The oxygen-gut dysbiosis connection

What high Proteobacteria really means, and how to break the cycle of gut inflammation and dysbiosis

By Lucy Mailing, PhD | Last updated September 2026

Virtually every cell in the human body requires oxygen. That is, every human cell. Most of our microbial companions, however, thrive in environments without oxygen. When excess oxygen leaks into the gut, it disrupts the balance of the ecosystem, increasing Proteobacteria, reducing butyrate-producers, and promoting inflammation, often leading to stubborn gut symptoms. 

The human body requires oxygen for survival. But the most recent estimates suggest that we’re only about 43 percent human.¹ The other 57 percent of us is made up of microbes – most of which do not tolerate oxygen very well. Fortunately, these microbes reside in the colon, which is naturally 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, energy starvation, and inflammation. In this article, I’ll break down the oxygen-gut dysbiosis connection and discuss the implications for how we might approach 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, without all of the scientific details.

The short version: In a healthy colon, gut bacteria make butyrate. Butyrate is consumed by the cells that line the colon, in a process that uses up oxygen, keeping the colon low in oxygen. That low-oxygen state is what beneficial bacteria need to thrive. When anything disrupts that cycle, oxygen leaks into the gut, allowing opportunistic bacteria to grow. This kicks off a self-sustaining cycle of inflammation, oxygen leakage, and dysbiosis.

How I came across this research

This article was first published in 2019. Back then, I was finishing up my PhD work at the University of Illinois when I heard a fascinating lecture by Dr. Sebastian Winter on his visit to campus. I went in expecting an interesting hour on Salmonella, and came out with an entirely new perspective on the gut microbiome.

It finally seemed to answer so many of my longstanding questions about gut health: Why do antibiotics induce long-term shifts in the microbiome? Why can a single food poisoning episode leave someone with IBS for years? Why do so many patients relapse after antimicrobial treatments? How can we sustainably reverse severe gut dysbiosis in an individual once it has occurred?

For the months after, I felt compelled to explore this research further and share the implications it could have for gut health treatment. I spent several months digging into the research, culminating in this article.

Now in 2026, I’ve revisited it to include a few recent studies that only strengthened its core message, along with a few new sections on gut redox, fungal overgrowth, stress, and creatine, and a reorganized therapeutics section. I’ve also made a few minor corrections along the way. It will continue to be a living document, so please be sure to subscribe for updates, and a huge thank you to everyone who has shared it widely or commented with their results.

The healthy colon: a low oxygen environment rich in microbes

The human colon is home to a dense microbial community, with an estimated 38 trillion bacterial cells (along with some fungi, archaea, and viruses). When we talk about the “gut microbiome”, we are most often talking about the colon, where bacteria are most abundant.

Most are obligate anaerobes, bacteria that thrive in low-oxygen environments and break down fiber into short-chain fatty acids (SCFAs). The key butyrate producers belong to a class called Clostridia, which includes genera like Faecalibacterium, Roseburia, Eubacterium, and Coprococcus. 

A smaller minority of bacteria are facultative anaerobes, which can grow and reproduce with or without oxygen present. In the gut, most of these belong to the family Enterobacteriaceae, which includes microbes like E. coli, Klebsiella, and Citrobacter. These are normal residents of the gut, typically making up less than one percent of the community, and only become opportunistic pathogens when conditions change in their favor. This same family also includes true pathogens like Salmonella.

In a healthy colon, oxygen levels remain low, and the presence of obligate anaerobes helps suppress the growth of facultative anaerobic species. Obligate anaerobes also produce SCFAs like butyrate, which serves as fuel for the cells that form the gut barrier.

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 ferment 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 the oxygen-dysbiosis connection.

In the healthy gut, butyrate supplies about 70 percent of the energy required by colonocytes, the cells that line the colon and form the gut barrier. After entering the colonocyte, butyrate and other SCFAs are broken down through a process called beta oxidation, which takes place in the mitochondria and utilizes large amounts of oxygen. Turns out that this utilization of oxygen is very important to maintaining gut homeostasis.

In 2015, a research group at the University of Colorado demonstrated that gut metabolism of butyrate was required for maintaining “physiologic hypoxia” (low oxygen) 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 essentially acts as the “oxygen sensor” of the cell. When oxygen levels are low, HIF is stabilized and 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, oxygen levels had risen, and 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”, rescuing HIF stabilization and gut barrier function. But more on that later.

A microbial signature of gut dysbiosis: low butyrate producers and high facultative anaerobes

The term “gut dysbiosis” refers to an altered state of the gut microbiota, often associated with disease. In the last decade, scientists have cataloged the gut microbiome across hundreds of different diseases. While there are no universal patterns of dysbiosis in terms of particular species, one broader signature appears to be consistent across numerous chronic, inflammatory diseases: high Proteobacteria.

“Perhaps the most consistent and robust ecological pattern observed during gut dysbiosis is an expansion of facultative anaerobic bacteria belonging to the phylum Proteobacteria.” – Litvak et al. 2017 ³

Proteobacteria, formally renamed Pseudomonadota in 2021, is one of the major bacterial groups (phyla) in the human gut, and includes microbes like Escherichia, Shigella, Salmonella, Vibrio, and Yersinia. Most labs and clinicians still say Proteobacteria, and so will I. Within that phylum, the group that actually drives the story in this article is the Enterobacteriaceae we met above.

A key factor driving their expansion? Oxygen. As facultative anaerobes, Enterobacteriaceae can respire oxygen when it’s available, which lets them grow quickly. This gives them a significant advantage over beneficial obligate anaerobes when oxygen levels rise. (Note: oxygen rarely rises alone, as we’ll see later. Inflammation increases nitrate and other alternative electron acceptors that these bacteria utilize as well.)

