Gut health is an exciting, emerging field in medicine. With the ever-increasing wealth of information on what makes our microbiomes tick, it can be difficult to know what, exactly, you should adopt to improve your gut. As is the case with just about any routine change, doing something small to begin is always a good idea. And while there are many small changes you can make for better gut health, one area that’s been receiving more attention is getting enough butyrate, a little-known, gut-friendly compound.
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We spoke with Jennifer Katz, a former health coach with Parsley Health, to learn more about how butyrate works and butyrate deficiency symptoms.
Butyrate, or butyric acid, is what’s known as a postbiotic: a byproduct of our gut’s natural fermentation process. Katz explains, when we eat foods that are rich in fiber, our gut bacteria consumes that fiber and leaves behind beneficial compounds—including, with certain foods, butyrate. She adds that butyrate is one of several short-chain fatty acids that support our overall health. Where long-chain and medium-chain fatty acids are relatively easy to acquire through the foods we eat, short-chain fatty acids tend to be less common in most people’s diets. Nevertheless, they’re important to seek out.
“Short-chain fatty acid is so important because it serves as almost an instant energy source,” Katz explains, adding that short-chain fatty acids are easier to turn into energy than their long and medium counterparts. “It can be a burst of energy for the brain; it can turn into ketones very quickly; it can help rebuild the epithelial cells in the intestinal lining.” Research suggests short-chain fatty acids may also help bolster the immune system and improve sleep quality.
According to Katz, recent and emerging research suggests that our microbiome specifically stands to benefit from a diet that provides us with an adequate amount of butyrate: “[It] can help maintain balance in the gut, it can help provide energy for the colon, and it has been shown to help reduce all-around inflammation.” And, given short-chain fatty acids’ ability to repair the intestinal lining, butyrate may also help prevent leaky gut.
This condition arises when our intestinal barrier is compromised: Normally, our intestinal lining consists of tightly connected cells with regulated junctions between them that do not permit any bacteria or toxic substances to go across the intestinal lining and get into your blood. If those perforations become more permeable, unwanted molecules (including large food particles, bacteria, and toxins) can make their way through as well, leading to an increase in inflammation, gastrointestinal discomfort (i.e., gas, cramps, and bloating), chronic conditions like celiac disease and gluten intolerance and other, potentially more serious, health complications.
There are many reasons these perforations may become more permeable, from inflammation in the body to antibiotics to infections. Katz adds, "Everything from diabetes to cancer to food allergies to general malaise to brain fog — you name it — can be associated with a leaky gut."
Butyrate—a short-chain fatty acid produced by gut bacteria during the fermentation of dietary fiber—plays a critical role in improving the function of the intestinal barrier. It enhances the assembly of tight junctions between intestinal cells, reduces inflammation, and helps maintain gut integrity. Butyrate may also protect against food allergies, stabilize blood sugar levels, support brain health, and reduce systemic inflammation.
However, Katz is quick to note, however, that these benefits come with a caveat: “[Butyrate is] newly studied, so a lot of these [findings] are brand new. The studies haven’t been repeated but they have shown really good things thus far.” In other words, butyrate is by no means a silver bullet, but it may still be in your interest to add butyrate-rich foods to your diet.
Because butyrate is a fairly specific and isolated compound, it’s unlikely that anyone will suffer from symptoms that can be directly linked to a butyrate deficiency. Instead, Katz says looking at your eating habits may help you determine whether you’re getting enough butyrate. “Those with a low fiber diet are probably lacking butyrate,” she says. “Fiber is extremely important for butyric acid to actually do its thing and to be made.” Again, the good bugs in your gut consume the fiber from the foods you eat and create butyrate in the process—so, insufficient fiber can mean insufficient butyrate.
Katz says people dealing with inflammation or gut imbalances, perhaps due to antibiotic use, indigestion, or IBS, are also more likely to lack butyrate. Aside from that, anyone who’s invested in having a healthy microbiome may want to take a greater interest in their butyrate intake, due to the positive impact it can have on intestinal function.
As far as how to increase your butyrate intake goes, Katz’s recommendation is simple: “This is one of those things that you can take preventatively. You can take a butyrate supplement, but you really do want to get it from your food.”
