Traditional Fermented Foods: Challenges, Sources, and Health Benefits of Fatty Acids

Abstract

Traditional fermented foods harbor microbes that transform raw food components, improving their nutritional, shelf life, organoleptic, and health-promoting characteristics. Fermented foods are an important conduit of contact between bioactive components that act like antigens and the human body system. Versatile microbes in traditional fermented foods are associated with many health-promoting end-products, including dietary fatty acids and inherent fermenting microbial cells. Evidence shows that dietary fatty acid components regulate genes in a hormonally dependent manner, either directly via specific binding to nuclear receptors or indirectly by changing regulatory transcription factors. Fatty acids are implicated in anti-inflammatory, anti-obesogenic, immunoregulatory, cardioprotective, etc., activities. Challenges with scaling the production of traditional fermented foods stem from losing effective consortiums of microbial groups and the production of differential end-products. Industrialists scaling the production of traditional fermented foods must overcome safety and consistency challenges. They need to combine processes that lessen the advent of public health issues and introduce omics technologies that identify and maintain effective consortium groups, prune genes that code for toxic products, and inculcate microbes with additional beneficial characteristics. Incorporating omics in production will avail the benefits of traditional fermented foods to a larger population that craves them outside their native areas.

1. Introduction

Traditional fermented foods are veritable sources of health-promoting biomolecules, despite associated challenges. The health effects are made possible due to ubiquitous microbes that self-perpetuate by employing versatile metabolic activities to ferment suitable substrates. Fermentation compounds a complex milieu of active microorganisms, their metabolic activities, which they foster through a system of enzymes, and the raw materials or macromolecules they act upon to yield products of interest [1,2,3,4,5]. These critical by-products elicit significant benefits for gut microbes, the mucosal immune system, and other organs under the direct influence of the mucosal immune system [6]. Although most fermentation occurs without oxygen, acetic acid fermentation can go on aerobically. In biochemical terms, all processes that have organic compounds as electron donors are fermentative: whether raw food substrates are in man-made bio-processors, ingested diets in human intestines, or agro-wastes that clog our environments, microbial processes and metabolisms are effective enough in releasing encrypted and valuable components from transforming these macromolecules [7,8,9,10,11,12]. Figure 1A–C shows the transformation of essential macromolecules in foods into bioactive by-products with metabolic functions.

Historically, the conversion of ethanol to acetic acid in vinegar production is the oldest known microbial transformation process. Similar well-documented processes were traced to the human hunter-gatherer transitional times about 15,000–20,000 years ago [10]. Many ancient Chinese reports found fermented rice, honey, and fruits in earthen pots dated 7000 BC [2,7,13]. In a nutshell, the discovery of fermentative processes might have occurred concurrently on every continent and might have helped sustain humankind and societies [10,14]. However, Louis Pasteur is said to have laid the foundations for the modern knowledge of fermentation and sterilization processes [13], which have contributed immensely to food safety and preservation. It is hard to propound an exhaustive traditional fermented food list. The reason is their diverse nature, which largely influences their territories of origin, various cultures/traditions, and the geography of the people [15]. Capable microbes transform well-arranged and energy-dense macromolecules, releasing simpler, biologically active molecules, and energy packs during fermentation by utilizing several catabolic pathways. Fermentation by-products are released into microbial extracellular spaces under stress conditions or in the exponential growth phase [4,16]. Both the scientific community and consumers are paying close attention to the beneficial influence fermented foods exert on the host’s health via the gut microbiome.

Fermented foods and associated biotechnologies have played important roles in poverty alleviation, malnutrition curation, food security, sustainable development, and economy boosting and have sparked multidisciplinary, permeating interests [4,17]. Fermented foods and concomitant microbes and metabolites modulate the hosts’ microbiome, leading scientists to consider this interaction a crucial health-influencing route with great potential in precision medicine. They complement human metabolic processes by expressing non-human encodable enzymes [3,17,18]. A cross-sectional study showed that early intake of fermented foods reduced the risk of childhood atopy [19,20]. Second, the gut harbors two-thirds of every migratory immune cell in the body—a colossal impact on the host’s health [6,20]. As an important fermentation by-product, fatty acids, in their correct quantity, permeate cellular biological functions, energy homeostasis, and physiological and immune responses [21,22,23] and increase the nutritional and organoleptic characteristics of fermented foods [24,25,26,27]; (see

Table 1. Fatty acids from fermented foods and health benefits.