Their expansion is almost always also accompanied by a decline in butyrate-producing bacteria. This “microbial signature” of gut dysbiosis, high Proteobacteria and low butyrate-producers, has been found across numerous chronic conditions, including inflammatory bowel disease (IBD), irritable bowel syndrome (IBS), colorectal cancer, diverticulitis, type 2 diabetes, obesity, and histamine intolerance.^4-10

As we’ll see in the next section, this microbial signature often reflects a deeper issue: gut epithelial metabolic dysfunction.

Epithelial cell metabolism drives gut dysbiosis

The human colon is lined with a single-cell thick layer of epithelial cells, also known as colonocytes. In a healthy gut, colonocytes consume butyrate for energy through a process (mitochondrial beta-oxidation) that consumes oxygen. This helps maintain a low-oxygen (i.e. hypoxic) environment in the gut lumen, supporting a microbiota dominated by beneficial obligate anaerobes.

This creates a positive feedback loop that reinforces gut homeostasis:

1. Obligate anaerobes produce butyrate.
2. Colonocytes consume butyrate in a process that uses oxygen.
3. The gut remains hypoxic (low-oxygen), which keeps obligate anaerobes happy and suppresses facultative anaerobic pathogens.

However, when colonocyte metabolism is disrupted, whether due to antibiotics, inflammation, or other stressors, this loop breaks down. Energy-starved colonocytes switch away from fatty acid oxidation and are forced to begin utilizing glucose from the bloodstream instead. This shift to anaerobic glycolysis consumes little oxygen and results in the production of lactate.¹¹

At the same time, inflammation ramps up production of nitrate. Without the usual oxygen demand, excess oxygen, lactate, and nitrate begin to leak into the gut lumen.

This new environment, richer in oxygen and alternative electron acceptors, alters the redox potential of the gut. This oxidized environment gives a competitive edge to facultative anaerobic pathogens like Salmonella, Klebsiella, Citrobacter, and E. coli, which can tolerate oxygen and thrive on lactate and nitrate. Meanwhile, beneficial obligate anaerobes, including key butyrate-producers, are suppressed by the oxygenation of the gut.

This creates a different feedback loop:

1. Butyrate levels drop (due to antibiotics, low fiber)
2. Energy-starved colonocytes begin consuming glucose in a process that does not consume oxygen.
3. Oxygen, lactate, and alternative electron acceptors leak into the gut lumen, suppressing obligate anaerobes and fueling the growth of opportunistic facultative anaerobes.

In short, the energy metabolism of the gut lining acts as the primary control switch for the microbiome between healthy and dysbiotic.¹¹

So, what causes epithelial cells to make this switch that ultimately leads to gut dysbiosis? Next, we’ll explore the common disruptors that trigger this metabolic switch: antibiotics, infections, and low-fiber diets.

Antibiotics deplete colonic butyrate and drive oxygen leakage into the gut

Broad-spectrum antibiotics are notorious for indiscriminately wiping out gut bacteria, including major butyrate-producers. In a 2016 animal study, Dr. Bäumler’s lab at UC Davis demonstrated that a single dose of the antibiotic streptomycin resulted in a fourfold reduction in gut butyrate levels.¹² This was primarily due to the depletion of Clostridia—a class of bacteria that includes many key butyrate-producers, like Eubacterium, Roseburia, and Coprococcus.

Using a special staining technique, they showed that antibiotic treatment increased oxygen levels in colonocytes and disrupted mucosal hypoxia. The resulting oxygen leakage into the gut lumen allowed oxygen-tolerant pathogens to expand rapidly.

It’s worth noting that streptomycin was chosen precisely because of its strong impact on Clostridia—making it ideal for studying the effects of butyrate depletion. It’s not commonly used orally in humans. However, many broad-spectrum antibiotics are known to impact butyrate-producing bacteria, suggesting that other antibiotics may cause a similar breakdown in epithelial metabolism and oxygen balance. Some antibiotics may also damage colonocyte mitochondria directly (more on that below).

Pathogenic bacteria can hack colonocyte metabolism to promote gut dysbiosis

Certain pathogens may also exploit colonocyte metabolism to gain a competitive advantage in the gut. In the 2016 paper from Dr. Bäumler’s lab I mentioned earlier, the research group demonstrated that certain pathogens (specifically Salmonella enterica serotype Typhimurium, hereafter abbreviated S. Tm) can manipulate the host epithelium to promote gut dysbiosis.¹²

S. Tm is a virulent bacterium that invades the intestinal mucosa, triggering severe inflammation. This inflammation depletes butyrate-producing Clostridia and leads to the release of reactive oxygen and nitrogen species, which react with simple sugars to form substrates that selectively feed not only S. Tm itself, but also support the growth of other Proteobacteria. Similar studies have been done with Citrobacter rodentium and Campylobacter jejuni.¹³

Notably, the depletion of butyrate-producers induced by an infectious bacterium appeared to be much 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.

Dr. Andreas Bäumler and Dr. Sebastian Winter’s labs have also shown that during active inflammation, the host actively pumps out antimicrobial oxidants, like hydrogen peroxide, into the gut lumen.^33,43 Unfortunately, many pathogens are equipped with an enzyme called catalase, which allows them to break down that hydrogen peroxide and convert it directly into oxygen.

In other words, some pathogens can “hack” host metabolism: by inducing inflammation and reducing production of butyrate, they alter the gut environment in ways that promote their own growth.

Overall, this suggests that acute gut infections (i.e. food poisoning) may contribute to oxygenation of the colon and promote a prolonged state of gut dysbiosis and gut symptoms (including post-infectious irritable bowel syndrome, or PI-IBS), Clearing any lingering pathogens promoting inflammation and restoring epithelial energy metabolism may both be necessary for recovery.

A low fiber diet may drive oxygen leakage and Proteobacteria expansion

We’ve now seen how antibiotic use and gut infections can deplete butyrate, leading to oxygen leakage and dysbiosis. But there’s another, much more common factor that may trigger the same cascade: a low fiber diet.