Where some foods contain the fiber necessary to create butyrate in the body, other foods are, in and of themselves, rich in butyrate. Chief among this latter category is a variety of dairy products (though if you’re intolerant or sensitive to dairy, you’ll want to steer clear) including the following:
Butter
Milk
Certain hard cheeses
You can also consume foods that don’t necessarily contain butyrate but will help the bugs in your gut create it. Here are the best foods to add to your diet:
High-fiber fruits and vegetables, including apples, broccoli, potatoes, and dark greens
Legumes
Nuts, particularly walnuts
Sauerkraut
While most people should be able to get enough butyrate from foods alone, Katz notes two groups who may want to consider supplementing it instead.
First, she points to those with food intolerances and allergies. If you’re lactose intolerant, for example, you certainly shouldn’t try eating butter and cheese just because they contain this helpful compound. In that case, Katz says you may want to talk to your doctor about trying a supplement—and to consider gut healing or allergy therapy in order to work your way out of that intolerance.
Second, she points to people with imbalanced gut microbiomes and digestive issues that range from those who deal with IBS to those who have an ostomy bag or are undergoing colon therapies.
This group may have microbiomes that are in such a “deficient state,” as Katz puts it, that starting with a butyrate supplement may help them play catch-up and eventually reach a point where they can more easily digest the kinds of foods that will naturally provide them with more butyrate. “It’s sort of a catch-22,” Katz says. “You need great digestion in order to get what you need out of the foods that give you butyrate, but you also need butyrate to get good digestion. It may depend on where you’re starting from.”
When in doubt, ask your healthcare provider about what you can do to increase or maintain your gut health. Starting that conversation will give you a much better idea of your microbiome’s individual needs.
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“[Butyrate] can do so much, but it has to go hand-in-hand with other lifestyle modifications and habits,” Katz says. Alone, it won’t make much of a difference, but when butyrate works in tandem with a lifestyle that prioritizes gut health—one that features prebiotic and probiotic foods, exercise, adequate rest, and stress-management practices—it proves itself to be a valuable cog in the machine that is your microbiome.
The World Health Organization (WHO) defines obesity as an abnormal fat accumulation that may impair health (1). The evidence of the relationship between the gut microbiome and the development of obesity and type 2 diabetes mellitus (T2DM) has been rising for the last decade (2). The gut microbiota plays a pivotal role in regulating energy homeostasis. Among other host factors, this balance between energy intake and expenditure relies on the microorganisms and their metabolites, helping in nutrient processing, nutrient access regulation, and storage in the body by secreting hormones and mediators of energy homeostasis (3). Some glycemic alterations that cause a detrimental cascade effect have also been linked to chronic inflammation, cardiovascular diseases, and gut dysbiosis, where the loss of several butyrate-producing bacteria has been observed (4).
The short-chain fatty acids (SCFAs) are ingested through diet or produced by fermentation of non-digestible fiber by gut microbiota; the three major SCFAs produced are butyrate, propionate, and acetate (5). After production or consumption, butyrate, the SCFA with the most important systemic effects, is absorbed rapidly in the gut and acts as a source of energy and a signaling molecule in numerous cell types (6). It has been reported to have metabolic effects on obesity and glucose homeostasis. In a recent study, individuals with obesity and T2DM showed a decreased abundance of butyrate-producing bacteria and downregulation of genes related to butyrate production (7). Despite these findings, its exact role remains unclear since obese individuals present higher fecal butyrate concentrations than the control group, with similar diet consumption (8, 9). Restoration of butyrate-producing bacteria and butyrate levels by ingesting butyrate-rich foods or dietary fibers that lead to butyrate production might provide new treatment options for T2DM and obesity-related metabolic diseases (5). Here we review the basic mechanisms that explain the role of butyrate in this context.
SCFAs, including butyrate, are present in high amounts in milk and milk derivatives from different mammals. Bovine fat milk and its derivatives are a great source of butyric acid, e.g., butter (∼3 g/100 g), goat’s cheese (∼1–1.8 g/100 g), parmesan (∼1.5 g/100 g), whole cow’s milk (∼0.1 g/100 g) (10). Human milk (HM) has also been reported as a source of butyrate, where the concentration measured in HM samples from healthy women fluctuates between 0.15 and 1.93 mM in colostrum and 0.16–1.97 mM in mature milk. Considering a median butyrate concentration of 0.75 mM in mature HM, a breastfed infant could receive a daily dose of butyrate of approximately 30 mg/kg body weight (11).