Fermented Food Source	Microbes Involved	Fatty Acid	Reference
Tarhana	Yogurt bacteria and baker’s yeast	Butyric acid 4.6 ± 1.1.	Erbas et al. [28]
Guava fruit	Lactobacillus plantarum	Butyrate 17.85 ± 0.68 ng/100 mL; caproate 62.03 ± 0.55 ng/100 mL; caprylate 34.93 ± 0.62 ng/100 mL; caprate 6.97 ± 0.52 ng/100 mL; and laurate 17.97 ± 0.51 ng/100 mL.	Bhat et al. [24]
Skim milk	Lactobacilli and Bifidobacteria	B. animalis subsp. lactis + 5% w/v inulin: acetic acid 2.72 mM; propionic acid 0.92 mM; and butyric acid 0.41 mM. B. animalis subsp. lactis + 5% w/v hi-maize: acetic acid 2.11 mM; propionic acid 0.68 mM; and butyric acid 0.24 mM. L. rhamnosus GG + 5% w/v inulin: acetic acid 2.56 mM; propionic acid 0.85 mM; and butyric acid 0.34 mM. L. rhamnosus GG + 5% w/v hi-maize: acetic acid 2.58 mM; propionic acid 0.70 mM; and butyric acid 0.25 mM.	Asarat et al. [29]
Goat milk	Lactobacillus rhamnosus GG	Butyric acid 0.75 ± 0.002.	Jia et al. [25]
Tea	Lactobacillus spp.	Butyric acid after 180 min – L. Plantarum (1.277 ± 0.024 µg/g); L. acidophilus (1.561 ± 0.033 µg/g); L. rhamnosus (1.014 ± 0.053 µg/g); L. bulgaricus (2.2880 ± 0.031 µg/g).	Annunziata et al. [30]
Kombucha with pollen	Kombucha/SCOBY (symbiotic culture of bacteria and yeasts) consortium	Kombucha alone: acetic acid 4.46 ± 0.025 g/L; propionic acid 0.24 ± 0.016 g/L; and butyrate 0.30 ± 0.021 g/L. Kombucha + pollen: acetic acid 3.51 ± 0.11 g/L; propionic acid 0.56 ± 0.041 g/L; and butyrate 1.78 ± 0.054 g/L.	Uțoiu et al. [31]
Carrot juice	Lactobacillus rhamnosus GG	Acetic acid 0.42 ± 0.05 mg/mL; propionic acid 0.72 ± 0.09 mg/mL; and butyric acid 0.95 ± 0.09 mg/mL	Hu et al. [32]
Beer wort	Yeast	2.3–8.1 mg/L of butyric, isobutyric, isovaleric, caprylic, and caproic acid.	Olsovska et al. [33]
Goat milk	Lactobacillus rhamnosus GG	Lauric acid 3.06 ± 0.06.	Jia et al. [25]
Tarhana (traditional Turkish fermented food)	Yogurt bacteria and baker’s yeast	Myristic acid 16.4 ± 1.4; myristoleic acid 0.5 ± 0.0; palmitic acid 40.1 ± 1.0; stearic acid 25.0 ± 1.6; oleic acid 12.7 ± 0.91; and linoleic acid 0.9 ± 0.2.	Erbas et al. [28]
Goat milk	Lactobacillus rhamnosus GG	Palmitic acid 24.35 ± 0.01; margaric acid 1.39 ± 0.02; stearic acid 0.23 ± 0.007; C18:1 9.174 ± 0.04; and C18:2 18.04 ± 0.05.	Jia et al. [25]
Nātto	NA	Myristic acid 0.05 ± 0.10; pentadecylic acid 0.15 ± 0.08; palmitic acid 0.17 ± 0.12; margaric acid 0.14 ± 0.07; stearic acid <0.003; arachidic acid <0.003; and lignoceric acid <0.003.	Wang et al. [26]
Shrimp paste	NA	Myristic acid 0.02 ± 0.01; pentadecylic acid 0.14 ± 0.05; palmitic acid 0.11 ± 0.08; margaric acid 0.50 ± 0.25; stearic acid 0.25 ± 0.10; arachidic acid 0.05 ± 0.07; and lignoceric acid 0.36 ± 0.13.	Wang et al. [26]
Fish sauce liquid	NA	Myristic acid <0.003; pentadecylic acid 0.12 ± 0.01; palmitic acid 0.07 ± 0.00; margaric acid 0.09 ± 0.02; stearic acid 0.18 ± 0.02; arachidic acid <0.003; and lignoceric acid <0.003.	Wang et al. [26]
Fish sauce (paste-like)	NA	Myristic acid <0.003; pentadecylic acid 0.14 ± 0.00; palmitic acid 0.07 ± 0.00; margaric acid 0.28 ± 0.01; stearic acid 0.11 ± 0.02; arachidic acid <0.003; and lignoceric acid <0.003.	Wang et al. [26]
Miso	NA	Myristic acid <0.003; pentadecylic acid 0.20 ± 0.00; palmitic acid 0.04 ± 0.00; margaric acid <0.003; stearic acid 0.04 ± 0.02; arachidic acid <0.003; and lignoceric acid <0.003.	Wang et al. [26]
Kimchi	NA	Myristic acid 0.06 ± 0.01; pentadecylic acid 0.04 ± 0.01; palmitic acid 0.12 ± 0.01; margaric acid 0.08 ± 0.00; stearic acid 0.06 ± 0.02; arachidic acid <0.003; and lignoceric acid <0.003.	Wang et al. [26]
Douchi	NA	Myristic acid <0.003; pentadecylic acid 0.01 ± 0.01; palmitic acid 0.01 ± 0.00; margaric acid 0.02 ± 0.00; stearic acid <0.003; arachidic acid <0.003; and lignoceric acid <0.003.	Wang et al. [26]
Walnut milk	L. plantarum ZS2058, L. casei FZSSZ3-L1, L. rhamnosus JSWX-3-L-2 and B. breve CCFM683	linoleic acid 63.80 ± 0.08; and linolenic acid 14.70 ± 0.08.	Mao et al. [27]

