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Review

Therapeutic Potential of Short-Chain Fatty Acids in Gastrointestinal Diseases

by
Meng Tong Zhu
1 and
Jonathan Wei Jie Lee
1,2,3,*
1
Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117599, Singapore
2
Division of Gastroenterology & Hepatology, Department of Medicine, National University Hospital, Singapore 119074, Singapore
3
Institute for Health Innovation and Technology (iHealthtech), National University of Singapore, Singapore 117599, Singapore
*
Author to whom correspondence should be addressed.
Nutraceuticals 2025, 5(3), 19; https://doi.org/10.3390/nutraceuticals5030019
Submission received: 16 June 2025 / Revised: 18 July 2025 / Accepted: 22 July 2025 / Published: 24 July 2025
(This article belongs to the Special Issue Feature Review Papers in Nutraceuticals)
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Abstract

Short-chain fatty acids (SCFAs) are metabolites derived from the fermentation of dietary fibre by gut bacteria. SCFAs function as essential regulators of host-microbiome interactions by participating in numerous physiological and pathological processes within the gastrointestinal (GI) tract. In recent years, the depletion of SCFAs has been increasingly linked to the pathogenesis of GI diseases. In this review, we summarize the current understanding of the therapeutic mechanisms of SCFAs in GI diseases, including inflammatory bowel disease, irritable bowel syndrome, metabolic dysfunction-associated steatotic liver disease, and acute pancreatitis. We next highlight potential therapeutic approaches that increase the endogenous production of SCFAs, including prebiotics, probiotics, and fecal microbiota transplantation. We conclude that, although SCFAs are promising therapeutic agents, further research is necessary due to variability in treatment efficacy, inconsistent clinical outcomes, and a limited understanding of SCFAs’ mechanisms of action.

1. Introduction

Gastrointestinal (GI) diseases are conditions that affect the GI tract and the accessory organs involved in digestion. They disrupt normal digestive function and lead to symptoms such as pain, bloating, diarrhea, and constipation. In 2019, the global prevalence and incidence of GI diseases were 7.32 billion and 2.86 billion, respectively, remaining essentially unchanged between 1990 and 2019 [1]. Gut microbiota-derived metabolites, including short-chain fatty acids (SCFAs), have been shown to play a crucial role in the development of GI diseases. Acetate (C2), propionate (C3), and butyrate (C4) are the most prevalent colonic SCFAs produced from the intestinal microbial fermentation of dietary fibre. They act as signal molecules by activating G-protein-coupled receptors (GPCRs) GPR41, GPR43, and GPR109A, and inhibiting histone deacetylase (HDAC) activity [2,3,4]. The activation of GPCRs, in turn, regulates diverse cellular functions, including inflammatory response, metabolism, and immunity.

2. Therapeutic Roles of SCFAs in GI Diseases

SCFAs exert their therapeutic effects primarily by maintaining intestinal barrier integrity through the promotion of tight junction (TJ) proteins and mucus production, suppressing inflammation by inhibiting pro-inflammatory cytokines and downregulating key inflammatory signalling pathways, modulating the immune system, and enhancing energy production in colonocytes (Figure 1). SCFA levels are significantly reduced in GI diseases due to dysbiosis, resulting in compromised intestinal integrity, increased inflammation, and disrupted microbial balance, ultimately contributing to disease progression [5,6,7].