Salatrims, a fat calorie replacer commonly used in the food industry, is also a source of dietary butyrate. Salatrim has triglyceride mixtures in which butyric acid is inter-esterified with a long-chain fatty acid moiety such as stearic acid (12, 13). Since butyrate is esterified at the α(sn-3) position (14, 15), pancreatic lipase can cleave triacylglycerols releasing free fatty acids (FFA) in the small intestine (16, 17). To prevent digestion -and absorption- in the upper part of the gastrointestinal tract, butyrate might be esterified to a dietary fiber such as butyrylated or tributyrin, in which butyrate is esterified to triglycerides; as a result, these esterificated form of butyrate have also been shown to increase colonic butyrate concentrations (18, 19).
In most human clinical and rodent studies focused on obesity and diabetes, butyrate is supplied orally as sodium butyrate, which has an unpalatable flavor and odor. Novel strategies have been developed recently to improve palatability and the release and absorption of butyrate in the digestive tract (20). Coating sodium butyrate with cellulose-based capsules has been one approach to delay the release in the intestinal tract (21). According to pharmacological and clinical data from the literature, butyric acid is considered a safe drug. Therapeutic doses (150–300 mg) have shown no clinical side effects (22). Even when higher doses up to 2,000 mg/day, no adverse reactions have been observed (22, 23)
On the other hand, dietary fiber is used by some bacteria in the gut microbiota for butyrate production in two different ways: (I) Direct, where fiber acts as a substrate for bacterial fermentation producing butyrate, (II) Indirect since bifidogenic fibers help to increase the abundance of bifidobacteria, which increase butyrate production indirectly (24).
Maybe, the most efficient way to influence the composition of intestinal and colon microbiota is by ingestion of dietary fibers such as inulin-type fructans, xylooligosaccharides, arabinoxylans, arabinoxylan oligosaccharides, β-glucans, and oligofructose (25–28). Important foods to increase intestinal butyrate are complex polysaccharides not easily digested by saliva and pancreatic amylases. For instance, resistant starch, a group of molecules that resist digestion, may be added or fortified into bread and cereals (29) but is also found naturally occurring in some legumes, cooked potatoes, and unripened bananas. Studies have shown that resistant starch potentiates butyrate production and yields more butyrate than non-starch polysaccharides (30, 31). Other non-easily digested polysaccharides producing butyrate include cereal breakfasts, such as barley and oats, containing β-glucans, which are also naturally present in edible mushrooms and seaweed (32). Finally, inulin, on the other hand, is mainly found in artichokes, onion, and chicory roots (33) are also good foods to increase intestinal butyrate.
A high-fiber diet can cause gastrointestinal discomforts, such as gas, bloating, and constipation in patients with Crohn’s disease, irritable bowel syndrome, or ulcerative colitis. This is why a gradual increase in fiber intake is recommended for everyone (34).
Although butter is the most abundant source of dietary butyrate (up to 3 g per 100 g), the best way to increase the amount of intestinal butyrate is by consuming non-digestible carbohydrates (complex polysaccharides) to increase in situ production by human gut microbiota (35). Intestinal butyrate is produced by obligate anaerobic bacteria through fermentation (36). Most human butyrate producers belong to the Firmicutes phylum including species such as Clostridium butyricum, Clostridium kluyveri, Faecalibacterium prausnitzii, Butyrivibrio fibrisolvens, Eubacterium limosum (37–39).
Although several routes for the production of butyrate have been described, in human gut microbiota, butyrate is mainly synthesized from acetyl-coenzyme A (Ac-CoA) obtained from the breakdown of complex carbohydrates (e.g., xylan, starch) as a precursor (18, 37). Subsequently, two molecules of AcCoA condense into acetoacetyl CoA, and after several consecutive steps, it is transformed into butyrate (40). The final step in butyrogenesis is the conversion of butyryl-phosphate into butyrate by butyrate kinase encoded by the buk gene or butyryl-CoA to butyrate by butyryl-CoA: acetate-CoA transferase, encoded by the but gene (41). In addition to the colonization of the colon by butyrogenic bacteria, it has been proposed that cross-feeding interactions between Bifidobacterial strains and F. prausnitzii may ultimately enhance butyrate production (42).
