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 August 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, promoting inflammation and often leading to unpleasant symptoms. In this article, I explore the oxygen-gut dysbiosis connection, with a look at how cellular energy metabolism supports gut barrier integrity, microbial balance, and overall homeostasis. I also discuss various interventions that might be harnessed to help break the cycle.

This article was originally published in 2019, and updated in August 2026 with new research on gut redox balance, fungal colonization resistance, stress, and creatine, along with a few new therapeutic options. It’s one of the most-read pieces I’ve written, and one I still refer to regularly when working with clients.

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. Others, like Bacteroides, produce mostly propionate and acetate, which the butyrate producers then cross-feed on.

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 a single family, Enterobacteriaceae, which includes E. coli, Klebsiella, Citrobacter, Enterobacter, and Proteus. 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, and helps activate gut barrier protective pathways.

Importantly, oxygen doesn’t so much kill beneficial obligate anaerobes so much as it just puts their growth on pause. That distinction is key, because it offers hope that it can be reversed, if the environmental conditions are fixed.

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 arrives alone, as we’ll see later. Inflammation supplies nitrate and other alternative electron acceptors that these bacteria exploit alongside it.)

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.

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

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. 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.

Altogether, this suggests a mechanism by which acute gut infection (i.e. food poisoning) can drive prolonged dysbiosis and gut symptoms, a condition commonly known as post-infectious irritable bowel syndrome (PI-IBS). Restoring epithelial energy metabolism may therefore be key to gut 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, likely driven by a drastic reduction in their intake of dietary polysaccharides.

Recent work is filling in the mechanism. A 2025 study published in Gut Microbes found that the fermentable fiber inulin promoted colonic hypoxia and activated a low-oxygen sensor in gut epithelial cells called Hypoxia-Inducible Factor 1 (HIF-1), which switches on genes that support the gut barrier and mucus layer. Crucially, this only happened when the microbiota was present to ferment the fiber. 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.

In other words, dietary fiber isn’t just food for gut microbes. When fermented into butyrate, it acts as a signal that drives host oxygen consumption and keeps the colonic surface hypoxic.

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.)

Psychological stress drives oxidative leakage

Psychological stress doesn’t just affect your mood; it fundamentally alters the physical metabolism of your intestinal lining.

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. When the body experiences chronic stress, the host’s nervous and endocrine systems trigger the gut lining to upregulate specific genes like Nos2 and Duox2.

Nos2 is the gene responsible for generating excess nitrate, while Duox2 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. Because Proteobacteria and other facultative anaerobes thrive on these exact inflammatory byproducts, chronic stress acts as a direct stimulator for the growth of opportunistic pathogens.

Furthermore, this stress-induced metabolic shift actively compromises the gut barrier, leading to a thinning of the protective mucus layer and a measurable increase in bacterial translocation (often referred to as “leaky gut”). Other recent literature confirms this mechanism, noting that elevated cortisol and stress hormones not only stimulate the growth of pathogens but also enhance their ability to adhere to the mucosal tissue.

This explains why periods of high anxiety or emotional trauma can trigger or exacerbate conditions like IBS and IBD. The psychological stress itself is flipping the metabolic switch, keeping the microbiome trapped in an oxygenated, dysbiotic loop.

Interestingly, severe physiological stress, such as sleep deprivation, triggers this same cascade. A landmark 2020 study published in Cell found that sleep-deprived mice accumulate reactive oxygen species specifically in the gut. The effect was first identified in fruit flies, where neutralizing gut ROS with oral antioxidants allowed the animals to survive normal lifespans despite ongoing sleep deprivation. Whether the stress is emotional or physiological, it appears to flip the same metabolic switch, oxygenating the colon and driving dysbiosis.

This is worth sitting with, because sleep and stress management are the interventions most often skipped in favor of supplements, yet for some people it may be the primary thing generating oxidative stress in the gut.