3. Inflammatory Bowel Disease

Inflammatory bowel disease (IBD), which includes Crohn’s disease (CD) and ulcerative colitis (UC), is a group of chronic inflammatory conditions that affect the GI tract. A growing body of evidence supports the therapeutic effects of SCFAs in IBD. A recent multi-omics study of the intestinal microbiota ecosystem in IBD patients revealed a general decrease in SCFAs, which corroborates the observed depletion of butyrate-producing species Faecalibacterium prausnitzii and Roseburia hominis [5]. UC patients with a lower abundance of SCFA-producing species experienced more severe colonic inflammation and were less responsive to treatments [8]. In vitro studies have shown that administering high acetate concentrations to patient-derived epithelial monolayers induced anti-inflammatory effects and enhanced epithelial resistance [9]. Administration of sodium butyrate or propionate in mouse models significantly improved inflammation and intestinal barrier integrity [4,10].
There are several pathways by which SCFAs alleviate IBD. Firstly, they contribute to maintaining intestinal barrier function. Butyrate upregulates TJ proteins claudin-1, zonula occludens-1 (ZO-1), and occludin, which form a barrier between epithelia cells to control molecular movement and maintain cellular polarity, and mitigates lipopolysaccharide (LPS)-induced barrier impairment [11,12]. Propionate stimulates the differentiation of goblet cells and enhances the expression of genes related to mucus production [13]. Secondly, SCFAs exert potent anti-inflammatory properties by promoting the production of anti-inflammatory cytokines, suppressing pro-inflammatory cytokines, and inhibiting signalling pathways that trigger inflammatory responses. Butyrate mitigated colitis in mice by attenuating the expression of pro-inflammatory cytokines, including interleukin-6 (IL-6), IL-17, tumour necrosis factor-alpha (TNF-α), and IL-1β [14]. Administration of sodium butyrate improved inflammation in mice by activating GPR109A while suppressing protein kinase B and nuclear factor kappa B (NF-κB) p65 signalling pathways [4]. Cyclic GMP-AMP synthase (cGAS) and stimulator of interferon genes (STING) form the cGAS-STING pathway that activates NOD-like receptor protein 3 (NLRP3) inflammasome. Butyrate reduced intestinal inflammation in in vitro and in vivo CD models by inhibiting cGAS-STING-NLRP3 axis-driven pyroptosis in intestinal epithelial cells [15]. However, the anti-inflammatory actions of SCFAs are not universal and may be dependent on the immunological and metabolic context. For instance, Vancamelbeke et al. found that butyrate was ineffective and could exacerbate inflammation-induced barrier dysfunction in UC patient-derived cell lines, possibly due to butyrate hypersensitivity [16]. Moreover, butyrate and propionate activated NLRP3 inflammasome in human macrophages under inflammatory conditions by inhibiting the transcription of FLICE-like inhibitory protein and IL-10 through HDAC inhibition [17]. Nevertheless, these findings highlight the context-dependent roles of SCFAs in modulating disease progression. Thirdly, SCFAs are involved in modulating immune cells. Butyrate alleviated colitis in mice by inhibiting pro-inflammatory T helper 17 (Th17) cells via the activation of Sirtuin 1 and mammalian target of rapamycin [14]. Additionally, butyrate promoted M2 macrophage polarization, which attenuated intestinal inflammation in in vitro and in vivo colitis models [18]. The expression of amphiregulin in dendritic cells, a crucial regulator of cell proliferation and repair, relies on butyrate and its interactions with GPR43 and B lymphocyte-induced maturation protein 1 [19]. Butyrate suppressed the capacity of neutrophils to produce pro-inflammatory mediators and form neutrophil extracellular traps in mice [3]. Lastly, SCFAs, particularly butyrate, regulate intestinal metabolism by enhancing energy production. Adding butyrate to germ-free colonocytes restored oxidative phosphorylation and suppressed autophagy [20]. Butyrate metabolism enhanced mitochondrial respiration in normal human colon mucosal epithelial cells, supporting transporter-mediated butyrate utilization and thereby maintaining barrier integrity [21]. These synergistic actions collectively alleviate diarrhea, rectal bleeding, and abdominal pain symptoms.
Given their critical role in intestinal homeostasis and disease modulation, current research primarily focuses on prebiotics, probiotics, and fecal microbiota transplantation (FMT), which utilize the body’s natural capacity to enhance SCFA production. Oral administration of sodium butyrate as a postbiotic therapy is not preferred due to its rancid odour and limited efficacy, owing to rapid proximal small bowel absorption that results in low colonic bioavailability [22].