). Notwithstanding its numerous potentials, most traditional fermented foods are merely consumed in their native locality and bedeviled with inconsistent product outcomes. However, the globalization of the food markets has placed standardization and safety concerns with the scaled production of these health-beneficial foods. This review provides insight into the health effects of different fatty acids, and the challenges and regulatory issues surrounding commercializing traditional fermented foods.

2. Characteristic and Physiological Influence of Dietary Fatty Acids

2.1. Fatty acid Characteristics

The transformation and subsequent absorption of appropriate quantities of dietary fatty acids or lipids by intestinal epithelial cells fundamentally drive energy balance and metabolic health. Dietary lipids are first absorbed by small intestinal epithelial cells in a multistep process before being released into circulation. As such, the small intestine epithelium serves as a crucial gatekeeper, managing the transit of dietary components into the body by coordinating diverse metabolic pathways. The pancreatic enzymes in the intestinal lumen break down macromolecules into simpler molecules, including free fatty acids and monoacylglycerols [34]. Dietary fatty acids are described according to their carbon chain length characteristics [35]. Long-chain fatty acids (LCFAs) are mostly isolated from dietary triglycerides [36] and have between 13 and 21 carbons [35,37,38]. Medium-chain fatty acids (MCFAs) are also gotten from dietary triglycerides [34] and have between 6 and 12 carbons [35]. In comparison, short-chain fatty acids (SCFAs) are primarily from dietary fiber fermentation [36] and have less than 6 carbons [39]. There are also dietary odd-chain saturated fatty acids (OCFAs) that are present at trace levels in dairy fat [40,41]; (see

Table 2. Health functions of some dietary fatty acids.