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 similarly promote inflammation and drive dysbiosis. Foods that trigger a localized immune response in your gut can induce ROS, increase oxygen flux into the lumen, and potentially feed 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 I’ve largely focused on Proteobacteria, since this is where the bulk of the research has been, it’s also very common for individuals with a loss of gut hypoxia and high Proteobacteria to also suffer from the overgrowth of opportunistic Candida (yeast) species. Candida species are highly oxygen-tolerant.

A recent study by the Bäumler lab showed that antibiotics deplete beneficial gut bacteria, increased gut oxygen levels, and disrupt the ability of the gut to resist colonization by C. albicans. 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

If you see elevated Enterobacteriaceae alongside low butyrate producers on a stool test, it’s tempting to infer the mechanism described above. Before assuming that, it’s worth ruling out two common drivers that raise Proteobacteria by entirely different routes:

Proton pump inhibitors. Stomach acid is one of the gut’s most important habitat filters. Suppressing it allows bacteria from the mouth and upper GI tract survive the stomach and colonize further down, and it increases the chance of small or large intestinal dysbiosis. PPI users show reduced diversity, depletion of major butyrate-producing families, and increases in E. coli and other Enterobacteriaceae.

Researchers have not yet measured gut oxygen levels in PPI users, so we don’t know whether this feeds into the cascade described above. But depleting butyrate producers is one of the primary ways this cycle starts, so I’d consider it likely. And while stomach acid often recovers after stopping PPIs, the microbiome doesn’t often bounce back immediately. Once butyrate producers are depleted and Enterobacteriaceae have expanded, the cycle described in this article can keep it going on its own. In this case, PPI use may have been the initiating event, but the oxygen-dysbiosis cycle is what maintains it.

Supplemental iron. Iron is a direct growth substrate for Enterobacteriaceae, which are very good at scavenging it. Oral iron, especially ferrous sulfate at higher doses, has been associated with expanded Enterobacteriaceae and reduced Bifidobacterium. If you’re supplementing iron and seeing high Proteobacteria, it’s worth addressing iron availability first. If you need to supplement, the most useful levers are the lowest effective dose and consuming fermentable fiber alongside it, which has been shown to partially offset iron-induced shifts in the microbiota. Apolactoferrin, an iron-binding protein, may also be helpful by sequestering free iron, and may even help facilitate absorption.

Neither of these rules out the oxygen mechanism, and they often coexist with it. But if present, they are worth addressing 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

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.

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.

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.

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. 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.

Direct, luminal activators

These act directly inside the gut lumen to activate the receptors on the apical (top) side of the colonocytes.

• 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).

Key metabolic modulators

These work from the bloodstream (basolateral side) or via systemic metabolic shifts when the lumen is too compromised.

• Ketones and Fasting: A ketogenic diet or targeted fasting induces the body to produce endogenous ketones (beta-hydroxybutyrate and acetoacetate). 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. 
• 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

Botanical and dietary modulators

Plant compounds that act as direct ligands or indirect upregulators of the PPAR-gamma pathway, often by activating Nrf2 or calming tissue inflammation.

