Possible roles of short-chain fatty acids in the pathophysiology and treatment of irritable bowel syndrome

Abstract

Short-chain fatty acids (SCFAs) are metabolic products of bacterial fermentation of undigested/unabsorbed carbohydrates and fibers in the intestine. SCFAs are used by intestinal epithelial cells as an energy source and regulates several large-intestine functions, such as motility, visceral sensitivity, the immune system, and the gut barrier. About 95% of SCFAs are acetic, propionic, and butyric acids occurring in proportions of 60%: 20%: 20% in healthy subjects, while the proportion of butyric acid is lower than 20% in irritable bowel syndrome (IBS) patients. Acetic and propionic acids are not correlated with IBS symptoms, suggesting that they are not involved in symptom manifestation. The butyric acid level increased in IBS patients after fecal microbiota transplantation, and was inversely correlated with abdominal pain, diarrhea, and constipation. The effects of butyric acid on IBS symptoms such as abdominal pain, diarrhea, and constipation can be attributed to its modulation of the expression levels of serotonin, peptide YY, and glucagon-like peptide-1 in the intestinal enterochromaffin cells and L-cells. The butyric acid level was also inversely correlated with chronic fatigue, which occurs in about 54% of IBS patients. Treatment with sodium butyrate in capsule form is a promising therapeutic approach for IBS.

Key Words: Acetic acid; Butyric acid; Fatigue; Glucagon-like peptide-1; Peptide YY; Propionic acid; Serotonin

Core Tip: Butyric acid appears to play a significant role in irritable bowel syndrome (IBS) symptom manifestation and the overlapping chronic fatigue. Sodium butyrate in capsule form seems to be a promising treatment for IBS.

INTRODUCTION

Irritable bowel syndrome (IBS) affects about 9.2% to 3.8% of the global population[1,2]. Although IBS is not a life-threatening condition, it lowers the quality of life of the patients and represents an economic load on society[1,2]. A large proportion of IBS patients also suffer from chronic fatigue syndrome[3-5]. The gut bacterial profile in IBS patients differs from that in healthy subjects[6,7]. This difference has been attributed to either a difference in the bacterial composition or to a low bacterial diversity (dysbiosis) in IBS[6-12]. Abnormal gut microbiota in IBS patients is believed to play a role in the pathophysiology of this disorder[6,7]. The specific bacterial species that need to be restored in IBS patients are not exactly known[13,14]. Modulating the gut microbiome through prebiotics consumption, probiotics and synbiotics have been found to be relatively ineffective against IBS symptoms[13,14]. In addition, long-term intestinal colonization with the introduced bacteria through probiotic treatment is uncertain[15-17].

The main metabolic products of bacterial fermentation of undigested/unabsorbed carbohydrates and fibers in the intestines are short-chain fatty acids (SCFAs)[18,19]. About 95% of the SCFAs in the human intestines are acetic, propionic, and butyric acids occurring in proportions of 60%: 20%: 20% in healthy subjects[19,20]. SCFAs are used by large-intestine epithelial cells as an energy source and regulates several large-intestine functions, such as motility, visceral sensitivity, the immune system, and the gut barrier[21-25]. Nonabsorbed SCFAs by colonocytes reach the circulating blood and regulate the metabolism of glucose, lipid, and cholesterol[19,20]. SCFA levels in IBS patients have been found to differ from those in healthy subjects, with the fecal propionic acid level being markedly higher in IBS patients[20,26-30].

Fecal microbiota transplantation (FMT) is a promising treatment for IBS since it shows high efficacy and durable effects when performed using an appropriate protocol that includes using a single superdonor[31]. The changes in the bacterial composition induced by FMT result in marked changes in fecal SCFAs[32-34]. These changes in SCFAs were associated with the improvement in IBS symptoms and fatigue[34]. It is notable that chronic fatigue is common in patients with IBS and occurs in 54.5% of IBS patients[35].

The present narrative mini-review analyzed the possible role of SCFAs in the manifestation of IBS symptoms and the overlapping chronic fatigue based on FMT studies, as well as the potential use of SCFAs as a treatment for IBS.

TOTAL SCFAs

The total fecal SCFA levels increased at 1 month and 1 year after FMT, whereas they decreased at 2 and 3 years after FMT (Figure 1A). In healthy subjects, the intestinal acetic, propionic, and butyric acids are present in proportions of 60%: 20%: 20%[19,20]. In IBS patients, acetic and propionic acids also comprise around 60% and 20%, respectively, of total SCFAs, whereas butyric acid comprises less than 20% (Tables 1 and 2). In IBS patients treated with FMT, the proportion of butyric acid increased to over 20% at 1 month and 1 year after FMT, and to over 30% at 2 and 3 years after FMT (Table 1). In IBS patients who received their own feces, butyric acid accounted to 18%-15% of the total SCFAs at the corresponding observation times (Table 2). The increase in the proportion of butyric acid at 1 month and 1 year in patients treated with FMT can be attributed to the engraftment of the donor’s bacteria. On the other hand, the increase in the proportion of butyric acid observed 2 and 3 years after FMT can be explained by IBS patients being symptom-free following FMT, changed their diet to a more fiber-rich diet.