Prebiotics are non-digestible food compounds that are selectively utilized by host microorganisms to confer health benefits [23]. They act as substrates for the production of SCFAs through microbial fermentation. Common types of prebiotics include fructooligosaccharides (FOS), galactooligosaccharides (GOS), and polysaccharides. Some studies propose that SCFAs mediate the therapeutic effects of prebiotics, while others find no significant impact. For instance, Astragalus polysaccharides increased the abundance of SCFA-producing bacteria in UC mice, thereby suppressing NF-κB activation and improving the balance between Th17 and regulatory T (Treg) cells [24]. In contrast, a randomized controlled trial (RCT) involving patients with mild to moderate UC found that the efficacy of 1-ketose was not associated with significant changes in SCFA levels [25].
Probiotics are live microorganisms that confer health benefits to the host when administered in adequate amounts [23]. Preclinical data support probiotics as a promising therapy for IBD in dextran sodium sulphate (DSS)-induced colitis mouse model through multiple SCFA-related mechanisms that act in concert. Commonly studied single-strain probiotics include various species of Bifidobacterium and Lactobacillus. Firstly, prebiotics play a crucial role in maintaining intestinal barrier function. For instance, administration of Lactobacillus plantarum (L. plantarum) HNU082 in DSS mice protected the intestinal barrier by enhancing the production of SCFAs, ZO-1, ZO-2, occludin, goblet cells, and mucin-2 [26]. Escherichia coli Nissle 1917 (EcN) with genes encoding Elafin improved butyrate and valerate production and restored ZO-1’s activity in mice [27]. Acetic acid-producing Bifidobacterium bifidum (B. bifidum) H3-R2 and propionic acid-producing Propionibacterium freudenreichii B1 enhanced the production of ZO-1, occludin, and claudin-1 in mice through the rho-associated coiled-coil containing protein kinase 1 and Wnt/β-catenin signalling pathways, with the latter exerting more substantial protective effects [28].
Secondly, probiotics play a role in immune modulation. Oral administration of B. breve strains H4-2 and H9-3 in mice produced exopolysaccharides, which mitigated inflammation by promoting SCFA production and inhibiting the NF-κB signalling pathway [29]. Upregulation of SCFAs by B. breve Bif11, B. longum Bif10, and B. longum Bif16 helped to modulate immune responses in mice by limiting the translocation of LPS into the bloodstream, with B. longum Bif10 and B. breve Bif11 exerting stronger protective effects [30]. L. plantarum L15 led to a marked reduction in the translocation of NF-κB p65 to the nucleus through increasing colonic acetate and butyrate levels in mice [31]. Administration of low-dose L. rhamnosus CY12 in mice produced acetic acid, which inhibited the translocation of NF-κB p65 and the signalling pathway comprising toll-like receptor 4, myeloid differentiation primary response 88, and NF-κB [32]. Acetate-producing Bacillus paralicheniformis HMPM220325 suppressed the NLRP3 inflammasome signalling pathway and relieved UC in mice [33].
Lastly, probiotics help regulate the microbiota composition by promoting the growth of beneficial bacteria while suppressing the growth of harmful ones. L. plantarum ZJ316 enriched butyrate-producing genera in mice, including Faecalibacterium, Agathobacter, and Roseburia [34]. L. plantarum DMDL 9010 elevated the relative abundance of Bacteroidetes and Firmicutes and mitigated symptoms of depression-like behaviour in mice [35]. Similarly, L. rhamnosus strains SHA113 and KBL2290 alleviated colitis in mice by increasing the abundance of SCFA-producing genera [36,37]. EcN-Sj16 encoding a schistosome immunoregulatory protein (Sj16) increased butyrate levels through a selective enrichment of Ruminococcaceae, leading to elevated retinoic acid production, which relieved colitis in mice by promoting Treg cell activity and suppressing Th17 [38].
Most single-strain probiotics are still in the early stages of preclinical testing, with few having progressed to clinical trials. Three RCTs demonstrated that EcN’s effect on maintaining the remission of UC was comparable to that of mesalazine [39,40,41]. However, the clinical efficacy of EcN may not be associated with the production of SCFAs [42]. Nevertheless, it is increasingly being explored as a next-generation probiotic that could be engineered to enhance SCFA production. For example, EcNL4, a genetically engineered EcN strain to produce ketone body (R)-3-hydroxybutyrate, increased SCFA levels by 3.1 times in mice compared to the wild-type [43]. Moreover, many studies have not investigated changes in SCFA levels. For instance, B. longum 536 (BB536) and L. rhamnosus GG (LGG) have demonstrated clinical efficacy in inducing and maintaining remission in UC patients, respectively [44,45]. Despite previous indications of their ability to produce SCFAs, limited preclinical and clinical evidence measures changes in SCFA levels and correlates them with disease improvement [46,47]. Therefore, additional evidence is required to conclude whether SCFAs directly contribute to the prophylaxis of IBD.