Fatty Acid	Health Benefits	Reference
Butyric acid (SCFAs)	The main energy source for colonocytes. Stimulates the absorption of sodium and water in the colon. Stimulates the eubiosis of gut microbiota. Induces trophic action in intestinal cells. Anti-obesogenic effect. Inhibits inflammation and carcinogenesis. Promotes colonic defense barrier. Promotes satiety.	Miguel et al. [42] Stachowska et al. [43] Coppola et al. [44]
Caproic acid (hexanoic) (MCFAs)	Reverted HFD-induced visual and auditory cortex impairment. Reduced cancer cell viability from 70% to 90% (p < 0.05) compared to controls through by down-regulating cell cycle regulatory genes and up-regulating genes involved in apoptosis.	Tengeler et al. [45] Narayanan et al. [46]
Caprylic acid (octanoic) (MCFAs)	The energy source for patients suffering from pancreatic. insufficiency, impaired lymphatic chylomicron transport, and fat malabsorption. Neuroprotective potential against neurodegenerative disorders. Acylates ghrelin (peptide hormone with an orexigenic effect). Anti-microbial (bacteria, viruses, and fungi). Reduces bone weight	Lamarie et al. [47] Hismiogullari et al. [48]. Jian et al. [49]
Capric acid (decanoic) (MCFAs)	Energy source. Ameliorates neuropsychiatric disorders. Reduces oxidative stress levels in neuroblastoma cells. Neuroprotective. Suppresses mTORC1 activity independent of glucose and insulin signaling.	Shoji et al. [50] Mett and Muller [51] Dimiano et al. [52] Warrem et al. [53]
Lauric acid (dodecanoic) (MCFAs)	Modulated gut microbial composition. Increased anti-oxidative capacity. Inhibited Clostridium difficile growth in vitro. lowers the concentration of very low-density lipoprotein cholesterol (VLDL-c) and elevates total HDL cholesterol in human blood and tissues.	Ullah et al. [54] Yang et al. [55] Uday-Kumar et al. [56]
Isovaleric acid (Classical organic acidemias)	Improved neurologic and cognitive outcome. The predominant fatty acid end product of microbial origin is produced from the metabolism of leucine. The branched short-chain fatty acids can have effects on adipocyte lipid and glucose metabolism that can contribute to improved insulin sensitivity in individuals with disturbed metabolism. Ameliorates ovariectomy-induced osteoporosis by inhibiting osteoclast differentiation.	Grünert et al. [57] Szymanska et al. [58] Netto Candido et al. [59] Cho et al. [60]
Acetic acid (SCFAs)	Reduced plasma triacylglycerol (TAG) and fasting blood glucose (FBG) concentrations in individuals with type 2 diabetes. Reduced TAG levels in people who are overweight or obese. Restored bile acid homeostasis and suppress hepatic bile acid production. Inhibits intestinal-liver farnesoid X receptor (FXR)-fibroblast growth factor 15 (FGF15)-FGF receptor 4(FGFR4) signaling pathway. Anti-microbial and extended shelf life of cucumber puree (5 to 25oC). Upregulated the expression of TRIM40 which down-regulated TLR expression. Body weight and appetite regulation.	Lee et al. [61] Valdes et al. [62] Wang et al. [63] Yang et al. [64] Hernández et al. [65]
Propionic acid (SCFAs)	Reduces HFD-induced body weight gain and systolic pressure. Reversed HFD-induced visual and auditory cortex impairment. Increases glucose transporter type 1-positive cerebral blood vessels. Regulates adipokine production in human adipose tissue. Exacts anti-obesogenic effects through GPCR41 and 43, activates PPARγ and inhibits NF-κB. Altered gut microbiome composition and restored Treg cell/TH17 imbalance. Extends food shelf life, and increases glucagon, norepinephrine, and insulin resistance in humans. Activates the insulin-counterregulatory hormonal network. Down-regulated several inflammatory cytokines and chemokines (TNF-α and CCL5). Increased the expression of lipoprotein lipase and GLUT4, associated with lipogenesis and glucose uptake, respectively.	Tengeler et al. [45] Al-Lahham et al. [66] Duscha et al. [67] Adler et al. [68] Al-Lahham et al. [69]
Myristic acid (MCFAs)	High doses increased tissue levels of palmitic acid in rats. Regulates the biosynthesis and metabolism of highly unsaturated fatty acids. Enhanced intramuscular fat content in pork. Increased the expression of peroxisome proliferator-activated receptor-γ (PPARγ) and adipose-related genes, such as glucose transporter 1 (GLUT1), lipoprotein lipase (LPL), adipocyte fatty acid binding protein 4 (FABP4/aP2), fatty acid translocase (FAT), acetyl-CoA carboxylase α (ACCα), adipose triglyceride lipase (ATGL), and fatty acid synthase (FASN) in pigs. Increased plasma TG and ApoCIII concentrations.	Rioux et al. [70] Lu et al. [71] Olivieri et al. [72]
Palmitic acid	Increased milk energy output in cows (but disturbed energy balance). Attenuates the insulin signaling pathway through various mechanisms leading to insulin resistance. Induced apoptosis in β-cells is enhanced by T0901317 via the activation of LXRs and is blocked by EPA via the inhibition. Promoted cellular death, inhibiting of SREBP-1c, induced the expression of p27KIP1, transforming growth factor beta 1, and SMAD3 proteins in INS-1 cells.	de Souza et al. [73] Palomer et al. [74] Liang et al. [75]
Stearic acid	Influences mitochondrial morphology and functions. Reduces cardiovascular and cancer risk. Reduced serum glucose and increased monocyte chemotactic protein-1 (MCP-1). Induced apoptosis and cytotoxicity in preadipocytes through increased caspase-3 activity, increased Bax gene expression, and decreased cellular inhibitor of apoptosis protein-2 (cIAP2).	Senyilmaz-Tiebe et al. [76] Shen et al. [77]
Oleic acid	Suppressed atherosclerotic plaque size in LDLR-KO mice. Decreased the ratio of n-6/n-3 PUFA in the liver. Induces anti-inflammatory activities via inhibited histone acetyltransferases and compressed HPdLFs- increased H3Kac to IL 10 promoter regions. Induced anti-obesogenic effect-reduced body, liver, and epididymal fat weights, and reduced serum triglyceride and leptin levels. Down-regulated mRNA expression of lipogenic genes, proinflammatory cytokines, and upregulated lipid oxidation in the liver. Protected against colon structure damage by increasing the tight junction protein expression, increased Bifidobacteria, and reduced Enterobacteriaceae. Reduces blood pressure by regulating membrane lipid structure (HII phase propensity) via the G protein-mediated signaling	Yang et al. [78] Carrillo et al. [79] Schuldt et al. [80] Teres et al. [81]
Linoleic acid	Reduced plasma lipid and cholesterol levels through the regulation of cholesterol metabolism gene. Inversely correlated with cardiovascular disease risk and serum triacylglycerol. Benefits diabetes, lowers total and LDL cholesterols. Regulates the 5-LO pathway in anti-carcinogenesis and anti-tumour activities. Regulates fatty acid metabolism and inflammation via the COX-2 pathway. Contains AA and DHA which are essential for brain development and function.	Yang et al. [78] Farvid et al. [82] Zhao and Schooling [83] Wu et al. [84] Simopoulos [85] Bemelmans et al. [86] Jung et al. [87]
Margaric acid	Constitutes a major part of saturated fatty acids dominated in Graesiella sp. with good nutritional properties. Decreases sensory neurons’ mechanical excitability by Inhibiting PIEZO2 channels. Dietary fatty acid counteracts neuronal mechanical sensitization.	Gara-Ali et al. [88] Romero et al. [89]
pentadecanoic acid (OCFAs)	Lowers mortality and attenuates inflammation, anaemia, dyslipidaemia, and fibrosis in vivo, potentially by binding to key metabolic regulators and repairing mitochondrial function. Suppressed interleukin-6 (IL-6)-induced JAK2/STAT3 signaling, induced cell cycle arrest at the sub-G1 phase, and promoted caspase-dependent apoptosis in MCF-7/SC. Decreased risk of type 2 diabetes.	Venn-Watson et al. [90] Venn-Watson and Butterworth [40] Bao-To et al. [91] Weitkunat et al. [41]
Arachidic acid	Influenced liver and muscle fatty acid profiles, suppressed fatty acid synthase (FAS), and proliferator-activated receptor alpha (PPAR-α) expression. Reduced blood cortisol and glucose via eicosanoids synthesis gene expression and lipid metabolic pathways. Suppressed age-related excessive enhancement of the HPA axis responsiveness. Attenuated age-related reduction in GR translocation into the nucleus in the hippocampus after stress loading. Compose approximately 25% of brain grey matter. Induces neuronal growth and differentiation through the modulation of the physical properties of neuronal membranes, signal transduction associated with G proteins, and gene expression.	Araujo et al. [92] Sueyasu et al. [93] Sambra et al. [94]

