The oxygen-gut dysbiosis connection:
How to break the cycle of gut inflammation, dysbiosis, and epithelial energy starvation
Virtually every cell in the human body requires oxygen. That is – every human cell. Most of our microbial cells on the other hand, thrive in an environment devoid of oxygen. If oxygen leaks into the gut, it can promote bacterial imbalances and inflammation. Read on to learn more about the oxygen-gut dysbiosis connection, and how we might use this knowledge to improve gut health.
The human body requires oxygen for survival. But we’re only about 43 percent human.1 The other 57 percent are microbes – most of which do not tolerate oxygen very well. Fortunately, these microbes reside in the colon, which in a healthy state is a low-oxygen environment.
If the state of the gut is perturbed, however, oxygen can start to leak into the gut, beginning a vicious cycle of gut dysbiosis, cellular energy starvation, and inflammation. In this article, I’ll break down the oxygen-gut dysbiosis connection and discuss its potential implications in shaping gut treatment.
Fair warning: this one is going to be dense, as this is the culmination of several months of independent research, but it is probably one of the most important articles I’ve ever written. As always, I’ll provide a succinct summary & takeaways section at the end for anyone who just wants the actionable insights.
The healthy colon: a low oxygen environment rich in microbes
The human gut is home to a dense community of microbes. The healthy human colon contains an estimated 38 trillion bacterial cells, which are predominantly obligate anaerobes. These are bacteria that can only grow and reproduce in an environment largely devoid of oxygen. Many of these bacteria are crucial to breaking down complex carbohydrates to produce important gut metabolites like short-chain fatty acids.
The healthy colon may also contain a small number of facultative anaerobes, which are capable of growing and reproducing in an environment with or without oxygen. Facultative anaerobes include many gut pathogens. The low oxygen concentration of a healthy gut and the abundance of obligate anaerobes both suppress the growth of these facultative anaerobes.
Butyrate helps maintain “physiologic hypoxia” in the colon
One of the metabolites produced by obligate anaerobes is butyrate. Butyrate is a short-chain fatty acid (SCFA) produced when these bacteria metabolize dietary fiber in the colon. I’ve written before about the benefits of butyrate for health, including its ability to attenuate neuroinflammation, protect against colon cancer, and help maintain gut barrier function. It wasn’t until recently, however, that I learned about the role of butyrate in maintaining low gut oxygen levels.
In the healthy gut, butyrate supplies about 70 percent of the energy required by colonocytes. These are the cells that line the colon and form the gut barrier. After uptake by colonocytes, butyrate and other SCFAs are broken down in the mitochondria through a process called beta oxidation. This process utilizes large amounts of oxygen. As it turns out, this colonocyte oxygen consumption is very important to maintaining gut homeostasis.
In 2015, a research group led by Dr. Sean Colgan at the University of Colorado demonstrated that gut metabolism of butyrate was required for maintaining “physiologic hypoxia” in the colon.2 Through a series of experiments, they demonstrated that butyrate, and to a lesser extent, the SCFAs propionate and acetate, deplete oxygen levels in colonocytes. This leads to the stabilization of a protein called hypoxia-inducible factor (HIF), which acts as a sort of “oxygen sensor” in the cell. When oxygen levels are low, HIF promotes the expression of genes that help coordinate gut barrier protection. If oxygen levels rise, HIF is no longer stabilized, and these gut-protective genes are no longer expressed.
The researchers wondered whether antibiotics could affect this state of hypoxia. After just three days of broad-spectrum antibiotics, butyrate levels had dropped dramatically, gut oxygen levels had risen, and the state of epithelial hypoxia was lost. The oxygen-sensor HIF was no longer stabilized, and the gut-protective genes were no longer expressed, leading to a loss of gut barrier function.
And it wasn’t just a lack of fiber, the substrate for butyrate production. The gut microbiota of the antibiotic-treated mice had completely lost its ability to produce butyrate or other SCFAs from dietary fermentable fibers! Fortunately, they went on to find that the administration of supplemental butyrate was able to rescue the “physiologic hypoxia” and gut barrier function. But more on that later.
A microbial signature of gut dysbiosis: low abundance of butyrate producers and an expansion of facultative anaerobes
For now, we’re going to switch gears a bit. The term “gut dysbiosis” generally refers to an altered state of the gut microbiota, often associated with disease. In the last decade, advanced sequencing techniques have allowed us to characterize gut dysbiosis in hundreds of different diseases. While there are virtually infinite states of the gut microbiota that could be considered dysbiosis, there do seem to be a few patterns that are most frequently associated with disease.
In a 2017 review paper, Litvak et al. wrote:
“Perhaps the most consistent and robust ecological pattern observed during gut dysbiosis is an expansion of facultative anaerobic bacteria belonging to the phylum Proteobacteria.” 3
Proteobacteria is one of five major bacterial phyla that are commonly found in the human gut. It includes a wide variety of genera, including Escherichia, Shigella, Salmonella, Helicobacter, Vibrio, Yersinia, Pseudomonas, Campylobacter, and Desulfovibrio. Most of these are considered opportunistic pathogens – microbes that are harmless at low abundance, in the context of a balanced ecosystem, but quickly expand and cause issues when the environment becomes particularly suitable for their growth.
One environmental factor that leads to a rapid expansion of Proteobacteria is – you guessed it – oxygen. Most Proteobacteria are facultative anaerobes, meaning they can survive and reproduce in the presence of oxygen. This gives them a significant competitive advantage over beneficial obligate anaerobes in an environment that contains oxygen.
Notably, the expansion of Proteobacteria is almost always accompanied by a reduction in the abundance of butyrate-producing bacteria. This pattern – high Proteobacteria and low butyrate-producers – is a microbial signature of dysbiosis and has been associated with a number of chronic diseases, including:
- Inflammatory bowel disease4
- Irritable bowel syndrome5
- Colorectal cancer6
- Diverticulitis7
- Histamine intolerance8
- Type 2 diabetes9
- Obesity10
As we’ll learn in the next few sections, this signature also suggests an underlying epithelial dysfunction.
Epithelial cell metabolism drives gut dysbiosis
Epithelial cells are the cells that line the wall of the gut and are the primary interface for host-microbe communication. Recall from earlier that when the gut is healthy and in a state of homeostasis, colonocytes primarily metabolize fatty acids like butyrate through processes that utilize large amounts of oxygen. The resulting hypoxia (lack of oxygen) in the gut mucosa helps to maintain a gut microbiota dominated by obligate anaerobes. These obligate anaerobic bacteria in turn promote health by fermenting fiber into SCFAs like butyrate, which are absorbed by colonic epithelial cells. This positive feedback loop maintains a state of gut health.
However, when a disturbance shifts the metabolism of colonic epithelial cells away from beta oxidation of fatty acids, the system breaks down. Energy-starved colonocytes must look for other sources of energy. They end up pulling glucose from the bloodstream and fermenting it to lactate, a process that does not utilize oxygen.11 The resulting inflammation also leads to increased production of nitrate. Without anywhere else to go, oxygen, lactate, and nitrate “leak” into the gut mucosa.
This environmental change favors pathogens in the Proteobacteria phylum, such as Salmonella, Klebsiella, Citrobacter, and E. coli, which can tolerate oxygen and thrive on lactate and nitrate. At the same time, the oxygenation of the colon inhibits the growth of obligate anaerobes, including the ever-important butyrate-producers. In other words, “the metabolism of colonocytes functions as a control switch of the gut microbiota, mediating a shift between homeostatic and dysbiotic communities.” 11
So, what causes epithelial cells to make this switch that ultimately leads to gut dysbiosis? In the next few sections, I’ll discuss a few known inducers of this epithelial switch: antibiotics, infections, and a low fiber diet.
Antibiotics deplete colonic butyrate and drive oxygen leakage into the gut
Last spring, I had the pleasure of meeting Dr. Sebastian Winter, a professor of microbiology and immunology at UT Southwestern and one of the few prominent researchers trying to understand this control switch and its impact on host health.
In an animal model, Dr. Winter’s lab demonstrated in 2016 that a single dose of the antibiotic streptomycin resulted in a four-fold reduction in gut butyrate concentrations.12 This was primarily attributed to depletion of populations of Clostridia, a class of bacteria that consists of many known butyrate-producers, including Eubacterium, Roseburia, Butyrivibrio, Clostridium, Coprococcus, and Ruminococcus species.
Using a special staining technique, they went on to demonstrate that the antibiotic treatment had increased colonocyte oxygenation and resulted in a loss of hypoxia in the gut mucosa. This loss of hypoxia allowed for the oxygen-driven expansion of Salmonella and other facultative anaerobes.
Of course, Dr. Winter’s lab chose streptomycin specifically because it is particularly effective at depleting Clostridia, so that they could examine the effects of butyrate depletion on colonic metabolism. Streptomycin is not typically used orally in humans; however, many other broad-spectrum antibiotics are known to impact butyrate-producing bacteria, so it’s likely that a 1-2 week course of other antibiotics would also drive oxygen leakage into the gut via this same mechanism.
Pathogenic bacteria can hack colonocyte metabolism to promote gut dysbiosis
Certain pathogens may also exploit this colonocyte switch to gain a competitive advantage in the gut. If you’ve ever come down with an acute case of food poisoning and had trouble with your gut health afterwards, this could explain why.
In the same paper highlighted in the previous section, Byndloss et al. further demonstrated that certain strains of Salmonella (specifically Salmonella enterica serotype Typhimurium, hereafter abbreviated S. Tm) can manipulate the host epithelium to promote gut dysbiosis.12
S. Tm is a particularly virulent bacterium that invades the host mucosa, causing severe inflammation. This inflammation led to a depletion of butyrate-producing Clostridia, which further enhanced the ability of S. Tm to proliferate in the gut. In other words, this suggests that certain pathogens may “hack” gut metabolism to increase their own fitness, to the detriment of healthy bacteria.