Multi-strain probiotics exhibit synergistic effects that are superior to those of single-strain probiotics and are more commonly explored in clinical studies. VSL#3, a diverse formulation comprising eight bacterial strains, is one of the most effective probiotics. It exhibited anti-inflammatory effects in Muc2 mucin-deficient mice by stimulating acetate production, which facilitated the suppression of chemokines and reactive oxygen species while upregulating growth factors [48]. Patients with mild to moderate UC achieved better remission with VSL#3 and low-dose balsalazide than with balsalazide alone or mesalazine [49]. Three double-blind RCTs demonstrated that the daily administration of 3.6 × 1012 CFU of VSL#3 was safe and effective in inducing remission in adult patients with mild to moderate UC [50,51,52]. A body weight-dependent dose of VSL#3 was reported to be safe and maintained remission in children with UC [53]. Administration of VLS#3 in CD patients resulted in reduced mucosal inflammation and a lower post-surgery endoscopic recurrence rate [54].
Bifidobacteria-fermented milk (BFM) contains Yakult strains of B. breve, B. bifidum, and L. acidophilus. It significantly increased SCFA levels and butyrate utilization in the colonic mucosa of UC patients in an RCT [55]. Two RCTs demonstrated that administering BFM at 100 mL/day was superior to standard treatment and effective in maintaining remission of UC [55,56]. An RCT of B. breve strain Yakult, combined with the prebiotic GOS, markedly improved the clinical status of patients with mild to moderate UC [57]. A double-blind RCT on patients with quiescent UC did not corroborate the conclusion and found BFM ineffective in reducing relapse time and incidence compared to placebo [58]. Mixed results could be attributed to the difference in disease states and dosage frequency.
SymproveTM (Symprove Ltd., Farnham, UK), a four-strain probiotic, exhibited anti-inflammatory and wound-healing properties in in vitro UC and co-culture models by modulating the microbiota composition and promoting lactate and butyrate synthesis [59]. A single-centre RCT of SymproveTM showed no adverse effects or significant differences in IBD-related quality of life (QoL) scores between the treatment and placebo groups [60]. However, treatment significantly lowered fecal calprotectin levels and reduced inflammation in UC patients, while no statistical differences were observed in CD patients. An RCT of Bifidobacterium triple viable combined with mesalazine enhanced the therapeutic efficacy for UC by achieving a response rate of 91.11% [61]. Treatment enriched SCFA-producing genera, including Bifidobacteria, but direct changes in SCFA levels were not measured.
Other multi-strain probiotics have also demonstrated the capacity to stimulate SCFA production, which conferred protective effects in preclinical studies. GUT-108, an 11-strain probiotic, reversed colitis in mouse models [62]. Mechanisms include the upregulation of acetate, butyrate, and propionate, which promote mucosal healing and immunomodulation. A combination of seven SCFA-producing strains, 7-mix, promoted M2 macrophage polarization via inactivation of a signalling pathway involving Janus kinase (JAK), signal transducer and activator of transcription (STAT), and forkhead box O3 (FOXO3) [63]. This subsequently suppressed the inflammatory response and improved mucosal healing in in vitro and in vivo models. A four-strain probiotic’s ability to enhance CD-like ileitis in SAMP mice was associated with a significant increase in SCFAs and their capacity to act as GPCRs to maintain gut homeostasis [64].
FMT involves the transfer of microbial community, including SCFA-producing microbes, from a healthy donor to a recipient to restore the microbial imbalance. It has been effective in helping UC patients achieve remission by enriching SCFA-producing strains and SCFA biosynthesis [65]. FMT combined with probiotics containing Clostridium butyricum enriched fecal butyric acid content, and significantly prolonged remission in UC patients [66]. Lima et al. identified a core set of human donor-derived transferable strains where Odoribacter splanchnicus played a key role in alleviating colonic inflammation in mice, with its protective effects mediated by lymphocytes, IL-10, and SCFAs [67].
SCFAs demonstrated their potential in treating IBD by maintaining intestinal barrier integrity, suppressing inflammation, modulating the immune system, and supporting colonocyte function (Table 1). Oral supplementation of SCFAs is ineffective due to limited colonic bioavailability, whereas prebiotics, probiotics, and FMT enhance endogenous SCFA production, leading to sustained and localized effects. The probiotic VSL#3 has shown the most consistent clinical evidence for maintaining remission in UC patients. The clinical efficacy of SCFA therapies is more significant in UC patients than in CD patients, due to their distinct pathophysiological characteristics. Inflammation in UC is typically restricted to the colon and therefore responds more effectively to treatments such as probiotics. UC patients who show the highest response rates consist of those with mild to moderate disease activity, relapsing UC, and those experiencing dysbiosis with low baseline SCFA production. SCFA therapies are less effective for CD due to its transmural inflammation, which makes immune-targeted treatments, such as aminosalicylates, corticosteroids, and immunomodulators, the primary option.