Since dietary fiber is the primary raw material for butyrate production, inadequate intake of fiber starves colonocytes of the fuel they need for mitochondrial respiration. They must then switch to anaerobic glucose metabolism, which consumes much less oxygen. As a result, oxygen begins to leak into the gut, driving dysbiosis.

For years, observational studies have linked low fiber intake to an expansion of facultative anaerobes. A large comparative study of children in Europe vs. rural Burkina Faso found that European children on a low-fiber Western diet had significantly higher levels of Enterobacteriaceae .¹⁴ A 2009 study found that individuals on a gluten-free diet had increased Enterobacteriaceae and reduced Faecalibacterium prausnitzii, likely driven by a drastic reduction in their intake of dietary polysaccharides.⁶¹

Recent work has helped to elucidate the mechanism. A 2025 study published in Gut Microbes found that the fermentable fiber inulin promoted colonic hypoxia and stabilized HIF in gut epithelial cells.⁴⁴ Notably, this only happened when the microbiota was present to ferment the fiber, as germ-free and antibiotic-treated animals showed no effect. This is the same pathway Kelly et al. identified in 2015, when they showed butyrate stabilizes epithelial HIF and strengthens gut barrier function.²

In other words, dietary fiber isn’t just food for gut microbes. It also acts as a signal that drives host oxygen consumption and keeps the colonic surface hypoxic.³⁶

What about a low carb, ketogenic diet? As I’ve written previously, ketone bodies like acetoacetate and beta-hydroxybutyrate can serve as alternative fuels for gut epithelial cells. For this reason, it’s unlikely that a well-formulated ketogenic diet would trigger this same oxygen leakage mechanism. In fact, ketones may actually help restore epithelial hypoxia! (More on that later.)

Stress drives oxidative leakage in the gut

Stress doesn’t just affect your mood; it also fundamentally alters the metabolism of your gut lining. This may explain why periods of high anxiety or emotional trauma can trigger or exacerbate conditions like IBS and IBD.

In 2017, Langgartner et al. reported a rise in Proteobacteria in a mouse model of chronic psychosocial stress.¹⁷ More recently, a 2022 study authored by my former labmate Dr. Jacob Allen and colleagues demonstrated that psychological and social stress induces a robust “pro-oxidative” state directly within colonic epithelial cells.⁴⁵

When the body experiences chronic stress, the host’s nervous and endocrine systems trigger the gut lining to upregulate specific genes like Nos2, which generates excess nitrate, and Duox2, which produces reactive oxygen species (ROS). Just like the oxygen leakage caused by antibiotics or an energy-starved colonocyte, this stress-induced surge of nitrate and ROS floods the gut lumen. Proteobacteria and other facultative anaerobes thrive on these exact inflammatory byproducts, making chronic stress a direct stimulator of their growth.

This stress-induced metabolic shift also actively compromises the gut barrier and thins the gut mucus layer.⁴⁵ Other work has found that elevated cortisol and stress hormones not only stimulate the growth of pathogens, but also enhance their ability to adhere to the mucosal tissue.

Physiological stress, such as sleep deprivation, also triggers this same cascade. A landmark 2020 study published in Cell found that sleep-deprived mice accumulate reactive oxygen species specifically in the gut.⁴⁶ The effect was first identified in fruit flies, where neutralizing gut ROS with oral antioxidants allowed the animals to survive normal lifespans despite sleep deprivation.

Whether the stress is psychological or physiological, it appears to flip the same metabolic switch, oxygenating the colon and driving dysbiosis. Most of this work is in animals, so more research is needed in humans. But it’s worth noting, because sleep and stress management are the interventions most often skipped in favor of diet and supplements, and for some people they may be the primary thing keeping the gut trapped in this cycle.

Certain medications and supplements interfere with colonocyte metabolism directly

So far, most of the causes we’ve covered so far of the oxygen-dysbiosis cycle work by depleting butyrate or by triggering inflammation. In this section, I want to cover a few that may act on the colonocyte itself.

Note that this section is more based on mechanistic reasoning: we know these compounds can impair mitochondrial function, and we know they increase Proteobacteria, but nobody has yet measured gut oxygen levels in people taking them.

Metformin: While metformin has become popular in the functional medicine space for blood sugar regulation and longevity, it inhibits mitochondrial complex I. In liver cells, this reduces oxygen consumption and shifts cells toward glycolysis. If the same happens in colonocytes, it would impair their ability to metabolize butyrate and consume oxygen. The microbiome data are consistent with this. While metformin may have a net benefit on the gut in people with uncontrolled diabetes, it has been associated with gut dysbiosis in healthy humans.

I’ve seen this play out in practice as well. A few years ago, a doctor referred an older gentleman to me who had spent two months with chronic diarrhea and had recently been diagnosed with lymphocytic colitis, having had no gut issues prior to that. When we dove into his history, I learned that he had started taking metformin for longevity reasons a few months before the onset of his colitis. After I explained that the drug could be interfering with his butyrate metabolism, he discontinued the metformin and his colitis soon resolved.

Berberine is an herbal supplement that works through the same mechanism, and has more substantial microbiome data. Two human trials found berberine depletes butyrate producers and enriches certain Proteobacteria, the same signature of dysbiosis highlighted in this article.

Read more in my articles: The dark side of metformin and The dark side of berberine.

Some antibiotics can also interfere with mitochondria, which means they can instigate this cycle in multiple ways. A 2013 study published in Science Translational Medicine found that clinically relevant doses of bactericidal antibiotics, specifically quinolones, aminoglycosides, and beta-lactams, caused mitochondrial dysfunction and ROS overproduction in mammalian cells, with damage to DNA, proteins, and membrane lipids. Fluoroquinolones were the worst offenders, inhibiting key mitochondrial enzymes and causing loss of mitochondrial DNA. Tetracyclines did not trigger ROS or cause DNA damage, but can still impair mitochondrial function by blocking mitochondrial protein synthesis, since mitochondria descend from ancient bacteria and still use bacterial-type ribosomes.