Notably, the depletion of butyrate-producers appeared to be more gradual than with antibiotic treatment, occurring over about 1-3 weeks, but was also much slower to recover. At four weeks post-infection, the abundance of Clostridia was still two and a half orders of magnitude below baseline levels.
The inflammation induced by S. Tm also resulted in the release of reactive oxygen and nitrogen species into the gut, which reacted with simple sugars to form substrates that selectively fed S. Tm and other microbes within the Enterobacteriaceae family (Proteobacteria phylum).
This is not just true of S. Tm. In 2007, Lupp et al. demonstrated in a mouse model that Citrobacter rodentium and Campylobacter jejuni infection are also capable of causing host intestinal inflammation and driving overgrowth of Enterobacteriaceae.13
Overall, this suggests that gut infections may contribute to oxygenation of the colon and promote a prolonged state of gut dysbiosis. Thus, clearing existing infections may be a key step to restoring the normal metabolism of the gut epithelium and a healthy gut microbiota.
A low fiber diet may drive oxygen leakage and Proteobacteria expansion
So far, we’ve seen two examples where butyrate depletion led to gut oxygenation and dysbiosis. Given that the #1 source of butyrate is from dietary fiber, it’s likely that a low fiber diet could, in theory, promote the expansion of Proteobacteria via the same mechanism. If dietary fiber intake is low, butyrate and other SCFAs will not be produced at sufficient levels to provide for the energy needs of colonocytes. Colonocytes will turn to anaerobic glucose metabolism. Anaerobic metabolism will consume less oxygen and result in increased oxygen leakage into the gut.
While all of the steps in this mechanism have yet to be as elegantly demonstrated with a low fiber diet as they have for antibiotics and gut infections, several studies have indeed linked low fiber intake with higher levels of Proteobacteria:
- A large-scale comparative study among children from urban areas in Europe and children from a rural African village in Burkina Faso found that European children had higher levels of Enterobacteriaceae.14 The researchers speculated that this was due to the low fiber content in the Western diet.
- A 2009 study found that individuals on a gluten-free diet had lower relative abundance of Bifidobacterium and Lactobacillus, and higher amounts of Enterobacteriaceae. The gluten-free diet had significantly reduced the participants’ intake of polysaccharides.
What about a low carb, ketogenic diet? As I’ve discussed before, the ketone bodies acetoacetate and beta-hydroxybutyrate can supplement butyrate as a fuel source for gut epithelial cells. Thus, it’s unlikely that a low-fiber, ketogenic diet would activate this mechanism to drive gut dysbiosis. In fact, ketones might be beneficial in helping to restore epithelial hypoxia. We’ll come back to that later.
Other agents that contribute to gut inflammation may also drive gut dysbiosis
Intriguingly, all of these drivers of gut dysbiosis – antibiotics, gut infections, and a low fiber, processed diet – are associated with intestinal inflammation.
In 2007, Lupp et al. demonstrated in animal models that gut inflammation itself is enough to disrupt the gut microbiota and promote overgrowth of Enterobacteriaceae. Both exposure to dextran sodium sulfate, a chemical that disrupts gut barrier integrity, or severe genetic predisposition, via knocking out IL-10, were able to drive gut dysbiosis.13
Other, more mild inflammatory agents could also promote the expansion of these inflammatory bacteria. Chassaing et al. (2015) demonstrated that feeding mice carboxymethylcellulose and polysorbate-80, two emulsifiers commonly used in processed foods, for 12 weeks reduced microbial diversity and resulted in increased mucosa-associated Proteobacteria.15 Similarly, Palmnas et al. found that feeding rats the non-caloric sweetener Aspartame for 8 weeks resulted in increased Enterobacteriaceae.16
Stress can also promote inflammation and gut dysbiosis. Langgartner et al. reported an expansion of Proteobacteria in a mouse model for chronic psychosocial stress.17
Unrecognized food intolerances may also contribute to gut inflammation, altered colonocyte metabolism, and gut dysbiosis, though more research is needed to confirm this.
Alright, so we’ve reviewed a number of things that can cause gut hypoxia and drive gut dysbiosis. For the remainder of this article, I want to focus on things we can do to potentially interrupt this cycle and restore gut homeostasis. First up: butyrate!
Butyrate helps maintain gut hypoxia and protects against pathogen expansion after antibiotics
Ever since publishing my article on why probiotics might not be the best choice after antibiotics, I have received a lot of questions about what we can do to protect our gut health when we do have to take antibiotics.
At the time, I didn’t have a great answer. Now, having dug deeper into the research, I think there is enough evidence to suggest that butyrate supplementation might be particularly helpful! Over the next few sections, I’ll lay out the research that supports this hypothesis, and close with my recommendations for putting this into action.
In Dr. Winter’s studies mentioned above, streptomycin treatment depleted butyrate-producers and caused oxygenation of the mucosa – that is, unless the mice were treated with oral tributyrin, a form of butyrate that is targeted for release in the gut: “Remarkably, tributyrin supplementation restored epithelial hypoxia in streptomycin-treated mice and significantly increased the concentration of cecal butyrate.” 12
In the experimental infection model, tributyrin supplementation also reduced the fitness advantage of pathogenic bacteria! After streptomycin treatment alone, S. Tm had a significant competitive advantage in the gut, expanding to fill a greater percentage of the overall ecosystem. However, when tributyrin was provided orally three hours post-infection, the competitive advantage was lost.
Butyrate restores hypoxia and protects against C. difficile-induced colitis
In 2019, Fachi et al. demonstrated in a mouse model that administering butyrate alongside antibiotics could attenuate C. difficile-induced colitis.18 Clostridioides difficile (previously classified as Clostridium difficile and commonly abbreviated C. diff) is a gram-positive, spore-forming bacterium that is a common cause of intestinal infection after antibiotic use.
Supplemental butyrate was started one day before antibiotics and continued throughout the antibiotic course and 5-day infection challenge. Interestingly, butyrate had no effects on C. difficile colonization or toxin production, but through stabilizing HIF-1 and increasing gut barrier integrity, butyrate reduced intestinal inflammation and the movement of bacteria across the gut barrier.
The researchers went on to test two additional strategies for providing butyrate. High dose tributyrin administered in the three days surrounding infection was equally as protective as butyrate, as was feeding a high-fiber diet (containing a whopping 25 percent inulin) after antibiotics but prior to infection.
So clearly, butyrate protects against pathogen expansion after antibiotics. But can butyrate prevent the full spectrum of dysbiosis associated with antibiotics, by supporting colonocyte metabolism? This remains to be determined in controlled studies, but as we’ll see in the next section, the pieces certainly seem to fit together nicely.
PPAR-gamma as the control switch for colonocyte metabolism
So far, I’ve been talking rather abstractly about a “switch” in colonocyte metabolism that leads to gut dysbiosis. But it turns out that researchers have identified a particular gene, PPAR-gamma, that appears to mediate this switch. PPARs (which is short for peroxisome proliferator-activated receptors) are a group of proteins that bind to DNA to directly influence gene expression. PPAR-gamma is expressed in a number of cells but is most highly expressed in the adipose (fat) tissue and colon.
In a healthy gut, butyrate not only provides energy for colon cells, but also enhances PPAR-gamma activation. This acts a positive feedback loop: PPAR-gamma activates genes that increase metabolism of butyrate and other fatty acids. This reduces the oxygen concentration in the epithelium and gut mucosa, which inhibits the growth of pathogenic Proteobacteria and promotes the growth of beneficial, butyrate-producing bacteria.
In a dysbiotic gut, however, there is not enough butyrate or other substrates to activate PPAR-gamma. Lower PPAR-gamma expression results in increased expression of Nos2, the gene encoding inducible nitric oxide synthase (iNOS) and increased nitrate release into the gut. This, along with the lactate and oxygen from anaerobic glycolysis, fuels the growth of pathogenic bacteria.
PPAR-gamma activation is also crucial for the maintenance of gut innate immunity. A study published in the journal PNAS in 2010 demonstrated through a series of experiments that PPAR-gamma helps to maintain constant expression of the antimicrobial peptide β-defensin, which regulates microbial colonization of the colon.19 Mice that were deficient in PPAR-gamma showed defective immune defenses against Candida albicans, Bacteroides fragilis, Enterococcus faecalis, and E. coli. PPAR-gamma is also required for the production of secretory IgA.20
Could stimulating the PPAR-gamma pathway prevent or reverse gut dysbiosis?
Several studies have demonstrated that PPAR-gamma activation could potentially prevent or reverse gut dysbiosis and tissue injury associated with immune activation. For instance, PPAR-gamma expression is significantly reduced in inflammatory bowel disease (IBD).21 Rosiglitazone, a drug that binds to PPAR-gamma and increases its activity, has been shown to prevent dysbiosis and reduce symptoms of colitis in animal models, when given acutely.22 While this drug is still sometimes used in the U.S. as an antidiabetic drug, it has several unwanted side effects, and is not ideal for long-term use. Nonetheless, it demonstrates the ability of this pathway to exert significant changes on the gut microbiota.