).

Dietary fatty acids are essential fermentation end-products and crucial energy biomolecules for many tissues. They are important biomarkers that modulate several physiological activities, including immune responses via gut microbiome [22,23,95,96]; (see Table 2). Traditional fermented foods are a good source of healthy fatty acids [97]. The health benefits of dietary fatty acids and fermented foods have been reviewed elsewhere [97,98,99]. Although conflicting results are touching on the health effects of fatty acids, our reports would mostly focus on the positive aspects. Moreover, due to the availability of data, this section will elucidate the health functions and properties of SCFAs. SCFAs are small molecular metabolites that play local and systemic roles in immune shaping, gut, and blood–brain barrier integrity, microglia maturation and function, and neuroinflammation prevention [39]. The major microbial transformers of SCFAs in the human gut belong to the phylum Firmicutes (Faecalibacterium prausnitzii and Clostridium leptum producing butyrate), phylum Actinobacteria (Bifidobacterium species producing acetate and lactate), and phylum Verrucomicrobia (producing propionate and acetate). Furthermore, in reports on specific butyrate synthase-related genes/enzymes, members of Actinobacteria, Bacteroidetes, Fusobacteria, Proteobacteria, Spirochaetes, and Thermotogae potentially transform SCFAs [100]. In general terms, studies show a reciprocal relationship between fatty acids’ metabolism and their health impact. They elicit their influence on several physiological processes such as the structure and function of the epithelial membrane, intracellular signaling pathways, transcription factor activity, gene expression, and the production of bioactive lipid mediators [38,96]. We shall elucidate these functions using the well-studied short-chain fatty acids (SCFAs).

2.2. SCFAs’ Functions and Signaling Patterns

SCFAs are the most studied fatty acids produced from non-digestible saccharides via intestinal bacterial fermentation—intestinal microbes maintain beneficial relationships at the tight junction between the mucosal epithelial cells (the primary physical barrier in the intestines). Interestingly, SCFA levels in liver and blood tissues are substantially lower than in the intestine. However, SCFAs and other fatty acid types are the primary intestinal epithelial cells’ fuel; they promote colonic epithelial cell proliferation, mucosal blood flow, and colonic motility [101]. SCFAs promote epithelial barrier function and stimulate epithelial cells through increased transepithelial electrical resistance (TER). Absorbed SCFAs are metabolized and trigger composite signaling pathways in the intestinal mucosa [101].

Butyrate is transported to intestinal epithelial cells by monocarboxylate transporter 1 (MCT1) and sodium-coupled monocarboxylate transporter 1 (SMCT1) [101]. Butyrate initiates the activation or repression of signaling pathways by binding to GPCRs and/or directly inhibiting HDACs [100]. Its activation reduces monolayer permeability while increasing TER during cell culture in an intestinal epithelial model comprised of either cultivated Caco-2 cell monolayers, T84 cells, rat small intestine cdx2-IEC cells, or small intestine porcine IPEC-J2 cells [100]. Acetate/GPR43 signaling mediates anti-inflammatory effects through NLRP3 inflammasome or cytokine/mediator regulation [100]. Trigger cascades affect immunological functions through cell surface G-protein coupled receptors (GPCRs) such as GPR41, GPR43, and GPR109A. Moreover, fatty acids act as ligands and activate anti-inflammatory signaling cascades [100].

