correlated with a reduction in serum cholesterol levels. By binding to bile acids in the intestine, β-glucans promote their excretion in the faeces, encouraging the body to produce more by using the endogenous cholesterol stock [7]. Similarly, β-glucans can be used as a prebiotic by the intestinal flora, whose fermentation generates SCFAs capable of exerting hypocholesterolemic and anti-inflammatory effects that are essential for restoring the integrity of the intestinal barrier and pancreatic β-cells [78].

Mannan oligosaccharides (MOS) also have interesting properties for alleviating the subjacent complications of diabetes. MSOs supplementation in obese rats had no significant effect on carbohydrate homeostasis and inflammation, whereas in lean rats, it led to an increase in the number of immune cells (macrophages and eosinophils) in mesenteric white adipose tissue [79]. MSOs are also thought to have prebiotic effects that promote the modulation of the gut microbiota and therefore the reversal of dysbiosis. A study by Reiko Tanihiro et al. [80] showed that the consumption of MSOs increased the relative abundance of bacteroides, specifically Bacteroides thetaiotaomicron and Bacteroides ovatus, and reduced the concentration of faecal p-cresol, indole, and skatole, harmful metabolites associated with intestinal dysbiosis.

Yeast polysaccharides stand out for their low production cost, simple extraction technology, and stable and potentially inexhaustible supply, ensuring their strong dominant position in the market for various essential carbohydrate functional ingredients for years to come [31,81,82]. They exert multiple actions that, although not favourable for maintaining carbohydrate homeostasis, modulate and reduce immunity, inflammation, and intestinal dysbiosis and could be used as dietary supplements. The combined effects of these polysaccharides allow us to speculate on the possibilities of formulating effective nutritional supplements or nutraceuticals. Figure 3 shows the roles of yeast polysaccharides (β-glucans and mannan oligosaccharides) in regulating glycaemia, preventing metabolic syndromes, and boosting immunity.

4. Potential of Postbiotic Formulations, Knowledge Gaps and Perspectives

4.1. Potential of Postbiotic Formulations from Yeast

The translation of fundamental research towards therapeutic applications should generate more interest in exploring the metabolites of microorganisms, in this case, yeast, for the development of the postbiotic approach. This approach is sustainable insofar as it presents concentrates of pure or combined molecules that remain stable when combined with other formulations, have a fairly long shelf life (generally two years), and require less stringent storage conditions than probiotics, whose loss of viability during storage remains a challenge to overcome for certain formulations [17,83].

Unfortunately, postbiotic forms of yeast metabolites (Stetikal, Lipigo, EpiCor) are virtually non-existent in the world market. However, the best-known is EpiCor, a dehydrated fermentate of the yeast S. cerevisiae, renowned for its antioxidant content. It has been tested for its ability to protect cells against oxidative damage and its ability to improve immune health [84,85]. Several randomised, placebo-controlled clinical trials in which participants received a dose of 500 mg/d for 12 weeks showed significant curative effects on flu and colds compared with the placebo group [86,87]. Another 12-week trial showed that PE significantly reduced the average severity of specific symptoms of allergic rhinitis, particularly nasal congestion and rhinorrhoea [88].

More specifically, the consumption of EpiCor has antioxidant and immunomodulatory properties, transiently reducing the number of circulating T and NK lymphocytes and increasing interferon C levels [87,88,89]. Such mechanisms are thought to alleviate the basis of several inflammatory diseases, such as inflammatory bowel disease, irritable bowel disease, gout, and diabetes.

4.2. Knowledge Gaps and Perspectives

Synthetic biology is an interdisciplinary science that applies the principles of engineering (modular design, standardisation, automation) to biological systems. Thus, thanks to synthetic biology, it is possible to precisely reprogramme the metabolic pathways of yeast organisms for the overproduction of molecules of interest by optimising key genes, strengthening limiting enzymes, and adjusting the pool of co-factors (NADH/NAD⁺, ATP, coenzyme, etc.) [90]. These authors, respectively, described how the introduction of four metabolic reactions into the S. cerevisiae genome reduced ATP consumption and CO₂ losses and rebalanced the NADH/NAD⁺ redox couple for farnesene production. In addition, the establishment of synthetic consortia will enable bioactive molecules to be synthesised, thanks to the synergistic action of strains which will sequentially degrade substrates to mutually synthesise another.

A lasting solution to the challenge of treating metabolic disorders such as diabetes lies in the strategy for disseminating bioactive formulations. Researchers could focus on the supplementation of dried fermentates in appropriate foods to suit the diets of their subjects. In this way, the range of foods and beverages that are widely consumed, accessible, and without adverse effects on long-term health can be the subject of serious and relevant studies. In addition, bars, capsules, or powders could be proposed to prevent or manage the pathological components that support diabetes.

5. Conclusions

Exploring the under-explored metabolic profile of probiotic yeasts in the context of type 2 diabetes reveals a promising therapeutic potential. The metabolites identified (SCFAs, BSCFAs, bioactive peptides, carotenoids, and polysaccharides) have complementary anti-diabetic effects. SCFAs and BSCFAs improve the insulin sensitivity and glucose tolerance whilst modulating the lipid and immune homeostasis. Bioactive peptides inhibit α-glucosidase and DPP-IV, stimulate the secretion of incretins (GLP-1, GIP), and protect β-cells without inducing hypoglycaemia. Carotenoids bolster antioxidant defences, reduce oxidative stress and inflammation (NF-κB, COX-2), and lower HbA1c whilst improving the lipid profile. Finally, β-glucans and mannan oligosaccharides regulate blood glucose, triglycerides, insulin resistance, and inflammation (TNF-α); promote bile acid excretion; and positively modulate the gut microbiota. Exploiting these metabolites for postbiotic purposes could provide a standardised and stable alternative to probiotics. Nevertheless, the validation of these results via complementary in vitro tests will enable us to gain a deeper understanding of the mechanisms of action and to envisage clinical trials, the data from which, via meta-analyses, will enable us to make more generalised recommendations.