Researchers kept looking for other options to stimulate this pathway. Another drug, mesalamine, can also activate PPAR-gamma, but to a moderate extent. It has more localized action in the gut and therefore has fewer systemic side effects. This drug is now used as the first-line treatment of IBD. Notably, the anti-inflammatory effects of this drug are mediated through its ability to upregulate PPAR-gamma.23 Moreover, controlled studies have demonstrated that mesalamine treatment reduces Proteobacteria abundance and increases the abundance of Faecalibacterium and Bifidobacterium species!24
A group of researchers in Beijing have also identified Danshensu Bingpian Zhi (DBZ) as a PPAR-gamma agonist with potential for preventing or reversing gut dysbiosis. DBZ is a synthetic version of two compounds that are naturally found in the traditional Chinese medicinal formula Fufang Danshen. DBZ was found to activate PPAR-gamma to a lesser extent than rosiglitazone and other classic thiazolidinedione drugs, yet was still able to confer significant protection against the gut dysbiosis, intestinal barrier dysfunction, insulin resistance, and body weight gain in a mouse model of diet-induced obesity.25
Butyrate supplementation has also been shown to shift the gut ecosystem in humans. A prospective, randomized, placebo-controlled study of 49 patients with IBD found that 1800 milligrams per day of butyrate not only reduced inflammation and improved quality of life, but also increased the number of butyrate-producing bacteria! After two months of supplementation, individuals with Crohn’s disease had increased abundance of Butyricoccus and Subdoligranulum, while those with ulcerative colitis had a major increase in Lachnospiraceae.26 While the researchers did not directly measure PPAR-gamma, the involvement of this pathway is likely given such a dramatic change in the abundance of butyrate producers and inflammatory markers.
Altogether, this is an incredibly intriguing area of study that will no doubt get more attention in the years to come. As Litvak et al. wrote in their recent review published in the journal Science:
“Metabolic reprogramming of colonocytes to restore epithelial hypoxia represents a promising new therapeutic approach for rebalancing the colonic microbiota in a broad spectrum of human diseases.” 11
In other words, if we can target the metabolism of colonocytes, we can restore the low oxygen environment in the gut and potentially reverse dysbiosis. I am actively pursuing research collaborations to determine whether butyrate and other PPAR-gamma agonists can prevent the full spectrum of antibiotic-induced dysbiosis.
Strategies to target PPAR-gamma and support gut hypoxia
Below is a summary of interventions that can potentially increase PPAR-gamma activity in the gut to support gut hypoxia. I believe that a combination of the following may be helpful for difficult cases of gut dysbiosis that do not respond to other treatments, particularly those characterized by high Proteobacteria and a low abundance of butyrate-producers.
Disclaimer: I write about a lot of these detailed mechanisms and pathways to help people who have tried almost everything and are still struggling with their gut health. If you don’t already have the major health behaviors in place — eating a healthy/ancestral-type diet, getting regular exercise, adequate sleep, sunlight, and healthy social interaction – this is where your focus should be.
Furthermore, the following information should NOT be taken as medical advice. Always be sure to consult with your physician or gastroenterologist about whether a particular treatment is appropriate for you.
- Mesalamine (5-ASA): this drug is commonly used as first-line treatment of IBD. It’s anti-inflammatory effects have been shown to be mediated through its ability to upregulate PPARgamma.23
- Danshensu Bingpian Zhi (DBZ): this compound is derived from tanshinol and borneol, found in the traditional Chinese medicinal formula Fufang Danshen. It upregulates PPAR-gamma, and has demonstrated potential for attenuating dysbiosis.25 Note: Herbals should be sourced and dosed carefully, ideally under the direction of a physician experienced in herbal medicine.
- Butyrate: a short-chain fatty acid and potent stimulator of PPAR-gamma. Even low concentrations of butyrate have been shown to increase PPAR-gamma protein expression by 7-fold. I typically recommend ProButyrate, though ButyCaps Tributyrin may also be a viable option (no affiliations).
- Ketones: beta-hydroxybutyrate and acetoacetate almost certainly activate PPAR-gamma in intestinal epithelial cells, just as butyrate does. A ketogenic diet has been shown to upregulate PPAR-gamma across a number of tissues and also provides substrate for beta oxidation and epithelial energy production. I am hoping to support more research in this area.
- Fasting/caloric restriction: One study found that intestinal PPAR-gamma was required for sympathetic nervous system activation during caloric restriction.27 However, the degree to which fasting or caloric restriction induces this pathway in the gut is still unclear.
- Exercise: one research group found that the protective effects of voluntary exercise on the gut in both a colitis model and a diet-induced obesity model were mediated by the ability of exercise to increase endogenous glucocorticoids in the gut and upregulate PPAR-gamma!28,29 Future studies in our lab will be studying the potential implications of exercise on this pathway.
- Stress management: stress reduces PPAR-gamma expression in the gut.20
- Cannabinoids: cannabidiol (CBD) reduced iNOS activity in rectal biopsies of patients with ulcerative colitis, an effect that was mediated through activation of PPAR-gamma.30
- Sulforaphane: a 2008 found that this phytochemical from cruciferous vegetables enhances components of innate immunity via activation of PPAR-gamma.31
- Curcumin: one study found that curcumin inhibited chemically-induced colitis in mice by activation of PPAR-gamma.32 The oral dosage required to achieve these effects is unknown.
- Other herbals: chamomile, angelica, silymarin, licorice root, and lemon balm are all partial activators of PPAR-gamma. These herbs can be taken individually but are all found within the product Iberogast, which has been shown to be clinically effective for IBS and functional GI disorders.33
- Fatty acids: Conjugated linoleic acid (CLA)34 and omega-3 fatty acids (DHA)35 both enhance expression of PPAR-gamma.
- Probiotics: In vitro studies on colonocytes have demonstrated the ability of Saccharomyces boulardii to increase PPAR-gamma expression.
- Prebiotics: in vitro studies on colonocytes have shown that the anti-inflammatory effects of the oligosaccharides alpha3-siallylactose and FOS are mediated through their ability to induce PPAR-gamma.36
- Vitamin A: retinoic acid, a form of vitamin A, is required for the activation and function of PPAR-gamma.
The importance of mitochondrial health
Mitochondria are essential to butyrate metabolism and oxygen utilization, and are therefore crucial to maintaining the low-oxygen environment of the gut. PPAR-gamma activation itself helps support the formation of new mitochondria through a process called mitochondrial biogenesis. However, supplemental nutrients like L-Carnitine, CoQ10, alpha lipoic acid, and others may also be useful to optimize mitochondrial health and oxygen consumption.
Harnessing synergy for breaking the cycle
While each of these components may be helpful on their own, there is also potential for synergism between these components. For instance, mesalamine combined with curcumin or butyrate has been shown to be more effective for the treatment of IBD than mesalamine alone.37,38
The synergistic potential of more than two components together has not yet been studied, but we might imagine that an integrative approach, using a combination of mesalamine, curcumin, DHA, and CBD to activate PPAR-gamma, butyrate and ketones to provide energy for epithelial cells, and L-carnitine to ensure these substrates actually get into the mitochondria to be utilized.
I am currently trialing such approaches in my one-on-one work with clients and will post the results once I have a chance to test this out more. Please note that these individuals are working very closely with their gastroenterologists to implement this. I am not a licensed physician and do NOT recommend using the more potent PPAR-gamma agonists without the close oversight of a medical doctor.
What about dysbiosis of the small intestine?
So far, all of the research I’ve discussed has been focused on colon metabolism and colonic dysbiosis. But we now know that small intestinal dysbiosis, rather than bacterial overgrowth, is responsible for a great deal of gut symptoms, especially the abdominal discomfort and bloating that underlies irritable bowel syndrome (IBS).
As of this writing, this metabolic switch has only been shown in the colon, or large intestine. While PPAR-gamma expression is much lower in the small intestine than the colon, it’s entirely plausible that the same switch occurs in the small intestine.
Indeed, one 2016 animal study published in PNAS found that a processed high-sugar, high-fat diet downregulated PPAR-gamma in the small intestine almost two-fold, which led to altered antimicrobial gene expression and small intestinal dysbiosis.39 This was reversed when the mice were treated for one week with rosiglitazone, a PPAR-gamma agonist.
Glutamine, an amino acid that serves as the primary fuel for small intestinal epithelial cells, has also been shown to induce PPAR-gamma40,41, much like butyrate does in the large intestine.
What about mesalamine for IBS? Several research groups have explored the off-label use of this IBD drug for treating IBS. Most studies have found fairly low efficacy for IBS symptoms; however, a recent study using a higher dosage (1500 mg once per day) for 12 weeks demonstrated significant benefit in IBS-D patients.42
As in the colon, I believe that integrative, synergistic treatments may have potential for restoring small intestinal homeostasis. It’s possible that mesalamine or DBZ combined with glutamine and ketones would be more efficacious than mesalamine alone for IBS, though this remains to be tested in controlled studies.
Regrettably, treatment of “SIBO” has largely focused on antibiotics, which often reduce symptoms in the short-term, but may further stress the gut epithelium, leading to relapse or even the worsening of symptoms in the long-term. Rather than quelling bacterial overgrowth, we need to shift our focus towards creating a gut environment that favors growth of healthy microbes.
Summary & takeaways: how this knowledge may inform treatment
That was a lot of information and nitty-gritty pathways, but hopefully you can see the enormous potential of this knowledge for shaping how we approach gut dysbiosis and disease! Below are the key takeaways from this body of research and potential ways to put this knowledge into practice:
1) An abundance of Proteobacteria and lack of butyrate-producers is a common signature of gut dysbiosis and typically indicates epithelial metabolic dysfunction and gut inflammation. There are several commercially available microbiome tests that will allow you to check your abundance of Proteobacteria and butyrate-producers.
2) Antibiotics, gut infections, low fiber intake, or stress can all deplete gut butyrate, lead to oxygen leakage into the gut, and promote gut dysbiosis. Avoiding antibiotics whenever possible, treating existing gut infections, eating plenty of fiber, and managing stress are key to supporting healthy gut metabolism and in turn, a healthy gut microbiota.
3) This new understanding of how oxygen drives gut dysbiosis directs future research and offers important insight as to how we might be able to reestablish a healthy ecosystem. In other words, if we can overcome the epithelial energy starvation and restore gut hypoxia, we may be able to restore a healthy gut ecosystem and reverse dysbiosis.
