Dietary fibers and non-digestible carbohydrates (NDCs), which are difficult for the upper gastrointestinal system to digest and absorb, are the first ingredients in the fermentation of SCFAs. These consist of inulins, oligosaccharides, resistant starches, cellulose, hemicellulose, and pectin. These substances act as substrates for microbial fermentation once they arrive in the colon. In contrast to simple sugars, dietary fibers are not broken down by human enzymes, while being a vital source of energy for the gut flora. In particular, soluble fibers are more fermentable and strongly linked to higher generation of SCFA (4). SCFA profiles vary by fiber; for instance, resistant starch greatly raises butyrate levels, whereas inulin and oligofructose are known to create more butyrate and propionate. The kind and amount of SCFAs that are produced are also influenced by the fibre's physicochemical characteristics, including its solubility, viscosity, and fermentability. Through a variety of processes, including energy harvesting, lipid metabolism, and blood glucose regulation, this selective fermentation influences not only the microbiota's composition but also the host's physiology. Additionally, SCFAs are signalling molecules that affect insulin sensitivity, inflammation, and appetite control by interacting with GPR41 and GPR43 are examples of G-protein coupled receptors. Beyond their function as gastrointestinal tract bulking agents, dietary fibers have physiological relevance. The range of non-digestible carbohydrates (NDCs) includes not only traditional fibers like cellulose and hemicellulose but also more recent, functional carbohydrates like resistant maltodextrins, fructo-oligosaccharides (FOS), and galacto-oligosaccharides (GOS), all of which avoid small intestine digestion and reach the colon mostly undigested. These fibers are converted into SCFAs by microbiological fermentation in the colon, which then influences immunological and metabolic processes throughout the body (5). It's interesting to note that some dietary fiber types have been demonstrated to favourably develop specific microbial taxa that contain the enzyme machinery needed for fiber decomposition, such as lactobacilli and bifidobacteria. This selectivity is the foundation of the prebiotic idea, which holds that certain NDCs used in targeted dietary treatments can maximize the synthesis of SCFA by positively modulating the gut microbiome's composition and activity (6). Fibers influence stomach emptying, glucose absorption, and cholesterol metabolism in addition to acting as substrates for microbial fermentation. SCFAs produced from these fibers have hormone-like actions that impact peripheral organs. Through central pathways involving the hypothalamus, acetate, the most prevalent SCFA, may be used in skeletal muscle, adipose tissue, and other peripheral tissues, where it contributes to lipid synthesis and hunger control. Propionate primarily functions in the liver, where it helps regulate cholesterol production and gluconeogenesis. Butyrate is arguably the most physiologically active SCFA in the gut, controlling cell proliferation, apoptosis, and differentiation and playing a crucial role in preserving colonic epithelial homeostasis, despite having the lowest systemic concentration because of its preferential uptake by colonocytes (7).

Complex microbial populations flourish and perform fermentation in the intestinal lumen's special anaerobic environment. Since the proximal colon has the largest concentration of fermentable substrates, here is where the fermentation process mostly takes place. The lumen produces millimolar amounts of SCFAs, which are then taken up by colonocytes or circulated throughout the body. While acetate and propionate are more prevalent in peripheral blood, colonocytes quickly use butyrate in particular as their main energy source (8). The gut lumen's pH is crucial for controlling the makeup of microorganisms and the effectiveness of fermentation. Because SCFA synthesis reduces pH, harmful bacteria are inhibited and good anaerobes are favoured. Additionally, the ionized forms of SCFAs might affect water absorption and osmotic equilibrium, which helps to maintain stool consistency and avoid constipation. These SCFAs also control the formation of mucin and support the integrity of the mucosal barrier. Crucially, some transporters such sodium-coupled monocarboxylate transporters (SMCTs) and monocarboxylate transporters (MCTs) are involved in the lumen's absorption of SCFAs, helping to control their systemic effects and bioavailability (9). Bacteria, viruses, fungi, and archaea are all part of the gut microbiome, a dynamic and highly diverse microbial community. The phylum Firmicutes (e.g., Faecalibacterium prausnitzii, Roseburia spp.) and Bacteroidetes (e.g., Bacteroides spp.) contain the most common bacteria that produce SCFA. These species have particular enzymatic pathways that use acetyl-CoA synthesis, glycolysis, and reductive carboxylation to convert complex carbs into SCFAs. The amount and kind of SCFAs generated are significantly influenced by the variety and abundance of these microorganisms (10).