• Curcumin: A natural polyphenol isolated from turmeric that activates Nrf2 while simultaneously inhibiting NF-kappaB (the master inflammatory switch). It acts as a frontline, gut-soothing compound. One study found that curcumin inhibited chemically-induced colitis in mice by activation of PPAR-gamma.³²
• Conjugated linoleic acid (CLA): CLA activates both PPAR-gamma, and dietary CLA has been shown to protect against experimental inflammatory bowel disease.³⁴ It’s worth noting that supplemental CLA is typically a mix of isomers, and the t10,c12 isomer has been linked to insulin resistance and increased oxidative stress in human trials. The naturally occurring form in grass-fed dairy and beef is predominantly the c9,t11 isomer, so I’d favor food sources here.
• 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, 4-hydroxy-DHA, a metabolite of 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 quench 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 colitis models, silymarin increases the antioxidant capacity of colonic tissue and reduces inflammatory cytokines. Beyond the colon, silymarin also supports the liver-gut axis.
• Urolithin A: a microbiome-derived metabolite from ellagitannins in pomegranates and berries known for enhancing mitochondrial health and strengthening gut barrier integrity. Urolithin A activates Nrf2, and there’s evidence that Nrf2 in turn supports PPAR-gamma expression, though this specific chain hasn’t been directly demonstrated in colonocytes. While estimates vary across studies and populations, it’s believed that only an estimated 30-40 percent of people have the gut bacteria that can produce meaningful amounts of this compound. It can also be taken as a supplement (MitoPure, no affiliation).
• Cannabinoids (CBD): Cannabidiol (CBD) has been shown to reduce iNOS (inducible nitric oxide synthase) activity in rectal biopsies of ulcerative colitis patients, a direct anti-inflammatory effect mediated through activation of PPAR-gamma.³⁰
• Sulforaphane: this phytochemical from cruciferous vegetables is a famously potent activator of the Nrf2 pathway, shown to increase antimicrobial peptide release from isolated human colonic epithelial cells via the vitamin D receptor and PPAR-gamma signaling.³¹ (Note: While powerful, sulforaphane is a potent sulfur-containing compound and may cause cramping, gas, or irritation in an inflamed gut. It is best reserved for maintenance or introduced at very low doses.)

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: Facilitates the transport of fatty acids into mitochondria for beta-oxidation

• 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 known inhibitors of mitochondrial function:

• Berberine and metformin: While these are popular in the functional medicine and longevity space, they inhibit mitochondrial complex I, impairing the colonocyte’s ability to burn butyrate and consume oxygen. Two human trials found berberine depletes butyrate producers and enriches γ-Proteobacteria. And while metformin may have a net benefit in uncontrolled diabetes, in healthy humans it has been associated with gut dysbiosis. Read more in my articles: The dark side of metformin and The dark side of berberine.
• NSAIDs work on the epithelium in a similar way. They uncouple mitochondrial oxidative phosphorylation in the cells lining the gut, depleting ATP and increasing intestinal permeability. This mitochondrial effect, rather than prostaglandin inhibition, appears to be what initiates the damage. Notably, giving volunteers glucose and citrate alongside indomethacin prevented the permeability increase entirely, presumably by supplying the enterocyte with enough fuel to keep running.

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 have one of the highest turnover rates in the body, replacing themselves every 3 to 5 days. To continuously rebuild the gut barrier and actively consume oxygen, they require a constant supply of foundational building blocks:

• Bioavailable protein: Protein provides the structural components for tight junctions (proteins between epithelial cells), protective mucus, and the very mitochondrial enzymes required to burn butyrate. If you under-consume bioavailable protein or struggle with poor digestion (like low stomach acid), the gut barrier cannot physically rebuild itself, no matter how much butyrate is present.

• Micronutrients: To run the metabolic processes that consume oxygen and maintain gut hypoxia, cells depend on B-vitamins (riboflavin, niacin) and minerals (magnesium, iron, copper). Others, like zinc and vitamin A, are required for mucosal immunity. Because chronic gut inflammation inherently causes malabsorption, many people lack the chemical cofactors (“spark plugs”) needed to maintain a healthy cellular environment.

• Freedom from cellular stressors: Finally, host cells cannot heal if they are constantly facing cellular threat. Systemic toxins (mycotoxins, heavy metals, etc.) directly inhibit mitochondrial respiration and induce massive 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 2021 study ​​published in Gastroenterology found that colonocytes rely on creatine to help maintain energy production and barrier integrity during stress. Cells with inadequate creatine shifted into a glycolysis-predominant, pro-inflammatory metabolic state, whereas creatine supplementation helped preserve oxidative metabolism and reduce 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 standard bacterial probiotics do not directly activate colonic PPAR-gamma in vivo. However, they do approach the oxygen-dysbiosis cycle from a completely different angle: by scavenging oxygen directly from the lumen.