Generally, fatty acids can activate HIF-1, STAT3, and SP1 or repress NF-κB transcription factors, increasing epithelial barrier function, antimicrobial peptides (AMPs) production, cell proliferation, and decreasing inflammation [100]. These effects are elicited by SCFAs’ actions on the caecal epithelial cells and not the caecal wall’s vascular or neurological system. However, SCFAs impact intestinal blood flow and generate smooth colon muscle contraction via the enteric nervous system [100,101]. Additional health functions are listed in Table 2. The importance of dietary fatty acids’ health outcomes was emphasized in a study that linked antibiotic use with reduced butyrate-producing bacteria proliferation [102]. Prolonged use of antibiotics lowers intracellular butyrate/PPAR signaling, raises iNOS and nitrate levels, and encourages the proliferation of Enterobacteriaceae in the intestine.

2.3. Fatty Acid Mediators: Gene Expression and Antimicrobial Activity

The gut microbe–fatty acid interactions support epithelial cell proliferation, regulate gene expression, increase TER, and promote the development of intestinal organoids and antimicrobial peptides (AMPs) [39,100]. Histone post-translational modifications (HPTMs) are key regulators of gene expression. Histone crotonylation connects chromatin to the gut microbiota, possibly through short-chain fatty acids and histone deacetylases [103]. Although organic acids promote colonic epithelial cell proliferation, studies on the transcription factor Foxo3 have revealed different effects of butyrate on intestinal stem/progenitor cells. They inhibit proliferation and delay wound repair [100]. Butyrate’s activation of STAT3 and SP1 transcription factors modulates epithelial barrier function through the induction of genes encoding tight-junction (TJ) components and protein reassembly [100].

Apart from activating toll-like receptors (TLRs) and modulating the NF-kB pathway, fatty acids, such as pentanoate and butyrate, also have anti-cancer activities [104,105]. They improve anti-tumor activity by increasing cytotoxic T lymphocytes (CTLs), related transcription factors (T-bet and Eomes), and chimeric antigen receptor (CAR) T cells via metabolic and epigenetic reprogramming [105]. Dietary SCFA metabolites attach to GPR43 to regulate the expression of AMPs that act as defense effectors. Some examples of AMPs are piscidins, cathelicidins, defensins, hepcidins, and high-density lipoproteins, which are modulated via the mTOR-STAT pathway [106,107]. Moreover, in peripheral tissues such as pancreatic cells, SCFAs increased the expression of CRAMP, which helps prevent the development of diabetes [106]. According to Zhang et al. [106], SCFAs increase oxygen consumption and activate HIF-1 signaling in macrophages by inhibiting HDAC. Furthermore, SCFA-induced HIF-1 can increase antimicrobial effector synthesis and bacterial clearance by macrophages. This novel mechanism could potentially contribute to bacterial clearance by macrophages.

3. Health Benefits of Dietary Fatty Acids

The production and consumption of fermented food is a potent strategy for addressing societal socioeconomic and health issues (including malnutrition, allergies, obesity, and aging) [20]. Fermentation processes regenerate NAD⁺ through redox reactions that result in pyruvate, its derivatives, and diverse other end-products. Pyruvate is a simple α-keto acid and major intermediate formed at the biochemical junction of glycolysis and the tricarboxylic acid cycle. Pyruvate precursors many valuable biomolecules [108,109]. Sugar, amino acids, and fatty acid-containing compounds are oxidized by transferring hydrogen ions from intermediate products to organic molecules such as pyruvate and acetyl CoA—which are final receptors for hydrogen ions [110]. The metabolism of these biomolecules results in flatus and fatty acids—critical modulators of hosts’ immune responses (see Figure 1A–C).

Traditional fermented foods all over the globe are believed to foster health through the functions and characteristics associated with their myriad components. They foster health via the activities of biosynthesized organic acids, modified nutrient molecules, gut microbiota, whole microbial cells or cell components, and activated immune cells [20]. The amount and type of dietary fatty acids affect the composition of membrane phospholipids and gene expression [111]. These biomolecules influence the biological and chemical barriers in the intestine, such as epithelial cells, tight junctions, and mucins, respectively [37], and act as signaling agents with known influences on membrane receptors (both on epithelial cells and immune cells) [48]. This means that dietary fatty acids (such as other food components) are not only nutrient compounds; they are packed with information and regulate genetic expressions. Experts believe that dietary fatty acids compete for common receptor molecules/mechanisms and either shut down the production of disease-causing genes or promote the expression of health-promoting genes [37]. Fatty acids act like hydrophobic hormones, binding to and activating nuclear receptors [111,112]. They regulate gene transcription via changes in the activity or abundance of nuclear receptors such as PPARs, LXR, HNF4α, TLR, SREBP, and RXR (see Figure 2).