4) If you have to take antibiotics, take butyrate! Antibiotics wipe out butyrate producers, putting significant stress on the cells that line the large intestine. If we can support epithelial metabolism with supplemental butyrate until our butyrate-producers can recover, theoretically, we may be able to prevent an environment that favors opportunistic pathogens. (Likewise, supplementing with glutamine may prevent antibiotic-induced dysbiosis in the small intestine.)
5) If basic diet and lifestyle interventions are not enough, targeting PPAR-gamma and colonic energy starvation may be the key to breaking the cycle and reversing gut dysbiosis. This may be particularly useful for those with IBD and those with very stubborn “SIBO” or IBS symptoms.
6) There are numerous interventions with the potential to synergistically “reprogram” colonocytes, ranging from drug therapies to nutrients and lifestyle factors. I discussed many of the known interventions in this article but am hopeful that future research will further explore these therapies, both in isolation and in combination, to elucidate the best therapies to treat gut dysbiosis.
That’s all for now! Let me know what you think in the comments below, subscribe to my newsletter to be notified of any updates, and please share your experience if you use any of this information to improve your own health!
The oxygen-gut dysbiosis connection:
How to break the cycle of gut inflammation, dysbiosis, and epithelial energy starvation
Virtually every cell in the human body requires oxygen. That is – every human cell. Most of our microbial cells on the other hand, thrive in an environment devoid of oxygen. If oxygen leaks into the gut, it can promote bacterial imbalances and inflammation. Read on to learn more about the oxygen-gut dysbiosis connection, and how we might use this knowledge to improve gut health.
The human body requires oxygen for survival. But we’re only about 43 percent human.1 The other 57 percent are microbes – most of which do not tolerate oxygen very well. Fortunately, these microbes reside in the colon, which in a healthy state is a low-oxygen environment.
If the state of the gut is perturbed, however, oxygen can start to leak into the gut, beginning a vicious cycle of gut dysbiosis, cellular energy starvation, and inflammation. In this article, I’ll break down the oxygen-gut dysbiosis connection and discuss its potential implications in shaping gut treatment.
Fair warning: this one is going to be dense, as this is the culmination of several months of independent research, but it is probably one of the most important articles I’ve ever written. As always, I’ll provide a succinct summary & takeaways section at the end for anyone who just wants the actionable insights.
The healthy colon: a low oxygen environment rich in microbes
The human gut is home to a dense community of microbes. The healthy human colon contains an estimated 38 trillion bacterial cells, which are predominantly obligate anaerobes. These are bacteria that can only grow and reproduce in an environment largely devoid of oxygen. Many of these bacteria are crucial to breaking down complex carbohydrates to produce important gut metabolites like short-chain fatty acids.
The healthy colon may also contain a small number of facultative anaerobes, which are capable of growing and reproducing in an environment with or without oxygen. Facultative anaerobes include many gut pathogens. The low oxygen concentration of a healthy gut and the abundance of obligate anaerobes both suppress the growth of these facultative anaerobes.
Butyrate helps maintain “physiologic hypoxia” in the colon
One of the metabolites produced by obligate anaerobes is butyrate. Butyrate is a short-chain fatty acid (SCFA) produced when these bacteria metabolize dietary fiber in the colon. I’ve written before about the benefits of butyrate for health, including its ability to attenuate neuroinflammation, protect against colon cancer, and help maintain gut barrier function. It wasn’t until recently, however, that I learned about the role of butyrate in maintaining low gut oxygen levels.
In the healthy gut, butyrate supplies about 70 percent of the energy required by colonocytes. These are the cells that line the colon and form the gut barrier. After uptake by colonocytes, butyrate and other SCFAs are broken down in the mitochondria through a process called beta oxidation. This process utilizes large amounts of oxygen. As it turns out, this colonocyte oxygen consumption is very important to maintaining gut homeostasis.
In 2015, a research group led by Dr. Sean Colgan at the University of Colorado demonstrated that gut metabolism of butyrate was required for maintaining “physiologic hypoxia” in the colon.2 Through a series of experiments, they demonstrated that butyrate, and to a lesser extent, the SCFAs propionate and acetate, deplete oxygen levels in colonocytes. This leads to the stabilization of a protein called hypoxia-inducible factor (HIF), which acts as a sort of “oxygen sensor” in the cell. When oxygen levels are low, HIF promotes the expression of genes that help coordinate gut barrier protection. If oxygen levels rise, HIF is no longer stabilized, and these gut-protective genes are no longer expressed.
The researchers wondered whether antibiotics could affect this state of hypoxia. After just three days of broad-spectrum antibiotics, butyrate levels had dropped dramatically, gut oxygen levels had risen, and the state of epithelial hypoxia was lost. The oxygen-sensor HIF was no longer stabilized, and the gut-protective genes were no longer expressed, leading to a loss of gut barrier function.
And it wasn’t just a lack of fiber, the substrate for butyrate production. The gut microbiota of the antibiotic-treated mice had completely lost its ability to produce butyrate or other SCFAs from dietary fermentable fibers! Fortunately, they went on to find that the administration of supplemental butyrate was able to rescue the “physiologic hypoxia” and gut barrier function. But more on that later.
A microbial signature of gut dysbiosis: low abundance of butyrate producers and an expansion of facultative anaerobes
For now, we’re going to switch gears a bit. The term “gut dysbiosis” generally refers to an altered state of the gut microbiota, often associated with disease. In the last decade, advanced sequencing techniques have allowed us to characterize gut dysbiosis in hundreds of different diseases. While there are virtually infinite states of the gut microbiota that could be considered dysbiosis, there do seem to be a few patterns that are most frequently associated with disease.
In a 2017 review paper, Litvak et al. wrote:
“Perhaps the most consistent and robust ecological pattern observed during gut dysbiosis is an expansion of facultative anaerobic bacteria belonging to the phylum Proteobacteria.” 3
Proteobacteria is one of five major bacterial phyla that are commonly found in the human gut. It includes a wide variety of genera, including Escherichia, Shigella, Salmonella, Helicobacter, Vibrio, Yersinia, Pseudomonas, Campylobacter, and Desulfovibrio. Most of these are considered opportunistic pathogens – microbes that are harmless at low abundance, in the context of a balanced ecosystem, but quickly expand and cause issues when the environment becomes particularly suitable for their growth.
One environmental factor that leads to a rapid expansion of Proteobacteria is – you guessed it – oxygen. Most Proteobacteria are facultative anaerobes, meaning they can survive and reproduce in the presence of oxygen. This gives them a significant competitive advantage over beneficial obligate anaerobes in an environment that contains oxygen.
Notably, the expansion of Proteobacteria is almost always accompanied by a reduction in the abundance of butyrate-producing bacteria. This pattern – high Proteobacteria and low butyrate-producers – is a microbial signature of dysbiosis and has been associated with a number of chronic diseases, including:
- Inflammatory bowel disease4
- Irritable bowel syndrome5
- Colorectal cancer6
- Diverticulitis7
- Histamine intolerance8
- Type 2 diabetes9
- Obesity10
As we’ll learn in the next few sections, this signature also suggests an underlying epithelial dysfunction.
Epithelial cell metabolism drives gut dysbiosis
Epithelial cells are the cells that line the wall of the gut and are the primary interface for host-microbe communication. Recall from earlier that when the gut is healthy and in a state of homeostasis, colonocytes primarily metabolize fatty acids like butyrate through processes that utilize large amounts of oxygen. The resulting hypoxia (lack of oxygen) in the gut mucosa helps to maintain a gut microbiota dominated by obligate anaerobes. These obligate anaerobic bacteria in turn promote health by fermenting fiber into SCFAs like butyrate, which are absorbed by colonic epithelial cells. This positive feedback loop maintains a state of gut health.
However, when a disturbance shifts the metabolism of colonic epithelial cells away from beta oxidation of fatty acids, the system breaks down. Energy-starved colonocytes must look for other sources of energy. They end up pulling glucose from the bloodstream and fermenting it to lactate, a process that does not utilize oxygen.11 The resulting inflammation also leads to increased production of nitrate. Without anywhere else to go, oxygen, lactate, and nitrate “leak” into the gut mucosa.
This environmental change favors pathogens in the Proteobacteria phylum, such as Salmonella, Klebsiella, Citrobacter, and E. coli, which can tolerate oxygen and thrive on lactate and nitrate. At the same time, the oxygenation of the colon inhibits the growth of obligate anaerobes, including the ever-important butyrate-producers. In other words, “the metabolism of colonocytes functions as a control switch of the gut microbiota, mediating a shift between homeostatic and dysbiotic communities.” 11
So, what causes epithelial cells to make this switch that ultimately leads to gut dysbiosis? In the next few sections, I’ll discuss a few known inducers of this epithelial switch: antibiotics, infections, and a low fiber diet.
Antibiotics deplete colonic butyrate and drive oxygen leakage into the gut
Last spring, I had the pleasure of meeting Dr. Sebastian Winter, a professor of microbiology and immunology at UT Southwestern and one of the few prominent researchers trying to understand this control switch and its impact on host health.
In an animal model, Dr. Winter’s lab demonstrated in 2016 that a single dose of the antibiotic streptomycin resulted in a four-fold reduction in gut butyrate concentrations.12 This was primarily attributed to depletion of populations of Clostridia, a class of bacteria that consists of many known butyrate-producers, including Eubacterium, Roseburia, Butyrivibrio, Clostridium, Coprococcus, and Ruminococcus species.
Using a special staining technique, they went on to demonstrate that the antibiotic treatment had increased colonocyte oxygenation and resulted in a loss of hypoxia in the gut mucosa. This loss of hypoxia allowed for the oxygen-driven expansion of Salmonella and other facultative anaerobes.
Of course, Dr. Winter’s lab chose streptomycin specifically because it is particularly effective at depleting Clostridia, so that they could examine the effects of butyrate depletion on colonic metabolism. Streptomycin is not typically used orally in humans; however, many other broad-spectrum antibiotics are known to impact butyrate-producing bacteria, so it’s likely that a 1-2 week course of other antibiotics would also drive oxygen leakage into the gut via this same mechanism.