Whether butyrate is ingested through the diet or produced locally in the intestine from dietary fiber, it is absorbed into the enterocytes by diffusion and delivered through the portal vein into the liver and systemic circulation (43, 44). Due to its size and hydrophobicity, butyrate, like propionate and acetate, are absorbed through a non-ionic diffusion across the apical membrane of colonocytes (45, 46). Sodium-coupled monocarboxylate transporter 1 (SCMT1) utilizes colonic concentration of Na+ to internalize SCFAs within colonocytes. It has been described that SCMT1 transports propionate acetate at a slower rate compared to butyrate transport. The solute carrier family 5 member 8 (SLC5A8) is considered the primary butyrate transporter across the apical membrane of the colonocytes (47, 48).
The liver is the master organ for regulating energy homeostasis, particularly for lipid and glucose metabolism regulation. The liver plays a central role in the development of obesity-associated metabolic alterations. It is, therefore, highly relevant to outline the effect of butyrate on regulating lipid metabolism and liver function. Recent studies showed that butyrate supplementation reduced serum triglyceride levels and the respiratory exchange ratio in high-fat diet (HFD)-fed animals compared to controls with HFD only, suggesting that butyrate may exert its effect by promoting fatty acid oxidation (49–53). In addition, butyrate also reduced lipid content in brown adipose tissue (BAT) and, to a lesser extent, in the liver and muscle (51). Additionally, demonstrating its protective role, butyrate supplementation in animals with HFD resulted in a significant reduction of proinflammatory serum markers (TNF-α, MCP-1, and IL-1β) compared to the markers of animals with HFD only (50).
Although butyrate mechanisms of action are unclear, previous studies show that butyrate modulates the AMP/ATP ratio activating the AMPK pathway to promote oxidative metabolism (decrease lipid synthesis and increase lipid oxidation) in the liver and adipose tissue (53). In addition, butyrate increases the percentage of oxidative type fibers (actively using lipid oxidation for ATP biosynthesis) in skeletal muscle by activating AMPK and p38 (54) and increases mitochondrial function in skeletal muscle (49) and liver (50).
In addition to its well-known effects on intestine function (55), butyrate is a critical link between gut microbiota and the regulation of host energy homeostasis. Results from several groups have provided evidence supporting this role. For instance, chronic sodium butyrate supplementation in food (49, 51, 53, 54, 56) or orally delivered via gavage (50, 57–59) reduces body weight gain and fat mass of mice fed with a HFD compared to mice fed with an HFD alone, suggesting that butyrate can prevent or contribute for the treatment of diet-induced obesity (DIO). Also in agreement with this regulating role, intraperitoneal (IP) injection of sodium butyrate for ten consecutive weeks reduced body weight gain of rats treated with butyrate (60). A mechanism explaining the effect of butyrate on reducing body weight and fat mass is the activation of lipid oxidation initiated by butyrate in BAT and the liver (51). In addition to the increased energy expenditure and lipid oxidation, reduced food intake, also described as an effect of oral butyrate supplementation but not an intravenous injection, may contribute to decreased body weight gain induced by butyrate and reduced fat mass (51). The lack of effect of intravenous injection of butyrate suggests a role of this SCFA in regulating the gut-brain circuit.
Although there is evidence that sodium butyrate supplementation in standard diet-fed rats reduced weight gain (55), the effects of butyrate under chow diet-fed conditions remain controversial. There are contradicting results from other studies claimed that a chow diet plus 1% or 5% butyrate did not significantly affect body weight in mice (50, 61) and even that offspring rats of mothers fed a 1% butyrate in a chow diet had higher body weight (62). Major milestones of butyrate action and results from key therapeutic trials are summarized in Table 1.
TABLE 1As it has been extensively documented in the literature, insulin resistance can be attributed to a decrease in receptor sensitivity together with the functional impairment of β-cells in the pancreatic islets (63). Histological studies of human islet tissue have shown that butyrate has a protective effect against oxidative and mitochondrial stress promoting the survival of β-cells in vitro (64, 65). Remarkably, initial analysis of the conditions associated with β-cells autoimmunity in children at risk of type-1 diabetes mellitus (T1DM) found a reduction in the average population of butyrate-producing bacteria (66, 67). There is evidence that butyrate is involved in the metabolism of β-cells in the pancreatic islets due to its interaction with G-protein coupled receptors (GPR) like free fatty acid receptors FFAR3 (GPR41) and FFAR2 (GPR43), as seen in Figure 1 (64, 68, 69). In light of this association, one study suggested that butyrate could be responsible for a proliferative effect during in vitro mouse intestinal organoid development due to its interactions with GPR41 and 43 receptors (70).