Flavor-potentiating nucleotides and amino acids, which increase fermented foods’ attractiveness to consumers, are additional constituents that affect health [20]. Lastly, fermenting microbes in the food and host’s guts. Many ubiquitous and versatile microbial taxa elicit food spoilage or spontaneous fermentation processes by acting like chiral catalysts (high positional specificity and stereospecificity). They employ processes that add, remove, or modify functional groups of suitable macromolecules at specific sites [113]. Concomitant live microbes in fermented foods act as probiotics; they survive the gastric transit and reach the colon, where they exact their actions. Moreover, cellular components of inactivated microbes, such as peptidoglycan, surface proteins, exopolysaccharides, D-phenylacetic acid (by lactic acid bacteria: LAB), and lipoteichoic acids, elicit immune responses in many animal models [20]. Despite their transient nature, fermentation-associated microbes are metabolically active and aid in the synthesis of molecules from ingested food substances that modulate signaling effects via epithelial receptors [20]. Successions during fermentation eliminate most starters as substrates are transformed, harsh by-products are released, energy sources are used up, and the environment becomes unconducive [10]. Therefore, the characteristics and properties of finished products are determined by surviving microbes, including those in low concentrations [10]. However, not all fermented foods contain live microbes at the point of consumption—as some are deactivated [20].

4. Challenges with Traditional Fermented Foods

Scientists agree that microorganisms co-evolved with humans; however, studies are still exploring more profound levels of their influence on human health. For example, diets appreciably impact gut microbiome homeostasis. The gut microbiome is connected to the innate immune system, which virtually connects all-important body organs. Traditional fermented foods contain bioactive molecules that modulate the gut microbiome, systemic immune responses, and disease conditions. Fermentation outcomes can sometimes be mixed in desirability; acetic acid-producing bacteria such as Acetobacter, Gluconacetobacter, and Gluconobacter are valuable in vinegar production and microbial cellulose; however, their presence devalues wines through spoilage [114]. Studies also show that fatty acids bind and influence the expression of genes through the activation of receptors such as fatty acid binding proteins (FABPs) and peroxisome proliferator-activated receptors (PPARs) [36]. Haghikia and co-workers [22] showed that long-chain and short-chain fatty acids (fermentation by-products) had opposite modulating effects on T helper 1 cells. LCFAs upregulated the MAPK pathway via p38, enhanced the differentiation and proliferation, and impaired the intestinal sequestration of T helper 1 cells. In contrast, dietary SCFA suppressed the JNK1 and p38 pathways and expanded intestinal T-regulatory cells. This and many other studies show that fatty acids are energy sources and receptors for gene expression and systemic energy homeostasis regulation [36].

Natural fermentation processes (such as traditional food fermentation, intestinal diet-microbe interactions, and bio-geochemical cycling of agro or organic wastes) utilize diverse or mixed microbial cultures that inspire high productivity and functionality, resulting in the transformation of an extensive range of substrates. Co-evolution supports cross-feeding, co-metabolism, symbiotic growth, and increased microbial survival and diversity [11,115,116,117]. Traditional fermented foods contain microbial consortia, bioactive molecules, and specific anti-nutrient molecules (such as phytic acid) that could reduce the digestibility and bioavailability of proteins and carbohydrates [17]. Mixed cultures contrast axenic processes that utilize adapted or genetically engineered single-strain microbes to produce desired outcomes. For this purpose, axenic cultures are featured more in environmental remedial and commercially/scaled biotechnological processes that seek to achieve suitable substrate transformative results and less contamination [118].

Fermented foods have inherent signature microbes—both functional and non-functional. Traditional or subsistent production uses fermentation broths (or back-slopping) that contain autochthonous microbes to kick-start their processes; this is open to contamination and inconsistent outcomes. Another source of potentially beneficial or spoilage/pathogenic microbes is equipment-based organisms [119,120]—using the same vessel consistently facilitates the inoculation of raw food material from the previous batch. Fermentation processes create hostile eco-conditions that are unconducive to pathogenic microorganisms: appreciable proportions of organic acids (>100 mM), inhibitory growth substances (diacetyl, acetaldehydes, mycosin, and bacteriocins), salt, nitrite, antimicrobials, lowered water activity, and elimination of carbohydrate substrates [10,23,110]. However, in unhygienic conditions, hostile conditions may not be created fast enough to exclude toxin-producing and spore-forming microbes such as Escherichia coli, Listeria monocytogenes, Yersinia enterocolitica, Staphylococcus aureus, Bacillus cereus, Clostridium botulinum, etc. [121]. Industrialists will gather more sales clout if they label their products as having these signature characteristics, including the autochthonous microbes—as undefined and natural starter cultures possess high genetic diversity that might be responsible for product outcome [119,122]. Microbial fingerprints will not just allow consumers to distinguish similar products but also will ensure that consumers get the same thrill and benefits during and after consuming the said food. However, microbes are deactivated in a few fermented foods before consumption [20].

Traditional fermented foods are a significant source of protein, vitamins, minerals, and other vital nutrients [97]. However, the low or outright lack of modern biotechnology applications prevents clinically exploring their gut modulatory health function [10,17]. The most unexplored set of traditional foods is those from African and Asian countries, despite their high nutritional contents, from published data [10]. According to Oguntoyinbo [120] and De Filippis et al. [119], modernization and commercialization would eventually detect how traditional fermented products become mainstream commodities in the global market. Aspects such as safety, hygiene standards, and preservation of products’ characteristics would be of profound focus. According to Tamang et al. [10], Amplicon-based high-throughput sequencing and real-time quantitative PCR have been used to target different strains and species of microbes with high accuracy, elucidate their encoded metabolic pathways, and for quality control. As the demography of urban populations in Asia and Africa continues to grow, middle- and low-income earners will begin to demand standardized and well-packaged yet nutritious traditional-like fermented foods as part of their snacks or main diets.