4. Irritable Bowel Syndrome

Irritable Bowel Syndrome (IBS) is a chronic GI disorder that affects the colon. It is classified into four subtypes based on bowel habit abnormalities: diarrhea-predominant IBS (IBS-D), constipation-predominant IBS (IBS-C), IBS with mixed bowel habits (IBS-M), and unclassified IBS (IBS-U). Studies reported that IBS patients have differentially abundant SCFA-producing bacteria and altered levels of SCFAs. The reduction in butyrate-producing bacteria is a hallmark of IBS-M and IBS-D [6]. In contrast, IBS patients exhibited a significantly higher abundance of Veillonella and Lactobacillus, along with acetate and propionate, which were positively correlated with the severity of their GI symptoms [68]. Fecal propionate levels were also documented as a potential biomarker for diagnosing the IBS-D subtype [69].
There are several mechanisms by which SCFAs, particularly butyrate, alleviate IBS. One key factor in the pathophysiology of IBS is visceral hypersensitivity, which refers to the abnormally heightened sensitivity of the internal organs that leads to discomfort [119]. Butyrate attenuated visceral hypersensitivity in mice by lowering colonic expression of IL-1 receptor-associated kinase 1 [70]. Butyrate also alleviated visceral allodynia and colonic hyperpermeability in rats, likely through adenosine monophosphate-activated protein kinase (AMPK) and peroxisome proliferator-activated receptor γ, involving nitric oxide, opioid, and central dopamine D2 pathways [71]. Additionally, butyrate is involved in gut–brain axis communication by acting through the central nervous system to enhance intestinal integrity and visceral nociception via cannabinoid signalling in rats [72]. Due to the complex nature of IBS, SCFA therapies encompass a range of interventions designed to enhance the endogenous production of SCFA through diet, prebiotics, probiotics, and FMT rather than direct supplementation.
A diet low in fermentable oligosaccharides, disaccharides, monosaccharides, and polyols (FODMAP) normalizes abnormal fecal acetate and propionate levels and is the most effective treatment for IBS-D [69]. A prospective RCT involving 101 IBS-D patients found that both a short-term strict and a long-term modified low FODMAP diet (LFD) significantly improved QoL, alleviated symptoms such as abdominal pain frequency and bloating, and significantly decreased IBS medication use compared to traditional dietary advice [73]. However, restricted fibre intake may negatively impact gut health by altering the gut microbiota composition and limiting the production of SCFAs. Three RCTs showed a significant reduction in Bifidobacteria following an LFD [74]. Fibre-fix, a prebiotic supplement comprising different fibres, increased colonic fermentation and production of SCFAs. In a double-blind RCT, consumption of Fibre-fix alongside an LFD promoted butyrate production, which increased neurotransmitter synthesis and metabolism [75]. This led to improved mental health without inducing IBS symptoms. In an RCT, an LFD combined with prebiotic β-GOS relieved IBS symptoms but could not prevent the decline in fecal Bifidobacteria and butyrate, reaffirming the adverse effects of long-term LFD use [76]. Prebiotic partially hydrolyzed guar gum (PHGG) increased the relative abundance of Bifidobacteria and Faecalibacteria and induced the production of acetic and butyric acids in vitro [77]. Administration of PHGG at 6 g/day significantly relieved bloating in IBS patients, but was ineffective against abdominal pain, stool frequency, or QoL [78]. Intake of inulin at 10 g/day, together with choline and silymarin, improved abdominal pain and bloating in IBS-C patients [79]. Stool frequency and consistency were also improved, though the changes were not statistically significant. However, high doses of prebiotics may worsen symptoms due to excessive colonic gas production. For example, 20 g/day of FOS did not outperform the control in providing symptom relief. It led to a transient worsening of abdominal flatulence at the start of the treatment [120].
A probiotic cocktail, Bifico, improved visceral hypersensitivity in IBS mice, with Bifidobacteria playing a key role by increasing propionate, butyrate, and valerate production while reducing IL-6 and TNF-α [80]. A crossover RCT investigated the effect of a combination of BB536 and L. rhamnosus HN001 with vitamin B6 (LBB) in IBS-C and IBS-D patients [81]. LBB treatment significantly reduced abdominal pain, bloating, and disease severity. These effects may be attributed to the restoration of the gut microbiota and a significant increase in propionate, butyrate, and pentanoate levels, which improved colonic permeability. Stool consistency was significantly normalized in IBS-D patients, whereas only slight improvements were observed in IBS-C patients. A pilot RCT on L. plantarum CCFM8610 demonstrated a significant reduction in bloating and restoration of dysbiosis in IBS-D patients, likely through increasing butyrate-producing bacteria [82].
Numerous RCTs have investigated FMT as a therapeutic intervention for IBS, demonstrating varying degrees of efficacy. El-Salhy et al. compared the effectiveness of gastroscopic delivery of 30 g or 60 g FMT to placebo in a double-blind RCT involving 164 patients [83]. Treatment improved abdominal symptoms, fatigue, and QoL in IBS patients, with the response to treatment positively correlated with the dosage received. A continuation of the study found that the significant increase in fecal butyric acid levels in both treatment groups was negatively correlated to IBS symptoms, suggesting a potential involvement of SCFAs in the pathophysiology of IBS [84]. A 3-year follow-up study of 125 patients reported high response rates and long-lasting effects with few self-limiting adverse events [85]. Nasojejunal delivery of FMT in patients with refractory IBS led to a transient reduction in abdominal bloating. Although the effects diminished over a year, a second FMT was able to restore symptom relief in patients who had previously responded [86]. An RCT involving a single FMT via colonoscopy following bowel cleansing could relieve symptoms, but did not outperform autologous FMT [87]. Another RCT of single colonoscopic delivery induced a lasting change in the microbiota of IBS patients, but only provided temporary symptom relief [88]. Patients who received FMT via oral capsules also experienced increased fecal microbial diversity, but this did not translate into clinical improvement [89]. In contrast, the placebo group showed greater symptom alleviation than the treatment group. Similarly, bacterial engraftment in IBS-D patients following oral FMT did not result in superior symptom relief compared to placebo [90]. While the studies by El-Salhy et al. showed promising results, the overall results were inconsistent. The route of FMT delivery also affects its relative efficacy. A meta-analysis of eight RCTs, including the study by El-Salhy et al., found endoscopic delivery effective but not oral capsules [91].
Butyrate stands out as a potential therapeutic option for IBS as it reduces visceral hypersensitivity while enhancing intestinal barrier integrity. In contrast, propionate may serve as a biomarker for IBS-D. An LFD provided effective control of IBS-D symptoms, yet long-term strict compliance may reduce the diversity of the gut microbiota. Prebiotics like PHGG and inulin provided IBS-C patients with better relief from bloating symptoms, but high doses of prebiotics can render them ineffective and may exacerbate symptoms. Probiotics showed effectiveness mainly in IBS-D patients, whereas FMT yielded inconsistent results, depending on factors such as dosage, frequency, and route of administration. Many studies did not distinguish between the IBS subtypes as they are not always easily differentiated. This may lead to a heterogeneous patient population with varied responses, making it difficult to determine whether a treatment is effective for one subtype over another due to potential dilution of the average effects.