Pathogenic bacteria can hack colonocyte metabolism to promote gut dysbiosis
Certain pathogens may also exploit this colonocyte switch to gain a competitive advantage in the gut. If you’ve ever come down with an acute case of food poisoning and had trouble with your gut health afterwards, this could explain why.
In the same paper highlighted in the previous section, Byndloss et al. further demonstrated that certain strains of Salmonella (specifically Salmonella enterica serotype Typhimurium, hereafter abbreviated S. Tm) can manipulate the host epithelium to promote gut dysbiosis.12
S. Tm is a particularly virulent bacterium that invades the host mucosa, causing severe inflammation. This inflammation led to a depletion of butyrate-producing Clostridia, which further enhanced the ability of S. Tm to proliferate in the gut. In other words, this suggests that certain pathogens may “hack” gut metabolism to increase their own fitness, to the detriment of healthy bacteria.
Notably, the depletion of butyrate-producers appeared to be more gradual than with antibiotic treatment, occurring over about 1-3 weeks, but was also much slower to recover. At four weeks post-infection, the abundance of Clostridia was still two and a half orders of magnitude below baseline levels.
The inflammation induced by S. Tm also resulted in the release of reactive oxygen and nitrogen species into the gut, which reacted with simple sugars to form substrates that selectively fed S. Tm and other microbes within the Enterobacteriaceae family (Proteobacteria phylum).
This is not just true of S. Tm. In 2007, Lupp et al. demonstrated in a mouse model that Citrobacter rodentium and Campylobacter jejuni infection are also capable of causing host intestinal inflammation and driving overgrowth of Enterobacteriaceae.13
Overall, this suggests that gut infections may contribute to oxygenation of the colon and promote a prolonged state of gut dysbiosis. Thus, clearing existing infections may be a key step to restoring the normal metabolism of the gut epithelium and a healthy gut microbiota.
A low fiber diet may drive oxygen leakage and Proteobacteria expansion
So far, we’ve seen two examples where butyrate depletion led to gut oxygenation and dysbiosis. Given that the #1 source of butyrate is from dietary fiber, it’s likely that a low fiber diet could, in theory, promote the expansion of Proteobacteria via the same mechanism. If dietary fiber intake is low, butyrate and other SCFAs will not be produced at sufficient levels to provide for the energy needs of colonocytes. Colonocytes will turn to anaerobic glucose metabolism. Anaerobic metabolism will consume less oxygen and result in increased oxygen leakage into the gut.
While all of the steps in this mechanism have yet to be as elegantly demonstrated with a low fiber diet as they have for antibiotics and gut infections, several studies have indeed linked low fiber intake with higher levels of Proteobacteria:
- A large-scale comparative study among children from urban areas in Europe and children from a rural African village in Burkina Faso found that European children had higher levels of Enterobacteriaceae.14 The researchers speculated that this was due to the low fiber content in the Western diet.
- A 2009 study found that individuals on a gluten-free diet had lower relative abundance of Bifidobacterium and Lactobacillus, and higher amounts of Enterobacteriaceae. The gluten-free diet had significantly reduced the participants’ intake of polysaccharides.
What about a low carb, ketogenic diet? As I’ve discussed before, the ketone bodies acetoacetate and beta-hydroxybutyrate can supplement butyrate as a fuel source for gut epithelial cells. Thus, it’s unlikely that a low-fiber, ketogenic diet would activate this mechanism to drive gut dysbiosis. In fact, ketones might be beneficial in helping to restore epithelial hypoxia. We’ll come back to that later.
Other agents that contribute to gut inflammation may also drive gut dysbiosis
Intriguingly, all of these drivers of gut dysbiosis – antibiotics, gut infections, and a low fiber, processed diet – are associated with intestinal inflammation.
In 2007, Lupp et al. demonstrated in animal models that gut inflammation itself is enough to disrupt the gut microbiota and promote overgrowth of Enterobacteriaceae. Both exposure to dextran sodium sulfate, a chemical that disrupts gut barrier integrity, or severe genetic predisposition, via knocking out IL-10, were able to drive gut dysbiosis.13
Other, more mild inflammatory agents could also promote the expansion of these inflammatory bacteria. Chassaing et al. (2015) demonstrated that feeding mice carboxymethylcellulose and polysorbate-80, two emulsifiers commonly used in processed foods, for 12 weeks reduced microbial diversity and resulted in increased mucosa-associated Proteobacteria.15 Similarly, Palmnas et al. found that feeding rats the non-caloric sweetener Aspartame for 8 weeks resulted in increased Enterobacteriaceae.16
Stress can also promote inflammation and gut dysbiosis. Langgartner et al. reported an expansion of Proteobacteria in a mouse model for chronic psychosocial stress.17
Unrecognized food intolerances may also contribute to gut inflammation, altered colonocyte metabolism, and gut dysbiosis, though more research is needed to confirm this.
Alright, so we’ve reviewed a number of things that can cause gut hypoxia and drive gut dysbiosis. For the remainder of this article, I want to focus on things we can do to potentially interrupt this cycle and restore gut homeostasis. First up: butyrate!
Butyrate helps maintain gut hypoxia and protects against pathogen expansion after antibiotics
Ever since publishing my article on why probiotics might not be the best choice after antibiotics, I have received a lot of questions about what we can do to protect our gut health when we do have to take antibiotics.
At the time, I didn’t have a great answer. Now, having dug deeper into the research, I think there is enough evidence to suggest that butyrate supplementation might be particularly helpful! Over the next few sections, I’ll lay out the research that supports this hypothesis, and close with my recommendations for putting this into action.
In Dr. Winter’s studies mentioned above, streptomycin treatment depleted butyrate-producers and caused oxygenation of the mucosa – that is, unless the mice were treated with oral tributyrin, a form of butyrate that is targeted for release in the gut: “Remarkably, tributyrin supplementation restored epithelial hypoxia in streptomycin-treated mice and significantly increased the concentration of cecal butyrate.” 12
In the experimental infection model, tributyrin supplementation also reduced the fitness advantage of pathogenic bacteria! After streptomycin treatment alone, S. Tm had a significant competitive advantage in the gut, expanding to fill a greater percentage of the overall ecosystem. However, when tributyrin was provided orally three hours post-infection, the competitive advantage was lost.
Butyrate restores hypoxia and protects against C. difficile-induced colitis
In 2019, Fachi et al. demonstrated in a mouse model that administering butyrate alongside antibiotics could attenuate C. difficile-induced colitis.18 Clostridioides difficile (previously classified as Clostridium difficile and commonly abbreviated C. diff) is a gram-positive, spore-forming bacterium that is a common cause of intestinal infection after antibiotic use.
Supplemental butyrate was started one day before antibiotics and continued throughout the antibiotic course and 5-day infection challenge. Interestingly, butyrate had no effects on C. difficile colonization or toxin production, but through stabilizing HIF-1 and increasing gut barrier integrity, butyrate reduced intestinal inflammation and the movement of bacteria across the gut barrier.
The researchers went on to test two additional strategies for providing butyrate. High dose tributyrin administered in the three days surrounding infection was equally as protective as butyrate, as was feeding a high-fiber diet (containing a whopping 25 percent inulin) after antibiotics but prior to infection.
So clearly, butyrate protects against pathogen expansion after antibiotics. But can butyrate prevent the full spectrum of dysbiosis associated with antibiotics, by supporting colonocyte metabolism? This remains to be determined in controlled studies, but as we’ll see in the next section, the pieces certainly seem to fit together nicely.
PPAR-gamma as the control switch for colonocyte metabolism
So far, I’ve been talking rather abstractly about a “switch” in colonocyte metabolism that leads to gut dysbiosis. But it turns out that researchers have identified a particular gene, PPAR-gamma, that appears to mediate this switch. PPARs (which is short for peroxisome proliferator-activated receptors) are a group of proteins that bind to DNA to directly influence gene expression. PPAR-gamma is expressed in a number of cells but is most highly expressed in the adipose (fat) tissue and colon.
In a healthy gut, butyrate not only provides energy for colon cells, but also enhances PPAR-gamma activation. This acts a positive feedback loop: PPAR-gamma activates genes that increase metabolism of butyrate and other fatty acids. This reduces the oxygen concentration in the epithelium and gut mucosa, which inhibits the growth of pathogenic Proteobacteria and promotes the growth of beneficial, butyrate-producing bacteria.
In a dysbiotic gut, however, there is not enough butyrate or other substrates to activate PPAR-gamma. Lower PPAR-gamma expression results in increased expression of Nos2, the gene encoding inducible nitric oxide synthase (iNOS) and increased nitrate release into the gut. This, along with the lactate and oxygen from anaerobic glycolysis, fuels the growth of pathogenic bacteria.
PPAR-gamma activation is also crucial for the maintenance of gut innate immunity. A study published in the journal PNAS in 2010 demonstrated through a series of experiments that PPAR-gamma helps to maintain constant expression of the antimicrobial peptide β-defensin, which regulates microbial colonization of the colon.19 Mice that were deficient in PPAR-gamma showed defective immune defenses against Candida albicans, Bacteroides fragilis, Enterococcus faecalis, and E. coli. PPAR-gamma is also required for the production of secretory IgA.20
Could stimulating the PPAR-gamma pathway prevent or reverse gut dysbiosis?
Several studies have demonstrated that PPAR-gamma activation could potentially prevent or reverse gut dysbiosis and tissue injury associated with immune activation. For instance, PPAR-gamma expression is significantly reduced in inflammatory bowel disease (IBD).21 Rosiglitazone, a drug that binds to PPAR-gamma and increases its activity, has been shown to prevent dysbiosis and reduce symptoms of colitis in animal models, when given acutely.22 While this drug is still sometimes used in the U.S. as an antidiabetic drug, it has several unwanted side effects, and is not ideal for long-term use. Nonetheless, it demonstrates the ability of this pathway to exert significant changes on the gut microbiota.
