Could a High-Fat Diet Worsen Gut Inflammation?

• Dramatic health changes occurred — Mice on the ketogenic diet experienced severe weight loss, more intense colitis symptoms, and a shortening of their colons, which is a sign of extensive inflammation and damage. Disease activity index (DAI) scores, which measure symptoms like diarrhea severity, blood in stool, and weight loss, were much higher in mice fed a ketogenic diet compared to the control diet.

• Key inflammatory markers skyrocketed — Blood and colon tissue samples showed sharply increased levels of harmful cytokines, such as IL-1α, IL-6, TNF-α, and IL-17. Each of these is linked directly to inflammation, tissue damage, and immune dysfunction. In short, high levels of these markers indicate that a ketogenic diet turns up inflammation dramatically when gut trouble starts.

• Ketogenic diet weakened the gut barrier — A healthy gut barrier allows nutrients to enter your tissues while blocking harmful substances. And as you can guess, mice on the ketogenic diet had lower activity of critical genes responsible for barrier integrity. “Increased intestinal permeability and decreased expressions of intestinal epithelial barrier associated genes were observed due to ketogenic diet administration,” the researchers said.

• Fat changed gut bacteria composition negatively — It encouraged harmful types such as Proteobacteria and Enterobacteriaceae while significantly reducing beneficial bacteria like Erysipelotrichaceae. Such microbial imbalance — also known as gut dysbiosis — is directly tied to increased gut permeability and inflammatory bowel conditions.

• Gut metabolism was altered — The high-fat mice group showed increased amounts of bile metabolites such as taurochenodeoxycholic acid and cholic acid, known to act as irritants and damage the gut lining. At the same time, bile metabolites linked to fatty acid synthesis were reduced, thus contributing to colitis.

• High fat dramatically alters gut microbiota — Populations of keystone gut strains are reduced. As noted by the researchers:

“Several studies have linked HFD-driven alterations in gut microbiota with increased gut barrier permeability, referred to as the leaky gut syndrome.

It is suggested to be caused by reduction in gut barrier — promoting microbes, such as Akkermansia muciniphila, Bifidobacterium spp., Bacteroidetes spp., Lactobacillus spp. and Clostridiales spp., accompanied by an increase in microbes disrupting gut barrier integrity, such as Oscillibacter spp. and Desulfovibrio spp.”

• Unhealthy dietary habits eroded the integrity of the intestinal mucus layer — When this layer thins out due to poor dietary choices, harmful bacteria and toxins come into direct contact with your intestinal lining, damaging cells and causing chronic inflammation. On the other end, the researchers pointed out that gut bacteria support a healthy mucus layer:³

“[E]xamples of bacteria strains with beneficial effects on the intestinal barrier are Bacteroidesvulgatus and Bacteroidesdorei, which increase TJ (tight junctions) expression and produce bacteriocins, proteins that inhibit the growth of specific bacteria, limiting the growth of harmful strains and helping to re-establish healthy microbiota.”

• High-fat foods activate inflammatory pathways — This is particularly seen from examples high in fats from animal products and processed snacks. Specifically, they trigger toll-like receptor 4 (TLR4), a key player in activating the inflammatory nuclear factor-kappa B (NF-κB) pathway:⁴

“The increase in both Firmicutes and Actinobacteria on HFD is positively correlated with the gene expression of proinflammatory cytokines in colonic macrophages (TNF-α, IL-1β, and IL-6). It is thus suggested that the observed changes are due to TLR4 activation as described above. TLR-bearing macrophages have also been identified in adipose tissue, skeletal muscles, and the liver.”

• Increased dietary fat and refined sugar consumption altered bile acid metabolism — Specifically, increased fat consumption led to higher bile acid (BA) production, resulting in altered gut health:

“It has been shown that HFD (high-fat diet) increases total BAs and total secondary BAs along with elevated BA concentration in the caecum, while chronically high gut and fecal BA concentrations can reduce gut barrier integrity.