5. Metabolic Dysfunction-Associated Steatotic Liver Disease

Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as non-alcoholic fatty liver disease (NAFLD), is characterized by abnormal hepatic lipid accumulation [121]. It encompasses a spectrum of diseases from simple steatosis to metabolic-associated steatohepatitis and cirrhosis. Although the terminology has changed, previous studies referenced in this review used NAFLD as the definition and diagnostic criteria. Recent multi-omics analyses have shown that patients with NAFLD exhibit distinct changes in gut microbiota and fecal SCFAs compared to healthy controls (HC), including a significant reduction in fecal acetic and butyric acids [7]. Moreover, SCFA levels could be used as a diagnostic tool to predict disease severity. Butyric acid could differentiate mild NAFLD from HC, while acetic acid could distinguish moderate NAFLD and severe NAFLD from HC.
SCFAs play a crucial role in managing MASLD primarily through reducing hepatic steatosis, enhancing insulin sensitivity, and inhibiting inflammation. Sodium butyrate inhibited steatosis in mice mainly via activating a key metabolic pathway involving liver kinase B1, AMPK, and insulin-induced gene [92]. Similarly, sodium acetate reduced steatosis in mice by activating AMPK [93]. Acetate is associated with reduced adipocyte lipolysis in healthy volunteers, which lowers the flux of free fatty acids to the liver, while propionate suppressed lipogenesis in vitro [94,95]. Sodium butyrate attenuated type 2 diabetes-induced NAFLD in mice by modulating intestinal tight junctions and restoring intestinal Takeda G-protein-coupled expression, increasing serum glucagon-like peptide-1 levels and insulin sensitivity [96]. Administration of sodium acetate, propionate, and butyrate significantly lowered serum levels of alanine aminotransferase (ALT) and aspartate transaminase (AST) in mice, suggesting an attenuation of hepatic injury and inflammation [93]. Sodium acetate demonstrated superior anti-inflammatory effects, which were primarily mediated by the inhibition of macrophage pro-inflammatory activation. In addition, SCFAs have also shown mild antifibrotic effects in preclinical models; however, their clinical efficacy in attenuating liver fibrosis remains limited. Butyrate protected mice from diet-induced NAFLD and fibrosis by attenuating collagen synthesis in hepatic stellate cells, whereas acetate and propionate did not exert similar effects [97]. Commonly studied SCFA therapies of MASLD/NAFLD include prebiotics, probiotics, and FMT.
Inulin is one of the most commonly explored prebiotics. Butyrate produced from prebiotic fermentation of inulin mediated the expression of Paneth cell α-defensins, potentially through histone deacetylation and STAT3 activation, leading to improved diet-induced barrier dysfunction in mice [98]. Acetate, another fermentation product of inulin, modulated hepatic lipid metabolism and insulin sensitivity through free fatty acid receptor 2 in hepatocytes, thereby attenuating NAFLD progression in mice [99]. Other prebiotics include FOS, which improved steatohepatitis, visceral fat accumulation, and chronic inflammation by increasing fecal and serum SCFA levels [100]. Sinapine, a prebiotic polyphenol derived from rapeseed, led to an enrichment of probiotic bacteria and SCFA-mediated expression of GPR43, which suppressed inflammation in mice [101]. Resistant starch from green bananas improved SCFA production and obesity-related steatosis in mice [102].
B. pseudolongum significantly attenuated NAFLD-hepatocellular carcinoma in mice by producing acetate, which binds to GPR43 on hepatocytes, inhibiting the IL-6/JAK1/STAT3 signalling pathway and suppressing tumour formation [103]. LGG combined with oat beta-glucan improved NAFLD by increasing liver acetate content, which reduced de novo lipogenesis in mice [104]. Astragalus polysaccharides-enriched Desulfovibrio vulgaris alleviated hepatic steatosis in mice, potentially through acetic acid production [105]. Acetic acid reduced high-fat diet (HFD)-induced weight gain and suppressed the expression of fatty acid synthase, an enzyme that can act as the rate-limiting step in hepatic fatty acid synthesis. A meta-analysis of 35 RCTs involving 2212 NAFLD patients revealed that a combination of Lactobacillus, Bifidobacterium, and Streptococcus may be the most effective in improving liver enzymes (ALT, AST, and gamma glutamyl transpeptidase), lipid profiles (low-density lipoprotein and total cholesterol), and inflammation factors (TNF-α) [106]. However, most of the studies did not assess changes in SCFA levels. One study that tested changes in fecal SCFA concentration following the administration of a synbiotic containing FOS and B. animalis subsp. lactis BB-12 found no association between changes in SCFA levels and liver fat percentage [107]. While the synbiotic was effective in promoting the growth of Bifidobacterium and Faecalibacterium, it did not lead to improvements in liver fat content or fibrosis markers. These findings highlight the need for further studies to evaluate the relationship between SCFA modulation by probiotics and therapeutic outcomes in MASLD/NAFLD.
FMT attenuated estrogen deficiency-induced NAFLD in mice by restoring butyrate concentration, thereby maintaining gut barrier integrity and preventing the translocation of LPS [108]. FMT of a nine-strain bacterial consortium comprising butyrate and propionate producers prevented the progression of NAFLD in rats [109]. The association between the increase in cecal butyrate and propionate levels and disease improvement is to be determined.
On the contrary, some studies indicated deleterious effects of SCFAs. Fecal acetate and propionate concentrations were elevated in NAFLD patients, along with a higher abundance of SCFA-producing genera, which were correlated with immunological markers of disease progression [110]. Likewise, Ruminococcaceae and Veillonellaceae were identified as key microbial contributors associated with fibrosis severity in non-obese NAFLD patients [111]. Moreover, fecal propionate levels were elevated in those with significant fibrosis. HFD led to gut dysbiosis in mice, characterized by an increased serum acetate level, which was normalized by Bacillus species through the reduction in acetate and GPR43 [112]. Nevertheless, these findings suggest that SCFAs play a role in MASLD/NAFLD regulation and could serve as potential diagnostic markers.
Overall, SCFAs alleviate MASLD/NAFLD by attenuating hepatic steatosis, increasing glucose sensitivity, and inhibiting inflammation. Current SCFA therapies, including prebiotics, probiotics, and FMT, have shown therapeutic promise in MASLD/NAFLD management, though their clinical application requires further validation. The greatest therapeutic benefits could be achieved in patients with early-stage disease, characterized by simple steatosis without fibrosis. Although SCFAs exhibit mild antifibrotic properties, their principal value lies in reducing fibrogenesis rather than reversing established scarring in advanced fibrosis or cirrhosis stages.