Researchers kept looking for other options to stimulate this pathway. Another drug, mesalamine, can also activate PPAR-gamma, but to a moderate extent. It has more localized action in the gut and therefore has fewer systemic side effects. This drug is now used as the first-line treatment of IBD. Notably, the anti-inflammatory effects of this drug are mediated through its ability to upregulate PPAR-gamma.23 Moreover, controlled studies have demonstrated that mesalamine treatment reduces Proteobacteria abundance and increases the abundance of Faecalibacterium and Bifidobacterium species!24
A group of researchers in Beijing have also identified Danshensu Bingpian Zhi (DBZ) as a PPAR-gamma agonist with potential for preventing or reversing gut dysbiosis. DBZ is a synthetic version of two compounds that are naturally found in the traditional Chinese medicinal formula Fufang Danshen. DBZ was found to activate PPAR-gamma to a lesser extent than rosiglitazone and other classic thiazolidinedione drugs, yet was still able to confer significant protection against the gut dysbiosis, intestinal barrier dysfunction, insulin resistance, and body weight gain in a mouse model of diet-induced obesity.25
Butyrate supplementation has also been shown to shift the gut ecosystem in humans. A prospective, randomized, placebo-controlled study of 49 patients with IBD found that 1800 milligrams per day of butyrate not only reduced inflammation and improved quality of life, but also increased the number of butyrate-producing bacteria! After two months of supplementation, individuals with Crohn’s disease had increased abundance of Butyricoccus and Subdoligranulum, while those with ulcerative colitis had a major increase in Lachnospiraceae.26 While the researchers did not directly measure PPAR-gamma, the involvement of this pathway is likely given such a dramatic change in the abundance of butyrate producers and inflammatory markers.
Altogether, this is an incredibly intriguing area of study that will no doubt get more attention in the years to come. As Litvak et al. wrote in their recent review published in the journal Science:
“Metabolic reprogramming of colonocytes to restore epithelial hypoxia represents a promising new therapeutic approach for rebalancing the colonic microbiota in a broad spectrum of human diseases.” 11
In other words, if we can target the metabolism of colonocytes, we can restore the low oxygen environment in the gut and potentially reverse dysbiosis. I am actively pursuing research collaborations to determine whether butyrate and other PPAR-gamma agonists can prevent the full spectrum of antibiotic-induced dysbiosis.
Strategies to target PPAR-gamma and support gut hypoxia
Below is a summary of interventions that can potentially increase PPAR-gamma activity in the gut to support gut hypoxia. I believe that a combination of the following may be helpful for difficult cases of gut dysbiosis that do not respond to other treatments, particularly those characterized by high Proteobacteria and a low abundance of butyrate-producers.
Disclaimer: I write about a lot of these detailed mechanisms and pathways to help people who have tried almost everything and are still struggling with their gut health. If you don’t already have the major health behaviors in place — eating a healthy/ancestral-type diet, getting regular exercise, adequate sleep, sunlight, and healthy social interaction – this is where your focus should be.
Furthermore, the following information should NOT be taken as medical advice. Always be sure to consult with your physician or gastroenterologist about whether a particular treatment is appropriate for you.
- Mesalamine (5-ASA): this drug is commonly used as first-line treatment of IBD. It’s anti-inflammatory effects have been shown to be mediated through its ability to upregulate PPARgamma.23
- Danshensu Bingpian Zhi (DBZ): this compound is derived from tanshinol and borneol, found in the traditional Chinese medicinal formula Fufang Danshen. It upregulates PPAR-gamma, and has demonstrated potential for attenuating dysbiosis.25 Note: Herbals should be sourced and dosed carefully, ideally under the direction of a physician experienced in herbal medicine.
- Butyrate: a short-chain fatty acid and potent stimulator of PPAR-gamma. Even low concentrations of butyrate have been shown to increase PPAR-gamma protein expression by 7-fold. I typically recommend ProButyrate, though ButyCaps Tributyrin may also be a viable option (no affiliations).
- Ketones: beta-hydroxybutyrate and acetoacetate almost certainly activate PPAR-gamma in intestinal epithelial cells, just as butyrate does. A ketogenic diet has been shown to upregulate PPAR-gamma across a number of tissues and also provides substrate for beta oxidation and epithelial energy production. I am hoping to support more research in this area.
- Fasting/caloric restriction: One study found that intestinal PPAR-gamma was required for sympathetic nervous system activation during caloric restriction.27 However, the degree to which fasting or caloric restriction induces this pathway in the gut is still unclear.
- Exercise: one research group found that the protective effects of voluntary exercise on the gut in both a colitis model and a diet-induced obesity model were mediated by the ability of exercise to increase endogenous glucocorticoids in the gut and upregulate PPAR-gamma!28,29 Future studies in our lab will be studying the potential implications of exercise on this pathway.
- Stress management: stress reduces PPAR-gamma expression in the gut.20
- Cannabinoids: cannabidiol (CBD) reduced iNOS activity in rectal biopsies of patients with ulcerative colitis, an effect that was mediated through activation of PPAR-gamma.30
- Sulforaphane: a 2008 found that this phytochemical from cruciferous vegetables enhances components of innate immunity via activation of PPAR-gamma.31
- Curcumin: one study found that curcumin inhibited chemically-induced colitis in mice by activation of PPAR-gamma.32 The oral dosage required to achieve these effects is unknown.
- Other herbals: chamomile, angelica, silymarin, licorice root, and lemon balm are all partial activators of PPAR-gamma. These herbs can be taken individually but are all found within the product Iberogast, which has been shown to be clinically effective for IBS and functional GI disorders.33
- Fatty acids: Conjugated linoleic acid (CLA)34 and omega-3 fatty acids (DHA)35 both enhance expression of PPAR-gamma.
- Probiotics: In vitro studies on colonocytes have demonstrated the ability of Saccharomyces boulardii to increase PPAR-gamma expression.
- Prebiotics: in vitro studies on colonocytes have shown that the anti-inflammatory effects of the oligosaccharides alpha3-siallylactose and FOS are mediated through their ability to induce PPAR-gamma.36
- Vitamin A: retinoic acid, a form of vitamin A, is required for the activation and function of PPAR-gamma.
The importance of mitochondrial health
Mitochondria are essential to butyrate metabolism and oxygen utilization, and are therefore crucial to maintaining the low-oxygen environment of the gut. PPAR-gamma activation itself helps support the formation of new mitochondria through a process called mitochondrial biogenesis. However, supplemental nutrients like L-Carnitine, CoQ10, alpha lipoic acid, and others may also be useful to optimize mitochondrial health and oxygen consumption.
Harnessing synergy for breaking the cycle
While each of these components may be helpful on their own, there is also potential for synergism between these components. For instance, mesalamine combined with curcumin or butyrate has been shown to be more effective for the treatment of IBD than mesalamine alone.37,38
The synergistic potential of more than two components together has not yet been studied, but we might imagine that an integrative approach, using a combination of mesalamine, curcumin, DHA, and CBD to activate PPAR-gamma, butyrate and ketones to provide energy for epithelial cells, and L-carnitine to ensure these substrates actually get into the mitochondria to be utilized.
I am currently trialing such approaches in my one-on-one work with clients and will post the results once I have a chance to test this out more. Please note that these individuals are working very closely with their gastroenterologists to implement this. I am not a licensed physician and do NOT recommend using the more potent PPAR-gamma agonists without the close oversight of a medical doctor.
What about dysbiosis of the small intestine?
So far, all of the research I’ve discussed has been focused on colon metabolism and colonic dysbiosis. But we now know that small intestinal dysbiosis, rather than bacterial overgrowth, is responsible for a great deal of gut symptoms, especially the abdominal discomfort and bloating that underlies irritable bowel syndrome (IBS).
As of this writing, this metabolic switch has only been shown in the colon, or large intestine. While PPAR-gamma expression is much lower in the small intestine than the colon, it’s entirely plausible that the same switch occurs in the small intestine.
Indeed, one 2016 animal study published in PNAS found that a processed high-sugar, high-fat diet downregulated PPAR-gamma in the small intestine almost two-fold, which led to altered antimicrobial gene expression and small intestinal dysbiosis.39 This was reversed when the mice were treated for one week with rosiglitazone, a PPAR-gamma agonist.
Glutamine, an amino acid that serves as the primary fuel for small intestinal epithelial cells, has also been shown to induce PPAR-gamma40,41, much like butyrate does in the large intestine.
What about mesalamine for IBS? Several research groups have explored the off-label use of this IBD drug for treating IBS. Most studies have found fairly low efficacy for IBS symptoms; however, a recent study using a higher dosage (1500 mg once per day) for 12 weeks demonstrated significant benefit in IBS-D patients.42
As in the colon, I believe that integrative, synergistic treatments may have potential for restoring small intestinal homeostasis. It’s possible that mesalamine or DBZ combined with glutamine and ketones would be more efficacious than mesalamine alone for IBS, though this remains to be tested in controlled studies.
Regrettably, treatment of “SIBO” has largely focused on antibiotics, which often reduce symptoms in the short-term, but may further stress the gut epithelium, leading to relapse or even the worsening of symptoms in the long-term. Rather than quelling bacterial overgrowth, we need to shift our focus towards creating a gut environment that favors growth of healthy microbes.
Summary & takeaways: how this knowledge may inform treatment
That was a lot of information and nitty-gritty pathways, but hopefully you can see the enormous potential of this knowledge for shaping how we approach gut dysbiosis and disease! Below are the key takeaways from this body of research and potential ways to put this knowledge into practice:
1) An abundance of Proteobacteria and lack of butyrate-producers is a common signature of gut dysbiosis and typically indicates epithelial metabolic dysfunction and gut inflammation. There are several commercially available microbiome tests that will allow you to check your abundance of Proteobacteria and butyrate-producers.