Figure 1 Post-fecal microbiota transplantation changes in irritable bowel syndrome patients receiving 60 g of donor feces. A: Total fecal short chain fatty acids levels; B: Fecal butyric acid level. ^aP < 0.05, ^bP < 0.0001, ^cP < 0.01 vs the baseline values. Based on pooled data from El-Salhy et al[32-34]. The total fecal short chain fatty acids, acetic acid, propionic acid, and butyric acid levels in the cited references were analyzed using gas chromatography (Agilent 7890A, Agilent, CA, United States). SCFA: Short chain fatty acids; FMT: Fecal microbiota transplantation.

Table 1 The proportion of the 3 main short chain fatty acids in irritable bowel syndrome patients that received 60 g of the donor’s transplant.

SCFAs	Baseline	1 month after FMF	1 year after FMT	2 years after FMT	3 years after FMT
Acetic acid	64	59	60	51	50
Propionic acid	19	18	18	16	17
Butyric acid	17	23	22	33	33

SCFA: Short chain fatty acids; FMT: Fecal microbiota transplantation.

Table 2 The proportion of the 3 main short chain fatty acids in the placebo group irritable bowel syndrome patients that received their own feces.

SCFAs	Baseline	1 month after FMF	1 year after FMT	2 years after FMT	3 years after FMT
Acetic acid	62	63	64	65	60
Propionic acid	22	19	18	20	23
Butyric acid	18	18	18	15	17

SCFA: Short chain fatty acids; FMT: Fecal microbiota transplantation.

Acetic acid

The main producers of acetic acid in the human large intestine are Akkermansia muciniphila and Bifidobacteria species[36-38]. Acetate appears to regulate the body weight via several mechanisms. Acetate crosses the blood-brain barrier and regulates appetite and satiety via the central nervous system and via satiety hormones secreted by enteroendocrine cells such as peptide YY (PYY) and glucagon-like peptide-1 (GLP-1)[39-42]. Acetate binds also to G-protein receptors expressed in adipose tissue, skeletal muscles, and the liver and pancreas[43-46]. Moreover, acetate may activate Olfr51E2 (olfactory receptor 51E2) and Olfr78 (olfactory receptor 78) in renal tissue, which are important for blood pressure regulation[42].

The proportion of acetic acid in IBS patients was similar to that in healthy controls, at around 60% (Tables 1 and 2)[34-36]. At 1 month and 1 year after FMT, IBS patients continued to have a normal proportion of acetic acid. However, at 2 and 3 years after FMT the proportion of acetic acid decreased to around 50%, with butyric acid increasing to about 30% (Tables 1 and 2). The acetic acid level decreased in IBS patients at 2 and 3 years after FMT (Figure 2A), and was not correlated with the total score on the IBS severity scoring system (IBS-SSS) (Figure 2B)[32-34].

Figure 2 Fecal acetic acid content. A: Fecal acetic acid level in irritable bowel syndrome patients who received 60 g of the donor’s feces; B: Correlation of the fecal acetic acid level with the irritable bowel syndrome-severity scoring system total score. ^aP < 0.05; ^bP < 0.01 compared with the baseline values. Based on pooled data from El-Salhy et al[32-34]. FMT: Fecal microbiota transplantation; IBS-SSS: Irritable bowel syndrome-severity scoring system.

Propionic acid

Several bacteria are known to produce propionic acid when undigested/unabsorbed carbohydrates and fibers are fermented in the intestines, such as Propionibacterium freudenreichii ssp. shermanii, Selenomonas ruminantium, Propionibacterium acidipropionici, Propionibacterium jensenii, Propionibacterium thoenii, Veillonella gazogenes, Veillonella criceti, Veillonella alcalescens, Veillonella parvula, Megasphaera elsdenii, and Megamonas funiformis[48-56]. In experimental animals, propionate inhibits the synthesis of cholesterol in the liver by regulating gluconeogenesis through acting on hydroxy-methylglutaryl-CoA reductase[57,58]. Propionate also plays roles in lipid metabolism, the cholesterol level, and the immune system[59]. In IBS patients, the proportion of fecal propionic acid was around 20%, which is similar to that in healthy subjects (Tables 1 and 2). In IBS patients treated with FMT, the proportion of propionic acid reduced to 16% and 17% at 1 and 2 years after FMT, respectively (Table 1)[32-34]. In IBS patients treated with FMT, the fecal propionic acid level did not change at 1 month and 1 year after FMT, but it decreased significantly at 2 and 3 years after FMT (Figure 3A). The fecal propionic acid level was not correlated with the IBS-SSS total score (Figure 3B)[34-36].