We are still learning how the medications we take reshape the gut, and I suspect it will be a significant area of research over the next decade.

Other agents that contribute to gut inflammation may also drive gut dysbiosis

Inflammation itself can also promote dysbiosis. In 2007, Lupp et al. showed that gut inflammation, triggered chemically or via genetic knockout, was sufficient to disrupt microbial balance and drive overgrowth of Enterobacteriaceae.¹³

Other, more subtle inflammatory agents may also fuel dysbiosis. For example:

• Chassaing et al. found that feeding mice the emulsifiers carboxymethylcellulose and polysorbate-80 for 12 weeks reduced microbial diversity and increased mucosa-associated Proteobacteria.¹⁵
• Palmnäs et al. showed that rats given the non-caloric sweetener aspartame for 8 weeks had increased Enterobacteriaceae.¹⁶

Unrecognized food sensitivities and histamine reactions may also promote inflammation and drive dysbiosis, though the loss of hypoxia is less well-established. However, foods that trigger a localized immune response in your gut can induce ROS, which could plausibly increase Proteobacteria.

Altogether, these findings reinforce a core idea: anything that inflames the gut or disrupts epithelial metabolism has the potential to oxygenate the colon and tip the microbiome toward dysbiosis.

The fungal connection: how a loss of gut hypoxia drives Candida overgrowth

While the bulk of the “oxygen-dysbiosis” research is on Proteobacteria, loss of hypoxia may also drive opportunistic yeast overgrowth. Candida species are highly oxygen-tolerant, and their populations in the gut are controlled by colonization resistance, the ability of butyrate-producing bacteria and other key commensals to take up space and essentially crowd them out.

A recent study by the Bäumler lab showed that antibiotics deplete beneficial gut bacteria, increase gut oxygen levels, and disrupt the ability of the gut to resist colonization by C. albicans.⁴⁷ Restoring gut hypoxia (using mesalamine, an IBD medication we’ll talk more about later), was able to prevent the post-antibiotic surge in fungal growth. (Read my full deep-dive here.)

This also explains why simply using antifungal herbs or prescription antifungals often fail to keep Candida away long-term. To more permanently crowd out yeast, you have to restore the hypoxic environment.

Two other reasons for high Proteobacteria: PPIs and iron supplementation

Before we assume that elevated Enterobacteriaceae or Proteobacteria on a stool test is due to this oxygen-dysbiosis mechanism, it’s important to rule out a few other common drivers that can raise these opportunists:

Proton pump inhibitors. Stomach acid is a key habitat filter in the gut (a factor that helps shape the gut ecosystem). PPIs, a common medication used for acid reflux, can suppress stomach acid. This allows bacteria to survive the stomach and colonize further down, and has been associated with small and large intestinal dysbiosis. PPI users have been found to have reduced diversity, depletion of major butyrate-producing families, and increases in E. coli and other Enterobacteriaceae.⁴⁸

Iron supplements. Enterobacteriaceae are very good at scavenging iron, which they use as a direct substrate for growth. Supplemental iron has been associated with expanded Enterobacteriaceae and reduced Bifidobacterium.⁴⁹ Interestingly, gentler forms of iron may not make much difference here: in a head-to-head trial, ferrous bisglycinate increased Enterobacteriaceae even at a third of the dose of ferrous sulfate, suggesting that better GI tolerance doesn’t always translate to a healthier microbiome. Food sources of heme iron (like red meat, liver, and shellfish) are worth prioritizing first, since they’re well absorbed. When supplementation is necessary, consider using the lowest effective dose, taking it alongside fermentable fiber⁵⁰ and possibly supplementing with apolactoferrin.⁵¹

Importantly, neither of these rules out the oxygen mechanism. Researchers have not directly measured gut hypoxia in individuals taking PPIs or oral iron, or looked at these as a cause in controlled studies. That said, reduced butyrate production and expanding Enterobacteriaceae are a primary way that the cycle starts, so PPI or iron use may be enough to initiate it, after which it can sustain itself.

Either way, if PPI or iron use is present, it’s worth addressing these as possible root causes of high Proteobacteria first.

Restoring homeostasis by restoring gut energy metabolism

Alright, so we’ve reviewed a number of things that can cause loss of 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.

Most of these work in one of two ways: supplying the colonocyte with fuel, or improving its ability to use it. First up: butyrate!

Butyrate helps maintain gut hypoxia and protects against pathogen expansion after antibiotics

Let’s return to Dr. Bäumler’s research. As mentioned earlier, streptomycin treatment depleted butyrate-producing microbes and led to oxygenation of the gut mucosa. But here’s the key finding: when mice were given oral tributyrin (a gut-targeted form of butyrate), epithelial hypoxia was restored, and cecal butyrate levels significantly increased.¹²

This effect extended to infection models as well. In mice infected with S. Typhimurium after streptomycin treatment, tributyrin supplementation reduced the pathogen’s competitive advantage. Without butyrate, S. Tm rapidly expanded in the gut. But when tributyrin was provided just three hours post-infection, that advantage disappeared.

Similarly, Fachi et al. (2019) found that butyrate supplementation during antibiotics could reduce the severity of colitis caused by Clostridioides difficile.¹⁸ 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. They found that 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.

This finding suggests that restoring epithelial energy metabolism with butyrate can directly limit the expansion and virulence of facultative pathogens in a post-antibiotic environment.

For more on how to protect your gut during and after antibiotics, see my complete guide to post-antibiotic recovery.

PPAR-gamma as the control switch for colonocyte metabolism

So far, I’ve referred to a metabolic “switch” in colonocytes that contributes to gut dysbiosis. This switch is largely mediated by a transcription factor called PPAR-gamma.

Transcription factors like PPARs (peroxisome proliferator-activated receptors) are proteins that regulate gene expression by binding to DNA. PPAR-gamma, in particular, is highly expressed in the colon.