The gut microbiome is a dynamic and highly diversified microbial population that includes viruses, fungus, bacteria, and archaea. The two most common phyla of bacteria that produce SCFA are Firmicutes (Faecalibacterium prausnitzii, Roseburia spp.) and Bacteroidetes (Bacteroides spp.). Through the processes of glycolysis, acetyl-CoA production, and reductive carboxylation, these species have particular enzyme pathways that convert complex carbs into SCFAs. Important factors influencing the amount and kind of SCFAs generated are the variety and abundance of these microorganisms (11). A key factor in controlling the makeup of microorganisms and the effectiveness of fermentation is the pH in the gut lumen. By lowering pH, SCFA synthesis promotes good anaerobes and inhibits harmful bacteria. Additionally, osmotic balance and water intake can be influenced by the ionized forms of SCFAs, which helps maintain stool consistency and avoid nausea. Additionally, by controlling the formation of mucin, these SCFAs support the integrity of the mucosal barrier. Importantly, some transporters, including as sodium-coupled monocarboxylate transporters (SMCTs) and monocarboxylate transporters (MCTs), are involved in the lumen's absorption of SCFAs. These transporters assist control the bioavailability and systemic effects of these molecules (12). By fermenting ordinarily indigestible substrates into bioactive chemicals like SCFAs, the gut microbiome functions as a metabolic organ that affects a broad range of host physiological processes. Numerous host and environmental variables, including as nutrition, age, genetics, drugs, and geographic location, affect the diversity and functional ability of this microbial population. Beneficial fermenters including Faecalibacterium prausnitzii, Roseburia intestinalis, and Akkermansia muciniphila, which effectively convert polysaccharides into SCFAs, predominate in a balanced gut microbiota. In dysbiotic conditions such as colon cancer, metabolic syndrome, and inflammatory bowel disease (IBD), these taxa are frequently reduced. In these circumstances, restoring SCFA-producing bacteria using probiotics, prebiotics, or faecal microbiota transplantation is becoming a practical treatment strategy (13). Through SCFAs, the microbiota has significant influence on host immunity in addition to food metabolism. Butyrate, for instance, affects immune cell gene expression via inhibiting histone deacetylases (HDACs). The development of regulatory T cells (Tregs), which are essential for preserving immunological tolerance and averting autoimmunity, is encouraged by this epigenetic modification. Similarly, it has been demonstrated that SCFAs affect the maturation of dendritic cells, the polarization of macrophages, and the generation of cytokines. Acetate has been linked to signalling pathways in the brain-gut axis that control behaviour and hunger through the activation of vagus nerves and the release of hormones including GLP-1 and PYY. Therefore, the SCFAs generated from the microbiota serve as a biological connection between dietary practices and immunological and metabolic responses in the body (14).

SCFAs interact with host tissues through: •

GPCRs: GPR41 (FFAR3), GPR43 (FFAR2), GPR109A

Colonocyte Energy Source: The main energy source for colonic epithelial cells is butyrate. It enhances intestinal barrier function, encourages mucin synthesis, and preserves epithelial integrity.

Immune Modulation: SCFAs regulate immune response by •

Enhancing regulatory T cells (Tregs): The commensal gut microbiota ferments food fibers to produce short-chain fatty acids (SCFAs), such as acetate, propionate, and butyrate. One of the most important of their numerous physiological roles is immunological regulation, especially the promotion of immune tolerance and homeostasis depend on regulatory T cells (Tregs). Through their modulation of Treg differentiation and function, SCFAs aid in the promotion of a balanced immune response. Both signalling pathways and epigenetic processes involving G-protein coupled receptors (GPCRs), such GPR43 and GPR109A, which are expressed on a variety of immune cells, including Tregs, are responsible for this (17, 18).

Metabolic Regulation: Acetate and propionate enter systemic circulation and modulate lipid and glucose metabolism (Table 2).

Gut-Brain Axis Influence: By stimulating vagal afferents, controlling neurotransmitters (serotonin production), altering microglia activity, and reducing inflammation in the brain, SCFAs have an impact on the central nervous system. The gut-brain axis is a two-way communication network that links the central nervous system (CNS), enteric nervous system, and gut microbiota. Using several direct and indirect methods scfa's are becoming key mediators in this conversation (Figure 1).

Passing over the Blood-Brain Barrier (BBB): By inhibiting histone deacetylase (HDAC), SCFAs, especially butyrate, can pass through the BBB and change gene expression in the brain. By encouraging neural plasticity and lowering neuroinflammation, HDAC inhibition has neuroprotective benefits (21). Vagal Nerve Activation: SCFAs improve neuronal signalling and control mood and behaviour by modifying gut-brain connection through vagal afferents. For instance, by vagal stimulation, butyrate can cause enteroendocrine L-cells to release GLP-1 and PYY, which affect 3mood and satiety (16). Immune Modulation and Neuroinflammation By modulating systemic immune responses through GPR41, GPR43, and GPR109A receptors, SCFAs prevent neuroinflammation by lowering levels of pro-inflammatory cytokines such IL-6, TNF-α, and IL-1β (23, 50).

Acetate, propionate, and butyrate are the main short-chain fatty acids (SCFAs) produced by the colon's microbiological fermentation of food fibers. The gut-brain axis (GBA) must be regulated by these significant metabolites. Through a variety of channels, such as immunological signalling, neuroendocrine pathways, epigenetic modification, and direct neuronal communication via the vagus nerve, these metabolites affect the function of the central nervous system (CNS). Among these, butyrate functions as an inhibitor of histone deacetylase (HDAC), which affects brain gene expression and fosters neuroprotective outcomes including increased neurogenesis and synaptic plasticity (13, 24).

Bacterial fermentation of proteins, peptides, and monosaccharides produces SCFAs in the oral environment. The metabolic pathways, especially the Stickland reaction (amino acid fermentation) and glycolytic pathway, are similar to those found in the colon. Lactic acid bacteria like Lactobacillus and Streptococcus create lactate, which is then further broken down by anaerobes into acetate and propionate. In subgingival plaque, butyrate is mostly produced in anaerobic environments when proteolytic bacteria break down peptides from host proteins or tissue degradation. Butyrogenic bacteria thrive in periodontal pockets with low oxygen tension. SCFA's have a beneficial role in a healthy oral microbiota by: Encouraging anti-inflammatory Treg cells by stimulating immunological signalling through G-protein-coupled receptors (GPR41, GPR43). Tight junction protein expression and histone deacetylase (HDAC) suppression to improve epithelial barrier function. Promoting the salivary glands' production of antimicrobial peptides, such as cathelicidins and β-defensins. Altering the makeup of saliva to preserve the microbial balance and mouth ph. By doing these things, you may lessen inflammation, stop germs from growing, and maintain the integrity of your oral tissue (28) (Table 3).