Figure 3 The content of propionic acid in feces. A: Fecal propionic acid level in irritable bowel syndrome patients who received 60 g of the donor’s feces; B: Correlation of the irritable bowel syndrome severity scoring system total score with the fecal propionic acid level. ^aP < 0.05; ^bP < 0.01 compared with the baseline values. Based on data from El-Salhy et al[32-34]. FMT: Fecal microbiota transplantation; IBS-SSS: Irritable bowel syndrome-severity scoring system.

Butyric acid

The main bacteria species that produce butyric acid in the human large intestine are Faecalibacterium prausnitzii and Eubacterium biforme[32-34]. The fecal levels of these bacteria increased in IBS patients at 1 month, 1 year, 2 years, and 3 years after FMT[32-34]. The fecal butyric acid level was also increased in IBS patients at 1 month, 1 year, 2 years, and 3 years after FMT (Figure 1B)[34-36]. The fecal butyric acid level was inversely correlated with the IBS-SSS total score and the scores for its four subitems, and with the Birmingham IBS Symptom Questionnaire total score and the scores for its subitems, indicating that butyric acid plays a significant role in IBS symptom manifestation[34]. The butyric acid level after FMT did not differ between IBS-subtypes[32-34]. A multicenter clinical trial involving a large cohort of IBS patients found that administering 150 mg of microencapsulated sodium butyrate twice daily for 12 weeks significantly improved their IBS symptoms[60]. Neither changes in the gut microbiota nor adverse events were reported for that previous study. Moreover, calcium butyrate supplementation was found to reduce IBS symptoms in in the treated children relative to placebo, and changes in the gut microbiota were observed[61]. There were also no adverse events reported for that study. The outcomes of both of these previous studies did not differ between IBS-subtypes[60,61].

Abdominal pain is the main symptom of IBS and is used as the main symptom-based Rome IV criterion for diagnosing IBS[62,63]. The fecal butyric acid level was inversely correlated with abdominal pain scores measured using both the IBS-SSS and the Birmingham IBS Symptom Questionnaire, and treatment with microencapsulated sodium butyrate has been shown to improve abdominal pain in IBS patients[34,60]. Moreover, administering butyrate as an enema to healthy subjects has been found to decrease the visceral sensitivity[64]. In an animal model of IBS, treatment with sodium butyrate decreased visceral hypersensitivity by inhibiting the expression of interleukin-1-receptor-associated kinase in the large intestine[65].

The improvement in abdominal pain in IBS patients after FMT and after administering butyrate as a capsule or enema can be explained by butyric acid regulating the expression of serotonin by enterochromaffin cells[21-25]. Serotonin is the main pain transmitter in the gut that activates the submucosal and myenteric sensory branches of the enteric nervous system. Visceral pain is experienced due to sensations from the gut reaching the cerebral cortex via the thalamus.

The fecal butyric acid level was inversely correlated with dissatisfaction with bowel habits according to the IBS-SSS total score and to both the diarrhea and constipation scores on the Birmingham IBS Symptom Questionnaire[34]. The butyrate level was also inversely correlated with the intestinal transit time in both healthy subjects and IBS patients, and positively correlated with stool frequency in IBS patients[26,66]. The effects of butyric acid on both diarrhea and constipation could be attributed to its regulation of gut motility. Butyric acid modulates the expression levels of serotonin, GLP-1, and PYY by activating FFAR2, FFAR3, GPR43, and GPR41 receptors[19,21,25,67]. and serotonin, PYY, and GLP-1 delay gastric emptying[68,69]. Serotonin also accelerates transit through the small and large intestines, and PYY and GLP-1 are the main mediators of the ileal brake[68,69].

Fatigue is experienced by 54.5% of IBS patients[35,70]. The fecal butyric acid level was inversely correlated with the total score on the Fatigue Assessment Scale (FAS) and with the scores for its subitems of physical fatigue and mental fatigue[32,34]. Butyric acid appears to play a crucial role in mental health disorders such as depression and anxiety[71]. Moreover, patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome showed deficiency in butyrate-producing capacity, and a decrease in major butyrate-producing bacteria such as Faecalibacterium prausnitzii and Eubacterium rectale[72,73]. In a mouse model of chronic fatigue syndrome, alleviation of CFS was associated with an increase SCFAs production in general and butyrate in particular[74]. Interestingly, the abundance of fecal Faecalibacterium prausnitzii and Eubacterium rectale increased in IBS patients following FMT. The abundance of these bacteria correlated inversely with both IBS symptoms as measured by IBS-SSS scores and fatigue as measured by FAS (Figure 4)[75].