2) Antibiotics, gut infections, low fiber intake, or stress can all deplete gut butyrate, lead to oxygen leakage into the gut, and promote gut dysbiosis. Avoiding antibiotics whenever possible, treating existing gut infections, eating plenty of fiber, and managing stress are key to supporting healthy gut metabolism and in turn, a healthy gut microbiota.
3) This new understanding of how oxygen drives gut dysbiosis directs future research and offers important insight as to how we might be able to reestablish a healthy ecosystem. In other words, if we can overcome the epithelial energy starvation and restore gut hypoxia, we may be able to restore a healthy gut ecosystem and reverse dysbiosis.
4) If you have to take antibiotics, take butyrate! Antibiotics wipe out butyrate producers, putting significant stress on the cells that line the large intestine. If we can support epithelial metabolism with supplemental butyrate until our butyrate-producers can recover, theoretically, we may be able to prevent an environment that favors opportunistic pathogens. (Likewise, supplementing with glutamine may prevent antibiotic-induced dysbiosis in the small intestine.)
5) If basic diet and lifestyle interventions are not enough, targeting PPAR-gamma and colonic energy starvation may be the key to breaking the cycle and reversing gut dysbiosis. This may be particularly useful for those with IBD and those with very stubborn “SIBO” or IBS symptoms.
6) There are numerous interventions with the potential to synergistically “reprogram” colonocytes, ranging from drug therapies to nutrients and lifestyle factors. I discussed many of the known interventions in this article but am hopeful that future research will further explore these therapies, both in isolation and in combination, to elucidate the best therapies to treat gut dysbiosis.
That’s all for now! Let me know what you think in the comments below, subscribe to my newsletter to be notified of any updates, and please share your experience if you use any of this information to improve your own health!
Great article, thanks Lucy.
Are there any tests out there to show if someone’s suffering from gut oxygen dysbiosis?
Hi Lucy, very interesting theory, but I’m a bit confused as to where zonulin fits into this picture? Assuming that someone has high zonulin and low butyrate levels, what would be the cause of leaky gut? Would it be due to low butyrate because of ppar-g, or due to zonulin? Does ppar-g stimulate zonulin, or is it the other way around? I don’t understand the chronological order of how this all plays out.
Congratulations for this great article!
I’m designing a treatment for my IBS-C, and I have read that E. Coli N1917 does actually down-regulate PPAR-g expression (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3515933/#!po=0.416667)
I’m taking it because of its demonstrated benefits for constipation. However I wouldn’t want to inhibit the PPAR-g pathway.
It would be wonderful to know your opinion on this.
Thank you!
I have been following Lucy’s work for the last couple years. This article definitely brings a lot of precious insights into healing dysbiosis. My case is exactly like the example she mentioned into this classic dysbiosis microbial signature. I am following this protocol and already seeing some improvement. Combining botanical broad spectrum herbs and potent nutraceuticals to help the gut come back into microbial balance and into a hypoxia state of regulation.
From Montreal, Canada
Thanks Lucy
1: how do some people thrive on a low/no fiber diet? Under normal conditions can the body produce enough SCFA/butyrate without large amounts of fiber? A lot of paleontologists have indicated that we evolved eating a meat heavy diet with little to no plant foods for periods of time.
2: can the effects of antibiotics have long lasting effects if the oxygen- gut dysbiosis is not properly addressed?
3: you mentioned in other blog posts that supplementing with butyrate can do more harm than good. If someone could not eat a lot of fiber due to food intolerances could using a low dose of tributyrin be an option?
Have really enjoyed your content and appreciate the time you put into your research
Very informative article, thank you! Fills in a piece of the GI puzzle that is very helpful.
Hi Lucy,
I take Mag O7 which is OZONATED MAG OXIDE due to constipation. Do you think this supplement can increase oxygen levels in the intestines and increase intestinal dysbiosis. I am going going to start tomorrow taking some of the abovementioned supplements and I do not want to slow down the healing process by taking Mag O7.
Fascinating article! I have chronic SIBO (have tried every treatment imaginable) and was encouraged to try Hbot therapy for it. After reading your article, I’m wondering if Hbot would be contraindicated?
We really enjoy your integrative approach and your teaching style, making primary research accessible, is excellent – thanks!
I have a question: my wife had an organic acids urine test which showed “High” butyrates – is this indicative of good levels of butyrate in the gut or is it something different? Thanks!
I stumbled on a scientific study – sodium butyrate a chemical inducer of in vivo reactivation of herpes simplex virus type 1 in the ocular mouse model. If a person is prone to severe hsv1 outbreaks do you think that butyrate supplementation could cause more outbreaks?
I stumbled on a scientific study – sodium butyrate a chemical inducer of in vivo reactivation of herpes simplex virus type 1 in the ocular mouse model. If a person is prone to severe hsv1 outbreaks do you think that butyrate supplementation could cause more outbreaks?
Can a product like SBI protect help? Or does that product possibly increase: PH?
I am trying to decide whether to take a product like that. I am not positive it is this product but twice I have taken it and get bloated and feel like it causes heartburn on an empty stomach which I don’t normally get so I wonder if it raises the pH and I got quite gassy also?
What else can we do to lower the pH of the colon? Thank you!
Great article indeed! One question, how much would parasites like cyclospora influence and maintain such dysbiosis, even if one person would have had them before antibiotic destruction of microbiota, without having any symptoms of parasite presence, but discovering it at low values in stool it during the quest for recovering from dysbiosis? Would treating the parasite with further antibiotics overweight the risk?
Great article. I find it interesting that you place great emphasis on oxygen as a source of dysbiosis and nitrate and lactate less so. Is there are reason for that based on your research? Could supplementing with lactate producing probiotics contribute to dysbiosis and would this apply equally to l-lactate and d-lactate? Curious to hear your thoughts. Thanks.
Great question! Increased leakage of oxygen, lactate, and nitrate certainly happen simultaneously when the gut is disrupted. Conceptually, “oxygen leakage” is perhaps easiest to understand, but I certainly did not intend to downplay the role of other substrates for pathogens to utilize once colon cell metabolism is disrupted. The strategies I recommend to target PPAR-gamma will decrease all of these substrates, not just mucosal oxygenation.
That’s a great question about lactate-producing probiotics. I did some searching and at least in vitro, Lactobacillus spp. seem to have a net inhibitory effect against Salmonella and other pathogens. It appears that the bacteriocins and other antimicrobial compounds secreted by Lactobacillus, in addition to its ability to drop the pH, outweighs any lactate that it might provide the S.Tm for growth: https://aem.asm.org/content/71/10/6008.short Of course, this may depend on the species and strain of Lactobacillus.
Hi Lucy, what about the supplements which contain oxygen such as magnesium oxide? Do they promote maybe intestinal dysbiosis? thanks
Hi Lampros – I’ve been asked this quite a bit and having thought about it more, I don’t think so, at least not via this mechanism. We consume water (H2O or hydrogen oxide) all the time, and many of the foods we eat contain oxygen groups, so it doesn’t make sense to me that the mere presence of oxygen in a supplement (like MgO) is going to lead to dysbiosis in the colon. The stomach and small intestine are actually fairly oxygenated in comparison to the colon. That said, in my experience, magnesium oxide is pretty harsh on the gut, and we don’t really have any studies on how it affects the gut microbiota or gut barrier function.
Great Blog thanks Lucy!
I have tried both of your suggested Butyrate sources, & with both, I notice all the white microcapsules in my BM, so assumed that they do not dissolve properly for me, so literally flushing money down the toilet :)
Would you agree that would be the case?
Thanks
Hi Lucy! You discuss glutamine as supporting the small intestinal epithelial cells, similar to the role butyrate plays in the large intestine. Do you have suggestions for how to boost glutamine production other than direct supplementation? Are there any known microbial producers of glutamine or is it only synthesized directly by the body (ie. the muscles) and through diet? Thanks for this great write-up!
Hi Peter – I like the way you’re thinking! Glutamine is produced endogenously in the body and is especially released by the muscle during times of fasting, so it’s possible that this fasted release of glutamine could provide added support to the epithelium…but it’s also a catch 22 because when you fast, you’re not getting dietary glutamine! It’s possible that intermittent fasting could maximize total glutamine, but I haven’t seen any studies to that effect. Bone and meat broths are particularly high in glutamine, so that is an option if you don’t want to supplement with isolated glutamine. To my knowledge, most microbes need glutamine, so they are more likely to consume it than produce it.
Thanks for all this information. I’m going to try adding interventions that target PPAR-gamma. If I decide to try a glutamine supplement, do you have a recommendation for dosage and timing? The studies you cite are in mice so that doesn’t give much information for humans.
Hi Sam! I can’t provide medical advice for your specific case, but most of the studies in humans that I’ve seen have used 5 grams of glutamine 2x/day as the therapeutic dose.
Hi Lucy
Are you seeing positive results with your clients that are taking the probutyrate.
Yes, I have for many!
What a great post! I love how you integrate knowledge from so many fields to solve the puzzles of the gut and the gut microbiota. I think there is still a lot of human intervention studies lacking in order to properly test out some of the alternative treatments proposed, however, your research of the literature and novel ideas definately will bring the field forward. I noticed in the section about mitochondrial health that you mention l-carnitine as a possible contributor to FA-transport. I do not know uptake of l-carnitine is in the gut epithelial cells, but many studies looking at it as a way to increase carnitine in muscle cells have failed though. There is one exception and that is when it was co-ingested with A LOT of CHO (Wall et al 2011). Somehting that suggests that insulin is necessary for the uptake into the cell. Do you know if it will be incorporated in the gut epithelial cells? And what about the products of bacterial fermentation of carnitine in the gut? Is it harmful?
