Updated on January 2, 2023
For patients with ulcerative colitis, developing an effective management strategy can be a major challenge. Symptoms vary widely between patients, and many of the most common therapeutics—including aminosalicylates, corticosteroids, antibiotics, and methotrexate—have side effects that can be just as disruptive to the patient’s quality of life as the condition itself. Because ulcerative colitis has no cure, scientists have spent decades searching for therapeutic options that can offer effective assistance in symptom management. Today, a growing body of evidence suggests that short-chain fatty acids are a promising option.
The benefits of short-chain fatty acids for patients with ulcerative colitis are numerous and wide-ranging. After early observations of the effectiveness of topical supplementation of short-chain fatty acids for ulcerative colitis patients, researchers have successfully identified multiple means through which short-chain fatty acids might be able to help manage symptoms in patients with ulcerative colitis. In particular, butyric acid supplementation might serve as an effective, accessible, well-tolerated nutritional support therapy.
Short-chain fatty acids are metabolites produced by the fermentation of dietary fiber by bacteria. These metabolites have a distinctive chemical structure—a carboxylic acid “head” with a saturated hydrocarbon “tail.” There are several different chemicals in this category, and they are distinguished from each other by the number of carbon atoms in their “tails.” The three most common short-chain fatty acids in the human gut are acetic acid (2 carbons in the tail), propionic acid (3 carbons in the tail), and butyric acid (4 carbons in the tail). Together, they make up about 95 percent of the short-chain fatty acids in the GI tract.
Researchers first became interested in the possible benefits of short-chain fatty acids for ulcerative colitis patients when they observed that the concentrations of these compounds in patients’ fecal samples were significantly lower than the concentrations in healthy controls. To examine the clinical relevance of these observations, researchers in the late 1980s and early 1990s conducted studies on the use of topical short-chain fatty acid therapies (such as enemas and rectal irrigation) for patients with distal ulcerative colitis. The results indicated that therapies that directly introduce short-chain fatty acids into the colon could effectively address common symptoms, including rectal bleeding and urgency.
Although the benefits of short-chain fatty acids were clearly observed in ulcerative colitis patients, researchers could only hypothesize as to why patients were experiencing a reduction in symptoms after the introduction of these fatty acids. Only after years of work have researchers been able to formulate a more complete picture of how short-chain fatty acids can support patients with ulcerative colitis.
One of the key benefits of short-chain fatty acids is that they support the structural integrity of the colon. Most patients with ulcerative colitis have a “leaky gut,” which means the intestinal wall is highly permeable to bacteria and other toxins. When these substances enter the bloodstream, they can cause harm throughout the body. However, studies suggest that short-chain fatty acids encourage the proliferation of colonocytes, which helps build a stronger intestinal barrier with a lower level of permeability. The short-chain fatty acid with the most significant role in this process is butyric acid, because it is the major energy substrate for epithelial cells.
Butyric acid also plays a role in the development of the mucosal barrier in the colon, which is also involved in leaky gut. In patients with ulcerative colitis, the thickness of the mucosal barrier is reduced, and its composition (which includes a wide range of proteins, carbohydrates, lipids and antimicrobial compounds) is different from that of healthy patients. In experimental models of ulcerative colitis, butyric acid promotes mucus production and helps restore the optimal level of mucosal permeability.
Another hallmark of ulcerative colitis is the inefficiency with which cells in the colon absorb fluid. Not only can this disrupt electrolyte balances in the body, it can also contribute to debilitating symptoms like diarrhea. Short-chain fatty acids in the colon can directly stimulate sodium and fluid absorption, which can lead, in turn, to a reduction in symptoms.
In addition to the direct impact of short-chain fatty acids on the structure and function of the colon, one particular short-chain fatty acid—butyric acid—has also been shown to directly benefit the inflammatory response in the intestines that is associated with ulcerative colitis. There are several key mechanisms through which butyric acid exerts this effect:
Inducing T regulatory cell differentiation in the colon. T regulatory cells play an important role in the up-regulation of immune function by suppressing the inflammatory response when necessary. By promoting the differentiation of T regulatory cells in the colon, butyric acid helps maintain a normal inflammatory response in patients with ulcerative colitis.
Signaling through G-protein coupled receptors. Butyric acid can interact with a wide range of proteins in the highly diverse signaling protein family of G-protein coupled receptors (GPCRs). In one study, researchers demonstrated that the interaction between butyric acid and a specific type of GPCR addressed the inflammatory response in mouse models of ulcerative colitis.
Acting as an epigenetic regulator. Butyric acid can interact with DNA and DNA storage molecules to determine when and where particular genes are expressed. In this way, butyric acid can influence the expression of multiple pro-inflammatory mediator proteins, such as NF-KB.
Addressing oxidative damage in the colon. Studies suggest that the presence of butyric acid is associated with higher levels of glutathione (GSH), an antioxidant that can beneficially address inflammatory responses by limiting oxidative damage.
Although early research focused on topical short-chain fatty acid therapy for ulcerative colitis patients—that is, through enema or rectal irrigation—more recent studies have suggested that oral supplementation might be effective in animal models. Comprehensive clinical studies on patients with ulcerative colitis are needed to provide more concrete evidence, but the strong biochemical research results have prompted some patients and providers to start considering nutritional support by taking advantage of oral supplementation options. Highly bioavailable butyric acid supplements show the most promise because butyric acid is the short-chain fatty acid with the largest body of evidence indicating potential benefits for ulcerative colitis patients.
One of the most promising nutritional supplements for Crohn’s patients is butyric acid, a cellular signaling molecule in the GI tract that is deficient in Crohn’s patients. Providing the GI tract’s immune cells with the butyric acid they’re missing helps normalize the microbiome. Evidence suggests this type of supplementation can have significant beneficial effects; one study found that 69 percent of participants responded to bioavailability-optimized orally administered butyrate supplementation, with 53 percent achieving symptom benefit.
Further research is necessary to more fully understand the potential of butyrate supplementation to address symptoms in Crohn’s disease. However, for now, its use in addition to conventional and non-conventional therapies like GFDs might benefit patients. Other supplements, like fish oil, exist in a similar state, with some evidence in favor of their benefit in Crohn’s, and many questions left to be answered.
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