In a healthy gut, butyrate doesn’t just fuel colonocytes—it also activates PPAR-gamma. PPAR-gamma enhances the cells’ ability to metabolize butyrate and other fatty acids. This creates a positive feedback loop: butyrate activates PPAR-gamma, which boosts fatty acid oxidation, consuming oxygen and reinforcing hypoxia. The hypoxic environment favors beneficial obligate anaerobes (including butyrate-producers) and suppresses facultative pathogens.

In a dysbiotic gut with low butyrate, however, PPAR-gamma signaling is reduced. Colonocytes shift to glycolysis and begin leaking oxygen, lactate, and nitrate, which fuel the growth of pathogens. Lower PPAR-gamma also drives up expression of a gene called Nos2, contributing to nitrate accumulation—another competitive advantage for pathogens like E. coli and Salmonella.⁵²

A 2017 study in Science from the Bäumler lab demonstrated this directly. The researchers bred mice whose gut epithelial cells couldn’t produce PPAR-gamma at all. Knocking out the gene was enough: luminal oxygen and nitrate rose, and E. coli expanded in the gut. Losing this single switch in the gut lining was sufficient to produce the dysbiosis pattern.⁵²

But PPAR-gamma’s role doesn’t stop at metabolism. It also supports innate immune defenses. PPAR-gamma is required for proper production of secretory IgA²⁰ and antimicrobial peptides like β-defensin.¹⁹ Mice deficient in PPAR-gamma have impaired defenses against Candida albicans, Bacteroides fragilis, Enterococcus faecalis, and E. coli.

In short: PPAR-gamma is a central regulator of both colonocyte metabolism and gut immune defense—and represents a promising therapeutic target for restoring gut homeostasis.

Could stimulating the PPAR-gamma pathway prevent or reverse gut dysbiosis?

Several studies suggest that activating PPAR-gamma could be a promising strategy for preventing or reversing gut dysbiosis and intestinal injury.

For instance, PPAR-gamma expression is significantly reduced in inflammatory bowel disease (IBD)²¹ and PPAR-gamma agonists (substances that activate this pathway) have shown therapeutic benefits. Rosiglitazone, a thiazolidinedione drug that binds and activates PPAR-gamma, has been shown to prevent dysbiosis and reduce acute colitis symptoms in animal models.²² Rosiglitazone is rarely prescribed today, having largely been abandoned after cardiovascular safety concerns, though it’s the agonist most of this research used. Pioglitazone, the PPAR-gamma agonist still in common clinical use, has been shown in animal models to reduce colitis severity, improve gut permeability, and lower Escherichia-Shigella abundance, though no one has directly measured whether it restores gut hypoxia.⁵³

Mesalamine (5-ASA), a first-line IBD treatment, also activates PPAR-gamma. Because it acts locally in the gut rather than systemically, it avoids the side effects that limit the thiazolidinediones: weight gain, fluid retention, and fracture risk with pioglitazone, and the cardiovascular concerns that led to rosiglitazone’s decline. Notably, mesalamine’s anti-inflammatory effects are known to be mediated in part through PPAR-gamma activation.²³ In the same 2017 study I mentioned previously, mice whose butyrate producers had been wiped out by antibiotics were treated with 5-ASA. It restored epithelial hypoxia and blunted the E. coli expansion.⁵² Clinical studies show mesalamine reduces Proteobacteria and increases beneficial species, like Faecalibacterium and Bifidobacterium, in patients with inflammatory bowel disease.²⁴

Researchers are also investigating natural compounds that activate PPAR-gamma. For example, a team in Beijing identified a synthetic compound called Danshensu Bingpian Zhi (DBZ)—derived from components of the traditional Chinese formula Fufang Danshen—as a PPAR-gamma agonist. Although weaker than rosiglitazone, DBZ still provided significant protection against dysbiosis, gut barrier dysfunction, insulin resistance, and weight gain in a mouse model of diet-induced obesity.²⁵

There’s also evidence that butyrate itself activates PPAR-gamma. In a randomized, placebo-controlled trial of 49 patients with IBD, daily supplementation with 1800 mg of butyrate reduced inflammation, improved quality of life, and increased the abundance of butyrate-producing bacteria!²⁶ While the researchers didn’t directly measure PPAR-gamma expression, the microbial and clinical shifts strongly suggest involvement of this pathway.

Altogether, this is an incredibly intriguing area of study that will no doubt get more attention in the years to come.

Litvak et al. wrote in a 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, stimulating PPAR-gamma may be part of the answer to gut recovery in a wide range of conditions.

Strategies to target PPAR-gamma and support gut hypoxia

Below is a summary of interventions that may help activate PPAR-gamma in the gut and restore the hypoxic environment necessary for microbial balance. These strategies may be particularly useful in stubborn cases of dysbiosis, especially those characterized by high Proteobacteria and low butyrate producers.

Important: I write about these mechanisms for individuals who have already addressed foundational lifestyle habits but are still struggling with gut health. If you’re not yet sleeping well, eating a nutrient-dense diet, getting regular movement, managing stress, and have purpose and community, start there.

This information is educational and not medical advice. Always consult your physician or gastroenterologist before beginning any new treatment, especially pharmaceutical or herbal interventions.