Thank you for sharing your extensive review of the literature!
Thanks, Benjamin! Great question. L-carnitine does undergo active transport into intestinal epithelial cells (https://onlinelibrary.wiley.com/doi/full/10.1111/j.1365-2249.2009.03879.x). At least one older study does suggest that this might be energy-dependent, meaning it might be best if you are going to supplement, to do so with a CHO-rich meal! (https://www.sciencedirect.com/science/article/abs/pii/S001650859670015X)
As for the harmful effects of byproducts, most of this is focused on TMA (precursor to TMAO), which is primarily absorbed in the small intestine and is likely a sign of small intestinal dysbiosis. If cardiovascular risk is a particular concern, one option would be to give L-carnitine via enema, which has shown benefits in ulcerative colitis. While I don’t recommend L-CAR supplementation to everyone, I do think that if you have signs of poor mitochondrial function, the benefits to cardiovascular health and overall reduction in inflammation (both in the gut, and systemically) would likely outweigh the risks of slightly increased TMAO in many cases. Of course, everyone should do a cost/benefit analysis for their own individual case with their physician. I’m hopeful that we may see L-CAR options that are specifically targeted to the colon available in the near future that would largely negate this issue!
Hi Lucy. I have been looking everywhere for information on what triggers gene expression with gut dysbiosis. My son at age 18mths had three rounds of antibiotics in one winter. We didn’t know anything about the danger of this so followed our doctors instructions. At age 8 my extremely fit and healthy son started piling on weight. Now at age 11 he is mildly obese yet he eats only wholefoods and exercises every single day and is overall an active kid. But the weight depresses him and he asks me when his old body will come back. Have you seen any studies where the gut has healed and the obesity expression is switched off. I’m desperate to help him while he’s still growing so he’s not left with a body that will never return to how it should’ve been. Thanks for any help you can offer. Do you have any other suggestions that aren’t to do with supplements and medicaiton. We went to an integrative doctor for four years and the problem got worse.
Hi Conni! I’m sorry to hear about your struggles with your son’s health. The antibiotics certainly could have contributed to his issues with weight regulation, though there could be a multitude of factors at play here. Unfortunately, most of the studies that have been done on obesity are looking at the dysbiosis that occurs with a processed, Western diet, and how that can potentially be reversed (like the study I cited on DBZ). If he’s really got the major health behaviors in place (diet, exercise, sleep, low stress), it might be worth looking into gut testing to see if there’s something else going on there. You could also consider trying periodic therapeutic ketosis or intermittent fasting, though given his age I would definitely recommend doing this under the oversight of a physician. All the best to you both!
Methane is associated with obesity. Antibiotics deplete butyrate and we know that butyrate and methane have an inverse relationship so maybe that’s something to investigate.
It might be worth looking into mold/mycotoxins. Somewhere in his documentary, Dave Asprey talks about his obese childhood due to mold: https://moldymovie.com/movie/
Hi Lucy,
We accidentally helped our daughter achieve remission for IBD 7 years ago (she is med-free), so we appreciate information like yours that helps us understand how to maintain it. My question is about LDN – I hear about it pretty regularly. Do you think it could be included in your list of PPAR-gamma pathway stimulators?
Hi Ginger – glad to hear that your daughter was able to achieve remission! I have not seen any evidence that LDN can activate PPAR-gamma; it seems to work via a different mechanism, by blocking TLR4 activation. However, anything that reduces inflammation will support colonocyte metabolism and hypoxia, so LDN could definitely be a key component in the treatment of IBD or other conditions characterized by gut dysbiosis!
Lucy, thanks for this interesting article. I’m currently digging through the info out there to tackle my own acne and scalp condition, and this looks like a promising piece of the puzzle.
No problem, Rene – thanks so much for reading and I hope it’s helpful in your healing!
Thank you for your hard work! It is so important with this kind of information for us that suffer from stomach problems. You also make it easy to digest which is great.
Thanks for your kind words, Elin! I’m glad to hear you found it easy to digest, I know I have a tendency to get carried away with the details! :)
Great article!
Question: Do you know of when/why it would be advantageous for colonocytes to suppress the hypoxia-inducible factor?
I’m curious as to why the body would ever shut off the genes regulated by HIF if they are so important for maintaining the gut barrier integrity…
Hi Sean – that is a fantastic question and one that definitely got my mind turning! There are a few potential explanations that come to mind here. The first is that HIF is a global oxygen sensor and facilitates the delivery of oxygen and adaptation to hypoxia in a number of different tissues. The genetic code is conserved across all body tissues — the lungs also have a HIF “oxygen sensor”, but because of the local microenvironment, it operates in a very different way in the lungs than it does in the gut, turning on different sets of genes.
The second is that there is actually a radial oxygen gradient in the gut; oxygen levels are much higher at the bottom of the colonic crypt, where the stem cells differentiate than at the top of the crypt, where greater number of microbes reside (see Figure 1B of this article for a visual: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4572369/) . When epithelial cells are at the bottom of the crypt, low HIF allows for rapid proliferation and differentiation. As the cells move up the crypt, they are exposed to more oxygen and shut off the stem cell pathways, turning on other pathways instead.
As for why low HIF in the epithelial mucosa and the resulting gut barrier dysfunction would ever be beneficial, I think this is likely a case of evolutionary mismatch. While our ancestors might have come across the occasional penicillin mold in the environment, they certainly would not have encountered a 7-14 day course of isolated antibiotics or highly processed foods, and periodic fasting and ketosis would have maintained epithelial hypoxia. The only other explanation I can think of is that somehow a mild gut barrier dysfunction is beneficial during infancy, to allow for greater interaction between microbes and the immune system and development of oral tolerance. Proteobacteria does seem to dominate early in infancy until the maturation of the immune system leads to a transition to allow obligate anaerobes to dominate (https://www.tandfonline.com/doi/full/10.4161/gmic.26489).
Hello Lucy and Sean,
While I’m no scientist, I am extremely pro-active for my health by researching, such as it is. Joel Greene on Ben Greenfield answers this, I think.
Lucy, excited for new info to apply in treatment. Thanks
Thanks for sharing this insightful article! I have seen that most doctors tend to focus on low-fiber diets to treat sibo. Yet, as you mentioned, fiber is pivotal. So what can I do as a patient to fight sibo without reducing my fiber consumption?
Hi James – yes fiber is pivotal for maintaining the gut microbiota, though the approach to maintaining a healthy microbiota is not always the same as the approach for treating severe dysbiosis. In this case, you might want to eat a more moderate-fiber diet and focus on other ways to support gut epithelial cells and shift the gut ecosystem, before increasing fiber. It’s also important to recognize that SIBO has been very misunderstood, and most people with bloating, abdominal pain, etc. actually have small intestinal dysbiosis, not an increased number of bacteria. I reviewed a lot of the latest research here: https://www.lucymailing.com/what-the-latest-research-reveals-about-sibo/
Fantastic Article Lucy. You should look up the Oxygen Scavenging property of Saccharomyces Cerevisiae var Boulardii.
Reasearch in use of live yeast in Animal Husbandary………………….https://www.allaboutfeed.net/Special-focus/Yeast-Special/The-big-quest-How-does-live-yeast-work-in-animal-feed/
Thanks, Ashwin! And wow, thank you for sharing that information about S.c.v.boulardii!! This could certainly explain why it is one of the most effective probiotics for preventing antibiotic-associated diarrhea, in addition to providing symptom relief in a number of chronic gut conditions.
Interesting research article. It also points out that the natural food for ruminants being grass is most beneficial to the rumen bacteria. The yeast is a band-aid used in CAFO (confined animal feeding operations) where animals are fed un-natural diets of grains and legumes. Choose 100% grass fed and finished, it’s healthiest for both humans and cattle :)
Also a big thanks to you Lucy for your dedication and research.
Mark Grignon
Lucy, (my name is Lucy as well). I am a Yale trained MD with a focus in integrative medicine. Please keep going! I know how much work you put into this.
It shows, it’s real, It’s well thought out. It deserves more attention. It deserves more research that perhaps you will do. Maybe it won’t gain you 1,000 “likes” or 1,000 new Facebook friends but such is not the meaning of professional life nor the purpose of true research.
It will help people.
Thanks for the kind words, Lucy! I truly appreciate it and certainly hope that it will help this topic to gain more attention in research and in clinical practice!
Absolutely fabulous – i have just started a histamine elimination diet after a green light prostate TURP surgery (no connection) except i used butyrate from vegetables to offset the impact of the antibiotic. I am also taking ProButyrate with the diet. In the run up to the surgery i stopped prostate meds and all supplements (including detox supplements which I thought were the cause of getting very hot and sweaty at night) But still got hot/sweaty which led me to explore histamine intolerance. Finally after 10 years with the elimination of all grains and on the SCD diet with variations, and long standing leaky gut, which has not been fully successful, I may be on the right path.
Perfect timing with this post Lucy, thanks
peter
Thanks for reading, Peter! I struggled with histamine intolerance for several years as well, but focusing on gut health made a huge difference to me. I’m glad you found this post helpful to you on your health journey!
Thanks so much for this, Lucy! I so appreciate your depth of knowledge, and the work you put into synthesizing it all for yourself and for us. It is a true service! A question – does this change your recommendation NOT to take butyrate supplements for IBD? Are you recommending them only after antibiotics still?
Thanks, Julie! Great question – I do recommend butyrate supplements for IBD, just at a lower dosage. I am planning to update my butyrate articles very soon, as there have been some new clinical trials on butyrate for IBD. In the meantime, ProButyrate is typically the product I recommend (no affiliation) because it is a low dose and targeted specifically to the colon.
What dosage do you suggest for butyrate, when there is active inflammation in IBD? Thank you, great article!