Thus, the HFD-associated gut hyperpermeability can be related to increased BA secretion. Moreover … a 10-fold increase in BA synthesis on HFD was associated with enriched bile composition in hydrophobic BAs … which are indicated to stimulate intestinal permeability when administered at high concentrations.”⁵

• Not all carbs are created equal — Refined sugars, such as those found in soda and candy, severely harmed gut health. Meanwhile, complex carbohydrates — particularly those rich in fiber — showed remarkable protective effects on gut inflammation and microbiome balance.

• Healthy food results in a healthier gut — Digging deeper into these beneficial carbs, the researchers highlighted fiber-rich foods like whole fruits, vegetables, and properly prepared whole grains as powerful defenders against gut inflammation. Dietary fiber dramatically increased the abundance of beneficial bacteria, especially those producing short-chain fatty acids (SCFAs), such as butyrate.

These SCFAs are crucial nutrients that strengthen your gut lining, helping protect your bloodstream from toxins and reducing inflammation. The researchers discovered clear differences in inflammation levels when comparing diets high in complex carbs versus those dominated by refined sugars. Animal studies consistently showed that diets rich in complex carbohydrates reduced inflammatory markers dramatically.

• The diet of IBD patients — The study noted that people diagnosed with IBD generally follow an unhealthy diet, giving you an insight on how to take care of your own gut health:⁷

“IBD patients have been reported to consume more sugar and confectionary foods than healthy control participants.

In the European Prospective Investigation into Cancer (EPIC) study, Antoine Racine et al. found that high sugar and soft drink consumption combined with low vegetable intake was linked to an elevated risk of developing UC (ulcerative colitis), in line with another large cohort study. And this association seems to be more pronounced in female patients, likely due to the influence of estrogen, on the pathogenesis and clinical course of IBD in women.”

1. Moderate your fat intake — As seen in the published studies, high fat intake eventually harms your health. That’s because your body is designed to burn glucose for energy, especially from healthy sources of carbohydrates. Hence, dietary fat, even from healthy sources, needs to be limited.

In addition, I recommend keeping your total fat intake to below 30% of your daily calories because of a metabolic switch in your body called the Randle Cycle. When fat consumption goes beyond this range, your body begins burning fat for fuel, which hampers glucose metabolism. Since glucose is unable to enter your mitochondria because your cells are still on “fat” mode, it ends up back in your bloodstream, which raises blood sugar levels.

2. Avoid vegetable oils — In addition to high-fat intake, excess linoleic acid (LA), an omega-6 polyunsaturated fat (PUF), is a big driver of systemic inflammation, as well as gut damage. In a previous article, I showed how LA induces metabolic stress to certain beneficial bacteria strains, such as Bifidobacterium breve (B. breve), while also increasing pathogenic strains, namely E. coli.

That said, I recommend keeping your LA intake below 5 grams a day. If you can keep it below 2 grams, that’s even better. To help you keep track, I recommend you download the Mercola Health Coach app, which will be out this year. One of its main features is the Seed-Oil Sleuth, which calculates your vegetable oil intake to the tenth of a gram.

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3. Choose healthy carbohydrates — Replace refined carbohydrates with whole, nutrient-packed foods like sweet potatoes, whole fruits, root vegetables, and white rice. Incorporating resistant starches, such as green bananas, also feed your beneficial gut bacteria reduce inflammation. For reference, most adults need around 250 grams of carbohydrates daily to give your body the fuel it needs.

4. Add sufficient amounts of dietary fiber — This is an important component for gut health, as this is what your beneficial bacteria ferment to produce SCFAs that strengthen your gut barrier. In light of this, aim for around 30 grams of fiber per day.

However, don’t just start eating fiber indiscriminately, especially if you have gut dysbiosis. That’s because even bad bacteria ferment dietary fiber, and once they do, endotoxins are produced. For an in-depth understanding of this approach, read “Butyrate — The Metabolic Powerhouse Fueling the Gut and Beyond.”

To fully utilize dietary fiber, again, feed your gut by consuming around 200 to 250 grams of healthy carbohydrates from whole, unprocessed foods.

5. Incorporate healing foods — Consistently include gut-nourishing foods like bone broth, collagen-rich meats, and fiber-rich root vegetables in your meals. These foods help repair your gut lining, maintain gut microbiome balance, and steadily reduce inflammation, allowing your gut to heal naturally over time.