• Mesalamine (5-ASA): A standard first-line IBD medication. Its anti-inflammatory effects are well-documented to be mediated through PPAR-gamma activation.²³  (Note: Periodic kidney function monitoring is standard, and caution is warranted with concurrent NSAID use. A small subset of people also experience paradoxical worsening of colitis symptoms. This is a prescription medication and should be used under a physician’s supervision.)
• Butyrate: A short-chain fatty acid and endogenous stimulator of PPAR-gamma. I recommend delayed-release, colon-targeted forms like ProButyrate or Tributyrin-X (no affiliations).
• Ketones and Fasting: A ketogenic diet or targeted fasting induces the body to produce endogenous ketones (beta-hydroxybutyrate and acetoacetate).²⁷ These can serve as alternative fuels for colonocytes and help maintain gut hypoxia when butyrate is low. This highlights the importance of overall metabolic flexibility; the better your body can switch between fuel sources, the better your gut lining can adapt to stress and prevent oxidative leakage. Exogenous ketones may similarly help to provide fuel for colonocytes when gut butyrate production is compromised, though research is limited. Read more here on how ketogenic diets and metabolic flexibility can support gut health. 
• Curcumin: A polyphenol isolated from turmeric that activates Nrf2 while simultaneously inhibiting NF-kappaB (the master inflammatory switch). One study found that curcumin inhibited chemically-induced colitis in mice by activation of PPAR-gamma.³²
• Omega-3 fatty acids: DHA-derived metabolites act as direct ligands of PPAR-gamma that help to resolve inflammation and support membrane fluidity in the colonic epithelium. In one study the DHA metabolite 4-hydroxy-DHA was identified as a potent PPAR-gamma agonist and alleviated symptoms in a colitis model.³⁵
• Milk thistle (silymarin): a gut-friendly herb that can neutralize reactive oxygen species and activate Nrf2, which in turn supports PPAR-gamma expression. One of its constituents, isosilybin A, has also been identified as a direct partial PPAR-gamma agonist. In animal models of colitis, silymarin increases the antioxidant capacity of colonic tissue and reduces inflammatory cytokines.
• Urolithin A: a microbiome-derived metabolite from pomegranates and berries that activates Nrf2 (and PPAR-gamma as a result). In mouse models of colitis, urolithin A enhanced gut barrier function and reduced intestinal permeability and inflammation through Nrf2. Only an estimated 40-50 percent of people have the gut bacteria to produce meaningful amounts from dietary precursors. It can also be taken as a supplement (MitoPure, no affiliation).
• Sulforaphane: this phytochemical from cruciferous vegetables is a potent activator of the Nrf2 pathway, and has been shown to increase antimicrobial peptide release in isolated human colonic epithelial cells via the Vitamin D receptor and PPAR-gamma signaling.³¹ 
• 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 are mediated by the ability of exercise to increase endogenous glucocorticoids in the gut and upregulate PPAR-gamma.^28,29

The importance of mitochondrial

health

Mitochondria are central to butyrate metabolism and oxygen utilization in colonocytes. Without healthy mitochondria, butyrate may not be effectively used to maintain gut hypoxia and epithelial integrity.

PPAR-gamma activation itself supports mitochondrial health by promoting mitochondrial biogenesis, the process of creating new mitochondria. This helps colonocytes meet their high energy demands and maintain oxidative metabolism, which consumes oxygen and protects against dysbiosis.

Targeted mitochondrial support may offer additional benefits. The micronutrients mentioned above are also critical to mitochondrial health. Additional key nutrients to consider include:

• L-Carnitine: Helps transport butyrate and other fatty acids into the mitochondria for metabolism

• CoQ10: Supports mitochondrial electron transport and ATP production

• Alpha-lipoic acid: A mitochondrial antioxidant that helps recycle other antioxidants and improve energy metabolism

It’s also important to avoid the known inhibitors of mitochondrial function we discussed earlier (e.g. metformin, berberine, NSAIDS).

Optimizing mitochondrial function may enhance the ability of colonocytes to use butyrate, ketones, or creatine efficiently—further supporting gut barrier health and microbial balance.

Other requirements for healthy epithelial cells

Gut epithelial cells turn over every 3 to 5 days, a process that requires a lot of energy and foundational building blocks. These include:

• Bioavailable protein: Protein provides the structural components for tight junctions (proteins between epithelial cells), protective mucus, and the enzymes required to burn butyrate in mitochondria.

• Micronutrients: Cells depend on vitamins (B2, B3) and minerals (magnesium, iron, copper) to run the processes that consume oxygen and maintain gut hypoxia. Others, like zinc and vitamin A, are required for mucosal immunity. Gut inflammation can also contribute to malabsorption, leading to deficiencies in these crucial nutrients that help maintain cellular health.

• Freedom from cellular stress: Systemic toxins like mycotoxins and heavy metals can directly inhibit mitochondrial function and induce intracellular oxidative stress. If colonocytes are being taxed constantly by systemic stressors, true gut restoration will stall no matter how perfect your diet or supplement routine is.

Creatine: An emerging tool for gut epithelial energy and mitochondrial support

Creatine has recently emerged as a valuable adjunct for supporting cellular energy metabolism, particularly under conditions of stress or inflammation. Well known for its role in muscle performance, creatine also plays a critical role in supporting cellular energy in the gut.

A 2020 study ​​published in Gastroenterology found that colonocytes rely on creatine to help maintain energy production and barrier integrity during stress.⁵⁶ Cells with inadequate creatine shifted into a glycolysis-predominant, pro-inflammatory metabolic state, whereas adequate creatine preserved oxidative metabolism and reduced metabolic stress.

This is particularly relevant in the context of dysbiosis, where mitochondrial function is often impaired, and energy-starved epithelial cells leak oxygen into the gut lumen—fueling inflammation and the expansion of Proteobacteria.

By helping epithelial cells meet their energy needs and maintain the low-oxygen environment that supports anaerobic microbes, creatine complements other metabolic supports like butyrate and ketones. It may be especially helpful in protocols aimed at restoring gut homeostasis after antibiotic use, chronic inflammation, or persistent barrier dysfunction.

Read more: Creatine: it’s about time we talked about it for gut health.

What about probiotics? S. boulardii and soil-based strains as potential oxygen scavengers

You might be wondering where probiotics fit into this picture. Most probiotics do not directly activate colonic PPAR-gamma in vivo. However, they can potentially approach the oxygen-dysbiosis cycle from a different angle: by scavenging oxygen from the lumen.