Figure 4 At 3 years after fecal microbiota transplantation[75]. A: Faecalibacterium prausnitzii level was inversely correlated with irritable bowel syndrome severity scoring system; B: Faecalibacterium prausnitzii was inversely correlated with Fatigue assessment scale total scores; ntation; C: Butyric acid levels were inversely correlated with irritable bowel syndrome severity scoring system; D: Butyric acid levels were inversely correlated with Fatigue assessment scale total scores. Citation: El-Salhy M. Intestinal bacteria associated with irritable bowel syndrome and chronic fatigue. Neurogastroenterol Motil 2023; 35: E14621. Copyright ©The Authors 2023. Published by John Wiley & Sons. The article is open access (Supplementary material). IBS-SSS: Irritable bowel syndrome severity scoring system; FAS: Fatigue assessment scale.

Human antigen R (HuR) protein plays a significant role in RNA metabolism, and is expressed in several cell types including those in adipose tissue, and the intestines[76,77]. HuR suppresses adipogenesis and regulates inflammation[76]. Butyric acid has been shown to alleviate chronic intermittent hypoxia, cell proliferation and lipid formation through accumulation of HuR and inactivation of AMPK pathway[78]. It is particularly interesting that being overweight or obese is considered to be a risk factor for developing IBS[79,80]. Moreover, inflammation appears to play a significant role in both IBS and chronic fatigue[81-83]. It can be speculated that the effects of butyric acid on these conditions are attributable to its effect on inflammation. Further studies are needed to identify the mechanisms underlying the effects on butyric acid on IBS and the associated chronic fatigue.

The polyphenol resveratrol is a natural substance present in several fruits and vegetables products such as peanuts, grapes, pineapples, and blueberries. Resveratrol supplementation reduces gastrointestinal inflammation, improve lipid metabolism, and exert positive effects on gut microbiota in experimental animals[84]. Furthermore, Resveratrol has been reported to exert anti-cancer effects[85]. β-Hydroxy-β-methyl butyric acid also reduces intestinal inflammation and affects the gut microbiota[84]. In mice, the butyric acid precursor; tributyrin alleviates gut microbiota dysbiosis, and suppresses inflammation via the slow release of butyric acid[86]. Further studies including clinical trials are needed to evaluate the possible use of these supplements in treating IBS and the associated chronic fatigue.

CONCLUSION

Although acetic acid has been found to induce visceral hypersensitivity in rodents, the fecal levels of acetic and propionic acids in humans were not correlated with either the total score on the IBS-SSS or the scores for its four subitems[34,87]. Moreover, there was no difference in the fecal levels of acetic and propionic acids between responders and nonresponders at 2 and 3 years after FMT[34]. Thus, acetic and propionic acids appear not to be involved in symptom manifestation in IBS patients.

In contrast, butyric acid appears to play a significant role in IBS symptom manifestation. The effect of butyric acid on IBS symptoms such as abdominal pain, diarrhea, and constipation can be attributed to its modulation of the expression levels of serotonin, PYY, and GLP-1 in intestinal enterochromaffin cells and L-cells. Treatment with sodium butyrate in capsule form is a promising therapeutic approach for IBS. A short period of treatment with sodium butyrate capsules would reduce their symptoms and allow the IBS patient to change their diet habits, such as eating a fiber-rich diet that would restore the gut microbiota to normal (Figure 5). The efficacy of treating IBS and the associated chronic fatigue with natural supplements such as Resveratrol, β-hydroxy-β-methyl butyric, and acid butyric acid precursor; tributyrin remains to be decided when data from clinical trials are available.

Figure 5 Summary of short chain fatty acids effects on irritable bowel syndrome symptoms and the associated fatigue, and their possible mechanisms of actions, as well as their potential therapeutic use for treating irritable bowel syndrome[34]. A: Mechanism of action; B: Clinical outcomes of treatment. Citation for B: El-Salhy M, Valeur J, Brønstad I, Gilja OH, Hatlebakk JG. Possible Role of Butyric Acid in Long-Term Symptom Relief in Irritable Bowel Syndrome Patients Following Fecal Microbiota Transplantation. Neurogastroenterol Motil 2025; 37: E70115. Copyright ©The Authors 2025. Published by John Wiley & Sons. The article is open access (Supplementary material). IBS: Irritable bowel syndrome; SCFA: Short chain fatty acids; FMT: Fecal microbiota transplantation.

Chronic fatigue is common in IBS patients and butyric acid appears to play a role in its pathophysiology. Further investigations of the mechanisms underlying the effect of butyric acid on chronic fatigue are needed.