6. Acute Pancreatitis

Acute pancreatitis (AP), or the inflammation of the pancreas, is characterized by an increase in the production of serum pancreatic enzymes that promote the necrosis of acinar cells. AP exacerbation is strongly associated with increased barrier permeability, SFCA depletion, and alteration of the gut microbiota [122]. Administration of butyrate in animal models could attenuate the disease by reducing systemic inflammation and promoting intestinal barrier integrity [113,114]. Possible mechanisms include upregulating TJ proteins and FOXP3, suppressing pro-inflammatory mediators, and inhibiting the NLRP3 inflammasome. Administration of butyrate in mice notably enhanced intestinal barrier function compared to ineffective antibiotic treatment [115,116]. Acetate production via Parabacteroides administration could also mitigate AP in mice by reducing neutrophil infiltration [117]. Not all findings, however, support the therapeutic role of SCFAs in AP treatment. Ammer-Herrmenau et al. found that all sixteen differentially abundant microbe species over-represented in severe AP patients compared to those with non-severe AP were common producers of SCFAs [118]. Despite that, the finding highlights the role of SCFAs in AP severity and their significance as therapeutic targets in disease management.

7. Conclusions and Future Perspectives

Collectively, there is increasing evidence on the association between gut microbiota and GI diseases. The local modulatory effects of SCFAs within the gut are demonstrated in IBD and IBS. At the same time, MASLD extends its influence to the gut–liver axis, and AP reveals a broader systemic impact that links gut dysbiosis and SCFA depletion to pancreatic inflammation. These results underscore the pivotal roles of SCFAs in GI diseases and establish them as viable targets for therapy. However, there is a need for additional research to fill existing knowledge gaps before these treatments can achieve full effectiveness. Treatment efficacy may differ among patients due to individual variability in gut microbiota, highlighting the importance of precision therapy. For instance, microbiome profiling enables clinicians to identify individual-specific microbiota, guiding the selection of appropriate probiotics. Moreover, current approaches lack standardized protocols and clinical trials to assess specific interventions among diverse populations over extended periods. Additionally, the mechanisms of action of SCFAs are not well understood. Many studies have not measured SCFA changes or associated them with improvements in disease. As SCFAs are often used as adjunct therapies, further research is needed to investigate their interactions with conventional treatments to ensure safety and efficacy.

Author Contributions

Writing—original draft preparation, M.T.Z.; writing—review and editing, J.W.J.L. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Data Availability Statement

No new data were created or analyzed in this study.

Conflicts of Interest

The authors declare no conflicts of interest.