In 2024, the Bäumler lab found that a probiotic E. Coli strain (E. coli Nissle 1917, or EcN) can act as a biological “oxygen sink.”⁴⁷ EcN is a facultative anaerobe and aggressively consumed excess oxygen that had leaked into the gut lumen. By scavenging this oxygen, it restored gut hypoxia, starving out pathogenic Proteobacteria (like Salmonella) and creating a low-oxygen environment for native obligate anaerobes to recover.⁵⁸

While EcN, available commercially as the product Mutaflor,  can be very helpful for some people and has some evidence in ulcerative colitis and IBS-C, I’ve seen mixed results and side effects in practice.

However, other better-tolerated probiotics may be able to achieve a similar (albeit slower) oxygen-scavenging effect:

• Saccharomyces boulardii: In a previous article covering this research, I proposed the hypothesis that this probiotic yeast may also function as a biological oxygen sink in the gut. While EcN consumes oxygen rapidly and blooms more quickly, S. boulardii may act as a slower, more sustained oxygen consumer. A 2024 study (Yang et al.) demonstrated that S. boulardii directly accelerates oxygen consumption in the neonatal gut, facilitating the colonization of strict anaerobic bacteria and protecting against pathogens.⁵⁷ While this was in early-life animal models, S. boulardii has also been shown to help facilitate the return of native diversity and support the gut environment after a major disturbance, like a course of antibiotics or gastroenteritis (stomach bug) in other models, and in humans. The food industry has used Saccharomyces yeasts in active packaging for decades specifically to consume ambient oxygen and prevent spoilage. (Note that S. boulardii is stool-forming and is not a good choice for those that tend towards constipation.)

• Bacillus species: certain soil-based, spore-forming probiotics may also have this oxygen-scavenging ability. Species like Bacillus subtilis, Bacillus coagulans, and Bacillus clausii are facultative anaerobes that can consume oxygen. (As I note in my guide to soil-based probiotics, not all probiotics are the same, and many soil-based strains used commercially are not well studied. Always choose strains with established safety profiles and human clinical evidence.)

Importantly, these probiotics do not colonize the human gut, but instead act as “transitional pioneers” of the ecosystem — they provide the temporary scaffolding that scavenges oxygen and allows for the return of native butyrate producers, if the rest of the conditions are right. In the study I mentioned above, protection against Salmonella required both oxygen-consuming bacteria and spore-forming anaerobes. Neither worked on their own.⁵⁸

Redox balance: the deeper story behind oxygen-gut dysbiosis

Throughout this article, I’ve been focusing on oxygen, because it provides a simple way to understand what happens when gut energy metabolism breaks down. But what I’m really talking about here is redox balance.

Redox (reduction-oxidation) balance refers to the exchange of electrons between host cells, the immune system, microbes, and dietary substrates in the gut.

A reduced environment, low in both oxygen and other electron acceptors, supports beneficial anaerobes in the gut, while keeping opportunistic pathogens in check.

If the gut becomes inflamed, immune cells activate enzymes that produce reactive oxygen species (ROS). This shifts the gut to an oxidized environment, which favors more pro-inflammatory, opportunistic pathogens.

It’s worth noting that low levels of ROS production is intentional and protective. The gut lining releases reactive oxygen species as part of innate immune defense. But high levels can cause damage, impair gut barrier function, and crucially, can be co-opted by pro-inflammatory bacteria. Because of this, managing redox balance can help address the cycle of inflammation and dysbiosis.

Polyphenols as key reducing agents

Polyphenols are compounds found in many brightly colored plant foods. Their poor absorption is one of their greatest strengths for gut health, bypassing the small intestine and arriving in the colon in significant amounts.

Polyphenols act as strong reducing agents because they easily give up electrons to reactive oxygen species and unstable free radicals. They can also act as prebiotics, feeding beneficial bacteria and supporting their growth.

Some polyphenols also activate the Nrf2 pathway in the gut lining, which switches on the cell’s own antioxidant enzymes.  Several of the botanicals listed as PPAR-gamma activators work in this way. Curcumin, milk thistle, urolithin A, and sulforaphane are all Nrf2 activators.

Here’s how to incorporate these:

• Polyphenol-rich foods: emphasize deeply colored plant foods daily, such as wild blueberries, pomegranate, dark cherries, green tea, and high-cacao dark chocolate.
• Targeted supplements: if dietary intake is limited, pomegranate husk powder, quercetin, or curcumin can provide a more concentrated dose of polyphenols. For this use case, I recommend avoiding  liposomal or “highly bioavailable” formulas, which are absorbed before reaching the colon.

Others with potential:

A few other antioxidants may play a role in the colon, but the evidence is more limited. High-dose vitamin C can reach the colon (small intestinal absorption saturates above about 200 mg) and two small pilot studies found shifts toward butyrate-producing families.⁵⁹˒⁶⁰ Riboflavin similarly spills over into the colon above about 25 mg, and Faecalibacterium prausnitzii is known to use it as an electron shuttle to survive at the mucosal surface. Glutathione supports redox balance more systemically, and is often depleted in the gut lining in IBD, though quality human trials are lacking. (If you do use glutathione, I recommend liposomal or S-acetyl forms, rather than N-acetyl cysteine, which can be more easily utilized by sulfate-reducing bacteria to form hydrogen sulfide.)

Harnessing synergy for breaking the cycle: restoring epithelial energy metabolism

While each of these components may be helpful on their own, there is also great potential for synergism between these components.

For example, mesalamine combined with curcumin or butyrate has been shown to be more effective for treating IBD than mesalamine alone.³⁷,³⁸ And in the oxygen research itself, germ-free animals were only protected against Salmonella only when oxygen scavenging probiotics and butyrate producers were present together.⁵⁸

The synergistic potential of more than two components together has not yet been studied, but we could imagine using a combination that might include:

• Butyrate, creatine, and ketones to fuel epithelial energy metabolism

• L-carnitine, and CoQ10, in addition to a nutrient-dense diet and possibly a good multivitamin, to support cellular and mitochondrial health and utilization of those fuels

• Mesalamine or curcumin to activate PPAR-gamma

• S. boulardii or Bacillus clausii to scavenge oxygen

• Polyphenols to reduce ROS in the colon and feed beneficial bacteria

This is the multi-targeted approach I use in my one-on-one work with clients, in collaboration with their physician or gastroenterologists. Though I’d love to perform more formal research on this someday, early observations and client feedback have been very encouraging.