A 2024 study published in Cell Host & Microbe demonstrated that the probiotic strain E. coli Nissle 1917 (EcN) acts as a biological “oxygen sink.” Because it is a facultative anaerobe and possesses high-affinity enzymes designed to rapidly capture oxygen, it aggressively consumes excess oxygen that has leaked into the gut lumen. By scavenging this oxygen, it restores the hypoxic environment, starving out pathogenic Proteobacteria (like Salmonella) and creating a safe, low-oxygen niche for native obligate anaerobes to recover.

While EcN (found in 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. This may be due to the fact that EcN is gram-negative and the rapid growth increases the levels of lipopolysaccharide (LPS) in the gut.

I instead recommend achieving a similar (albeit slower) oxygen-scavenging effect with these gentler, better-tolerated alternatives:

• Saccharomyces boulardii: In a previous article, I proposed the hypothesis that this probiotic yeast may also function as a biological oxygen sink in the gut. Unlike the explosive bacterial growth of E. coli, S. boulardii may act as a steady, sustained eukaryotic oxygen buffer. While conducted in early-life animal models, 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. This may be in part why 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). The food industry has also 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: this oxygen-scavenging may also be present in soil-based, spore-forming probiotics. Species like Bacillus subtilis, Bacillus coagulans, and Bacillus clausii are facultative anaerobes that possess complete respiratory chains. When Bacillus spores germinate into active cells in the gut, their “oxygen-capturing capability” rapidly consumes local oxygen, creating the exact low-oxygen niche required for strict, oxygen-sensitive native anaerobes to flourish. (As I note in my guide to soil-based probiotics, not all probiotics are the same, and many soil-based probiotic formulas contain Bacillus species that are not well studied. Always choose strains with established safety profiles and human clinical evidence. I’ve found Enterogermina [no affiliation] to be the most effective in my work with clients.)

Importantly, these probiotics do not colonize the human gut, but 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 that established oxygen competition as a mechanism, protection against Salmonella required both oxygen-consuming bacteria and spore-forming anaerobes. Neither worked alone.

Redox balance: the deeper story behind oxygen-gut dysbiosis

Throughout this article, I’ve used the term “oxygen leakage” because it provides an intuitive way to understand what happens when colonocyte metabolism breaks down. However, oxygen is actually part of a larger biological concept: redox balance.

Redox refers to the balance between oxidation and reduction reactions — the movement of electrons that powers cellular metabolism and shapes the chemical environment of the gut. A healthy colon is not simply “low oxygen”; it is a carefully regulated ecosystem where oxygen levels, reactive oxygen species, and other electron acceptors are tightly controlled.

When the gut barrier is inflamed, immune cells activate enzymes (like NOX1) that dump reactive oxygen species (ROS), such as hydrogen peroxide (H₂O₂) and superoxide radicals, directly into the gut lumen. This raises the colonic redox potential, shifting the environment from a highly reduced state to a highly oxidized one.

This is the environment where opportunistic Proteobacteria thrive. They use these oxidized molecules to outcompete native, strictly anaerobic beneficial bacteria. To reverse this, we have to provide electron donors (antioxidants) to quench the ROS and drop the redox potential back down. Below are the primary tools to achieve this:

• Polyphenols: Found in many brightly colored plant foods, polyphenols are major electron donors. Their poor absorption is one of their greatest strengths for gut health; they bypass the small intestine and travel directly to the colon to act as localized electron donors. Excellent sources include wild blueberries, pomegranate, dark cherries, green tea, and high-cacao dark chocolate. Supplements like pomegranate husk powder, quercetin, or curcumin can also provide a concentrated dose of luminal antioxidants to lower oxidative stress in the gut. (Note: Avoid “highly bioavailable” or liposomal formulas, as these are typically absorbed before reaching the colon — if we want colon-active polyphenols, poor absorption is a good thing!).