References

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Figure 1. Main therapeutic mechanisms of SCFAs in GI Diseases. SCFAs are produced from the intestinal microbial fermentation of dietary fibre. They mainly act through maintaining intestinal barrier integrity, reducing inflammation, modulating immune responses, and providing energy for colonocytes. ATP, adenosine triphosphate; DC, dendritic cell; GPR, G protein-coupled receptor; HDAC, histone deacetylase; IL, interleukin; NF-κB, nuclear factor kappa B; NLRP3, NOD-like receptor protein 3; Th17, T helper 17; TJ, tight junction; TNF-α, tumour necrosis factor-alpha; ZO-1, zonula occludens-1. This figure was created with BioRender (https://biorender.com/, accessed on 11 July 2025).
Figure 1. Main therapeutic mechanisms of SCFAs in GI Diseases. SCFAs are produced from the intestinal microbial fermentation of dietary fibre. They mainly act through maintaining intestinal barrier integrity, reducing inflammation, modulating immune responses, and providing energy for colonocytes. ATP, adenosine triphosphate; DC, dendritic cell; GPR, G protein-coupled receptor; HDAC, histone deacetylase; IL, interleukin; NF-κB, nuclear factor kappa B; NLRP3, NOD-like receptor protein 3; Th17, T helper 17; TJ, tight junction; TNF-α, tumour necrosis factor-alpha; ZO-1, zonula occludens-1. This figure was created with BioRender (https://biorender.com/, accessed on 11 July 2025).
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Table 1. A comparative summary of SCFA therapeutics in GI diseases.
Table 1. A comparative summary of SCFA therapeutics in GI diseases.
ConditionMain SCFA(s) InvolvedProposed MechanismsMethods to Improve SCFA ProductionLimitationsOverall Strength of Evidence *Key References
IBD (UC&CD)Butyrate, acetate, propionateEnhance barrier function: upregulate TJ proteins and promote mucus production
Suppress inflammation: inhibit pro-inflammatory cytokines, NF-κB, and NLRP3 inflammasome signalling pathways
Immune modulation: inhibit pro-inflammatory Th17, activate M2 macrophage polarization
Metabolic support of colonocyte function		Prebiotics
Probiotics: Bifidobacterium and Lactobacillus strains, and VSL#3
FMT: Enriches SCFA producers		Variable efficacy; butyrate hypersensitivity in some UC patients; CD’s transmural nature limits the effectiveness of SCFA therapiesUC: Strong
CD: Limited		[3,4,11,12,13,14,15,16,17,18,19,20,21,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67]
IBSButyrateAttenuate visceral hypersensitivity
Improve intestinal barrier integrity		Diet: LFD for IBS-D
Prebiotics: PHGG and inulin for IBS-C
Probiotics: Bifidobacterium and Lactobacillus strains
FMT: Endoscopic delivery is most effective		Acetate and propionate are positively correlated with the severity of GI symptoms; long-term LFD may alter the gut microbiota composition; inconsistent FMT results; subtype-specific responsesModerate[68,69,70,71,72,73,74,75,76,77,78,79,80,81,82,83,84,85,86,87,88,89,90,91]
MASLDButyrate, acetateAttenuate hepatic steatosis
Increase insulin sensitivity
Inhibit inflammation		Prebiotics: Inulin and FOS
Probiotics: Lactobacillus, Bifidobacterium, and Streptococcus strains
FMT		Less effective for reversing liver fibrosis; acetate and propionate are positively correlated with disease progressionModerate[92,93,94,95,96,97,98,99,100,101,102,103,104,105,106,107,108,109,110,111,112]
APButyrate, acetateAttenuate systemic inflammation
Restore barrier integrity
Modulate neutrophil infiltration		ProbioticsLimited human studies; microbial overproduction in severe AP may worsen outcomesLimited[113,114,115,116,117,118]
AP, acute pancreatitis; CD, Crohn’s disease; FMT, fecal microbiota transplantation; FOS, fructooligosaccharides; GI, gastrointestinal; IBD, inflammatory bowel disease; IBS, irritable bowel syndrome; IBS-C, constipation-predominant IBS; IBS-D, diarrhea-predominant IBS; LFD, low FODMAP diet; MASLD, metabolic dysfunction-associated steatotic liver disease; NF-κB, nuclear factor kappa B; NLRP3, NOD-like receptor protein 3; PHGG, partially hydrolyzed guar gum; SCFAs, short-chain fatty acids; Th17, T helper 17; TJ, tight junction; UC, ulcerative colitis. * Strong: supported by systematic reviews, meta-analyses, or large RCTs with consistent findings. Moderate: supported by small RCTs, well-conducted cohort studies, or strong observational/preclinical studies. Limited: supported by preclinical studies or small observational studies with inconsistent findings.
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Zhu, M.T.; Lee, J.W.J. Therapeutic Potential of Short-Chain Fatty Acids in Gastrointestinal Diseases. Nutraceuticals 2025, 5, 19. https://doi.org/10.3390/nutraceuticals5030019

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Zhu MT, Lee JWJ. Therapeutic Potential of Short-Chain Fatty Acids in Gastrointestinal Diseases. Nutraceuticals. 2025; 5(3):19. https://doi.org/10.3390/nutraceuticals5030019

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Zhu, Meng Tong, and Jonathan Wei Jie Lee. 2025. "Therapeutic Potential of Short-Chain Fatty Acids in Gastrointestinal Diseases" Nutraceuticals 5, no. 3: 19. https://doi.org/10.3390/nutraceuticals5030019

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Zhu, M. T., & Lee, J. W. J. (2025). Therapeutic Potential of Short-Chain Fatty Acids in Gastrointestinal Diseases. Nutraceuticals, 5(3), 19. https://doi.org/10.3390/nutraceuticals5030019

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