Reminder: I am not a licensed physician and only recommend using more potent PPAR-gamma agonists with the close oversight of a medical doctor.

What about dysbiosis of the small intestine?

So far, we’ve focused primarily on colonic metabolism and dysbiosis. But small intestinal dysbiosis—rather than a simple numerical bacterial overgrowth—is increasingly recognized as a major driver of gut symptoms, particularly in irritable bowel syndrome (IBS).

It is important to note that the small intestine operates under different rules than the colon. While the colonic environment is defined by strict hypoxia, the small intestine is naturally higher in oxygen, relying more on motility, gastric acid, bile acid signaling, and antimicrobial peptides as “habitat filters” to regulate its microbiome.

As of this writing, the epithelial metabolic “switch” has only been clearly demonstrated in the colon. That said, PPAR-gamma is also expressed in the small intestine (albeit at lower levels), and a similar host-driven metabolic mechanism may be at play.

In fact, a 2016 animal study published in PNAS found that a high-fat, high-sugar Western diet downregulated small intestinal PPAR-gamma in mice nearly twofold.³⁹ This was associated with altered expression of antimicrobial genes and clear small intestinal dysbiosis, effects that were reversed when the mice were treated with a PPAR-gamma agonist (rosiglitazone).

We also know that glutamine, the preferred fuel source for small intestinal epithelial cells, can induce PPAR-gamma expression—similar to how butyrate functions in the colon.⁴⁰,⁴¹ This makes glutamine a compelling candidate for supporting small intestinal epithelial function and barrier integrity. (Note: While glutamine can be a powerful tool for small bowel lining repair, it should be used cautiously in patients sensitive to glutamate conversion or those with active autoimmune flares).

NSAIDs may work against this same system. Heavy use of NSAIDs is known to initiate damage in the lining of the small intestine, depleting ATP and increasing gut permeability. This is thought to be due to their ability to uncouple mitochondrial oxidative phosphorylation in small intestinal epithelial cells.⁵⁴ Notably, giving volunteers glucose and citrate alongside indomethacin prevented the permeability increase entirely, presumably by supplying the cells lining the gut with enough fuel to keep running.⁵⁵  Whether this also disrupts the small intestinal habitat filters that regulate the small intestinal microbiome hasn’t been directly tested, but antimicrobial peptide production depends on enterocyte energy, so I think it’s a reasonable hypothesis.

What about mesalamine? As a known 5-ASA PPAR-gamma agonist, mesalamine has been explored off-label for IBS with mixed results. Standard low-dose trials often failed, though one trial using 1,500 mg once daily for 12 weeks showed significant improvements in patients with diarrhea-predominant IBS (IBS-D).⁴²

As with the colon, I believe that integrative, synergistic treatments hold promise for restoring small intestinal homeostasis. A combination of targeted PPAR-gamma activation (via mesalamine or DBZ), enterocyte fuel (glutamine), and ketones may be more effective than any single agent alone.

Regrettably, standard treatment of “SIBO” remains locked in a “kill-centric” mindset. While repeated courses of antibiotics may offer short-term symptom relief, they risk further stressing the gut epithelium, increasing the likelihood of relapse. Rather than perpetually trying to kill bacteria, we need to shift our focus towards creating a gut environment that naturally maintains a healthy microbial balance.

For more on this, see my articles: Time for a new chapter focused on the gut environment and A critical appraisal of the SIBO hypothesis.

Summary & takeaways: how this knowledge may inform treatment

That was a lot of information and nitty-gritty pathways, but hopefully you can see the exciting potential of this knowledge for shaping how we approach gut dysbiosis and disease! Here are the key takeaways from this research and potential ways to put this knowledge into practice:

1) High Proteobacteria and low butyrate-producers—a common signature of gut dysbiosis—typically indicates epithelial metabolic dysfunction and gut inflammation. This pattern can be seen on several commercially available microbiome tests and should be viewed as a readout of host cellular health.

2) Antibiotics, gut infections, low fiber intake, or psychological stress can all deplete gut butyrate and allow oxygen leakage into the gut—shifting the microbiota toward a dysbiotic, inflammatory state. Avoiding unnecessary antibiotics, treating existing infections, eating a nutrient-dense diet, and managing stress are key to supporting healthy gut metabolism.

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. 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 without relying on aggressive antimicrobials. Rather than perpetually trying to kill bacteria, we can shift our focus toward creating a gut environment that naturally maintains a healthy microbial balance.

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. Supplemental butyrate can support the gut epithelium until our native butyrate-producers can recover by maintaining an environment that limits opportunistic pathogens.

5) Creatine may be another powerful tool in restoring epithelial energy. Creatine helps buffer cellular energy demands during stress, supports mitochondrial efficiency, and may preserve the low-oxygen gut environment that protects against dysbiosis. Consider it alongside butyrate and ketones in energy-supportive gut protocols.

6) Scavenging luminal oxygen can help give native microbes a chance. Polyphenols act as reducing agents in the gut. Similarly, certain probiotics may consume oxygen as they pass through, providing a window for native anaerobes to recover.

7) If basic diet and lifestyle interventions are not enough, targeting PPAR-gamma may be key. This metabolic switch plays a central role in determining whether the gut supports health or inflammation. A combination of partial PPAR-gamma activators (like targeted botanical blends), energy substrates (butyrate, ketones, creatine), and mitochondrial nutrients may offer synergistic benefits, particularly for those with IBD or stubborn “SIBO”/IBS symptoms.

8) 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 at its metabolic root.

That’s all for now! If you found this helpful, feel free to share your thoughts in the comments and subscribe for future updates. I’d also love to hear how this information has impacted your own gut health journey.