FIGURE 1Animal data in obese mice have shown that butyrate administration rapidly decreased fasting insulin levels (50, 71). As a result, aside from its protective role in β-cells, butyrate has been proposed as a direct regulator of insulin secretion via GPR-mediated signaling. However, this direct role remains unconfirmed and controversial (72). Nevertheless, recent findings suggest sodium-butyrate treatment can indirectly enhance insulin secretion by repressing β-cell key functional genes in rat islets (73). More evidence about the indirect role of butyrate during insulin secretion has emerged after studies reported its involvement with glucagon-like peptide-1 (GLP-1) secretion from intestinal L-cells (74, 75). Activation of the GLP-1R (receptor) genes, also present in β-cell, and subsequent GLP-1 release can also be induced by butyrate (76). GLP-1 has the potential to minimize apoptotic events and induce neogenesis and regeneration of β-cells via cAMP (cyclic adenosine monophosphate) upregulation (77). Production of cAMP can also elicit postprandial-like insulin secretion by accelerating the glucose-dependent closure of ATP-regulated potassium channels (77–79).
On the other hand, the inhibitory activity of butyrate toward histone deacetylases (HDAC) has also been extensively described in literature due to HDAC involvement in transcriptional regulation, metabolism, metastasis, oncogenesis, and ischemic brain events (80, 81). HDACs have also been linked to hyperglycemia by promoting gluconeogenesis in the liver; therefore, becoming an important target to regulate glucose levels via the administration of HDAC inhibitors like metformin (a first-line antihyperglycemic drug for T2DM treatment) (82, 83). Type-2 diabetic animal studies have revealed that butyrate has similar effects to metformin in reducing insulin resistance and other T2DM-associated conditions (60). In addition, the role of butyrate-mediated HDAC inhibition has been described as an enhancer in the differentiation and maturation of β-cells in neonatal porcine islets (84). Altogether, there is strong evidence about the crucial role of butyrate and its interactions with insulin-secreting β-cells. The potential regulation of gluconeogenesis via HDAC and the robust induction of insulin secretion via GLP-1 appoint butyrate administration as a potential target for research in diabetes treatment.
Consequently, several therapeutic interventions have already been conducted to assess the effects of butyrate supplementation in diabetic patients and patients with obesity and metabolic syndrome (Table 1). Some trials reported a positive outcome after treatment with oral butyrate with a reduction in the patient’s blood pressure and blood sugar levels (85, 86). In addition, other trials also found significant reductions in HbA1c (hemoglobin-A1c: glucose linked to hemoglobin in red blood cells), total cholesterol, and triglycerides (87). On the other hand, several studies contradict some of these findings and report no significant effects on sugar levels, insulin sensitivity, and secretion (87, 88). One study suggests that butyrate therapy benefits healthy individuals, but this outcome is not reflected in patients with metabolic syndrome (89). Overall, there are still some limitations on these data, which may prevent direct comparisons and conclusions. Some of these trials may be conditioned by the short duration of butyrate administration, small sample size, lack of placebo control, and variability within the target population. Moreover, butyrate combination therapies with other potential antidiabetic drugs are still unexplored, so further research is encouraged.
In addition to the described effects on intestinal function and metabolic control, the system-level impacts of butyrate remain elusive, and the detailed molecular mechanisms responsible for butyrate action in host and microbial cells are still a very active research field. On the other hand, to detail the effects of butyrate on host metabolism and further promote butyrate as a therapeutic approach for designing novel clinical trials, it is critical to identify its effects on different animals and humans and evaluate different doses, treatment times and delivery methods. In addition, although many studies support the role of butyrate as an essential mediator in host metabolic control, some of its effects remain controversial.
Highly relevant questions in this exciting field are still awaiting elucidation. They should be decoded, including but not limited to determining the best conditions and food sources for butyrate production by gut microbiota in situ, absorption of dietary and microbially produced butyrate under different physiological and pathological conditions, the regulatory mechanisms of butyrate at a cellular and systemic levels and the potential of using it as a therapeutic alternative in some obesity-associated metabolic alterations.
CB-O and LG: conceptualization and research/investigation. AM-R, DS-R, and CB-O: writing—original draft preparation. LG and DS-R: writing—review and editing. LG: supervision. All authors contributed to the article and approved the submitted version.
We thank the Corporación Ecuatoriana para la Investigación y la Academia (CEDIA) and its funds from CEPRA XII--10 granted to LG.
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.
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