• Vitamin C (Ascorbic Acid): The small intestine can only absorb so much Vitamin C. When you consume higher amounts (typically over 200 mg), the unabsorbed portion spills over into the large intestine, where it acts as a potent, direct luminal antioxidant. Several small pilot trials support a beneficial effect of Vitamin C on anaerobic bacteria. One study found that two weeks of 1000 mg daily increased Lachnospiraceae, a family containing many butyrate producers. Another study using colon-targeted vitamin C found increased microbial diversity.

• Glutathione: This supports the body’s master antioxidant and provides systemic redox support from the inside out. While N-acetyl cysteine (NAC, the precursor to glutathione) is also popular for boosting glutathione levels, many opportunistic bacteria can feed on cysteine and convert it into gut-damaging hydrogen sulfide. Similarly, reduced glutathione forms may also be broken down to cysteine before they can be used to mitigate oxidative stress. I recommend liposomal or S-acetyl glutathione, which are better absorbed and offer less direct exposure of free cysteine to gut bacteria. it’s also important to ensure adequate selenium status, since the enzyme that helps glutathione fulfill its antioxidant functions is selenium-dependent.

• A note on riboflavin (vitamin B2): Riboflavin is the precursor to FAD and FMN, two cofactors that function in the electron transport chain and regenerate glutathione after it’s been oxidized. In other words, without adequate riboflavin, the cell’s own antioxidant recycling stalls. Riboflavin absorption in the small intestine saturates at around 25 to 30 mg, and higher doses spill through to the colon. This may explain why the doses studied for microbiome effects are far above the RDA of roughly 1.2 mg. Faecalibacterium prausnitzii, a keystone butyrate producer in the gut, has also been shown to use riboflavin as an extracellular electron shuttle, offloading electrons onto oxygen so it can grow right at the mucosal surface where oxygen is highest. Colon-targeted formulations have shown some intriguing microbiome effects, but are not commercially available yet. I’ll continue to watch this area, though I’m not currently comfortable recommending high-dose riboflavin on the strength of the current data we have.

Several of the botanicals listed in the PPAR-gamma section above also support redox balance. Curcumin, milk thistle, urolithin A, and sulforaphane all activate Nrf2, which upregulates the cell’s own antioxidant enzymes, complementing the direct electron donors described in this section. Curcumin and milk thistle also act as direct electron donors.

Harnessing synergy for breaking the cycle: restoring epithelial energy metabolism

In functional gut health, it’s incredibly tempting to look for a silver bullet. We want to find the one perfect probiotic, the right prebiotic, or the ideal butyrate supplement that will finally fix the gut.

But the gut is an ecosystem, and sustainable recovery from dysbiosis is only possible if the gut environment actually heals. This often requires synergistic approaches that support gut health from multiple angles.

For example, mesalamine combined with curcumin or butyrate has been shown to be more effective for treating IBD than mesalamine alone.³⁷,³⁸ The same principle turned up in the oxygen research itself, where germ-free animals were protected against Salmonella only when oxygen scavengers and butyrate producers were present together.

This suggests that integrating multiple, complementary therapies may improve outcomes beyond what any one strategy can achieve.

To fully restore the gut environment and the microbiome from a state of oxygen-gut dysbiosis, it’s likely that you need a combination approach. Such a regimen might include:

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

• A good multivitamin, L-carnitine, and CoQ10, in addition to a nutrient-dense diet, 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 leaked oxygen and protect native anaerobes

• Polyphenols to soak up excess ROS in the colon and feed beneficial bacteria

This is the multi-targeted approach I use in my one-on-one work with clients, though the exact protocol used often depends on the specifics of each client’s case, and any collaboration with their physician or gastroenterologists.

For instance, someone with high Proteobacteria presenting as constipation may respond to some of these interventions differently than someone presenting with high Proteobacteria and diarrhea. Someone with mast cell activation or strong sensitivities to supplements may also require a slower and more careful approach, eliminating certain interventions.

Though it will take large-scale clinical trials from the broader research community to fully quantify the synergistic potential of these tools, my 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).

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 12-week 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.

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 physical sponges in the gut to quench reactive oxygen species. Similarly, certain probiotics can temporarily 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.