5. Regulations and Perspectives

To commercialize traditional fermentation process(es), industrialists would have to beat the safety and consistency challenges. Additionally, other setbacks, including ethics and regulatory concerns, challenges with the applicability of research outputs due to the high cost of effective methods, the high cost of high-dimensional data analyses and interpretation, and low reproducibility [122,123], have to be overcome too. Many commercial industries that produce fermented food products apply good hygiene practice (GHP) and hazard analysis and critical control point (HACCP) systems to lessen the advent of public health issues. These systems must be applied to produce safe, uniquely improved products with bioavailable nutrients, an extended shelf life, and excellent sensory properties. These characteristics elicit eubiotic effects on the gut microbiome and high health-promoting functions [122,124]. Successful processes would have to factor in advanced and safe biotechnological processes that would preserve the peculiar characteristics of traditionally fermented foods and still retain the majority of those functional and non-functional microbes responsible for those characteristics [15,119,121,124].

Galimberti and team [122] suggest that applying multi-omics technologies when studying spontaneous microbial consortia, including their interaction in traditional fermented foods, helps preserve and predict unique microbial fingerprints, biotransformation processes that occur over time, and resultant health outcomes in humans. Multi-omics allows for the identification of capable microbes responsible for the production of targeted products. Obafemi and co-workers [17] suggest that researchers will have proper and in-depth profiles of active microbial consortia by utilizing high-throughput sequencing (HTS) techniques when studying African traditional fermented foods. HTS techniques reveal the taxonomy, diversity, functional potential, and gene expression patterns of capable microbes. Once these functional microbial genera are identified, regulations for labels could be formulated [20]. With improvements in several techniques, the cost and error setbacks can be reduced, allowing for near-predictive analysis and functions.

Advanced synthetic biology and controlled fermentation will not stripe the benefits of traditional biodiversity if done properly. It should enable the introduction of additional strains with known and advantageous functionalities [10]. However, designing and growing a selected community of starter cultures is not as simple as theocratized [119,125]. One will need a careful and informed orchestration of possible factors that could overshadow valuable traits. HTS application offers the potential to reconstruct draft and complete genomes directly from metagenomics reads, avoiding previous cultivation and isolation, overcoming the limitations of culture-based techniques, and allowing in situ strain monitoring [119]. Complex interactions that occur within microbial consortia in food environments can be elucidated with combined molecular approaches, increasing our understanding of how to exploit invaluable microbial resources, and ensure process efficiency as well as food quality and safety.

Metagenomics tools have been used to flag beneficial genes and harmful microbial traits, some of which code for flavor, alcohol production, antibiotic resistance, and mycotoxin production [20,126]. The rapidity and prediction accuracy help in forming safety policies, moving away from mere microbes’ searches to eliminating microbes with harmful products (toxins) and traits. For example, mycotoxin-producing Aspergillus and Penicillium have been successfully eradicated from cheese, koji, and other fermented food products [20]. However, as long as no complaints have been reported for certain of these traditionally fermented foods, the general public would continue to tolerate them up to their spoilage limit [14]. Because microbial cultures have transitioned from being part of food production to being viewed as food in itself [14], policies that ensure safe consumption and extended shelf life would be influenced by the type, culture, and origin of the food [127,128]. Therefore, regulations covering them as cultures for food production (ingredients), food additives, and foods would differ from the additional assessment level accorded novel or genetically modified microorganisms [14,127].

6. Conclusions

Although microbial growth and enzyme production in the food microenvironment can either result in spoilage or fermentation, the latter results in desirable attributes and end products. Traditional fermented foods render health to consumers through the actions of inherent probiotics or live microbes and other health-promoting components. Although there are no recommended levels, fermented foods laden with microbes and health-promoting components are good for gut health and the immune system—although only 26% of adults and 20% of children consume such foods. Recently, dietary recommendations suggested that we incorporate diverse sources of food components on our plates. Fermented foods are now seen as a good source of dietary fatty acids.

With the advent of concept foods that target select genes and pathways [129,130], traditional foods can act as templates for creating functional foods with multi-health and organoleptic functions. Fermented foods are popular due to associated health benefits: one-third of food consumed by humans is fermented types [130]. Studies show that although microorganisms are uniquely individual cells, they interact and act better in communal natural settings. Preserving these interactions could sustain the increasing demand for traditionally fermented foods—against those processed with axenic or single synthetic cultures, to initiate rapid processes and limit the emergence of spoilage or pathogenic strains. Bio-engineered consortia or inocula and their fermented by-products would benefit the consuming public more.