Scientists just discovered that a high-fat diet can cause gut bacteria to enter the brain

Live bacteria from the digestive system can travel directly into the brain when the intestinal barrier is weakened. This discovery offers a potential new explanation for how digestive health influences neurological conditions like Alzheimer’s disease and autism. The research was recently published in the journal PLOS Biology.

The digestive tract and the central nervous system are intimately connected through a biological communication network called the gut-brain axis. This network helps regulate bodily functions, digestion, and inflammation. Medical professionals have noted associations between the gut microbiome and various neurological conditions.

The gut microbiome is the massive collection of bacteria and other microorganisms naturally living inside the digestive tract. Changes in the types of bacteria living in the gut often occur alongside a condition called intestinal permeability. This condition happens when the lining of the intestines weakens, allowing substances to leak out into the body.

High-fat diets are known to alter the bacterial makeup of the gut and contribute to this intestinal leakage. Yet researchers did not fully understand the exact pathways allowing gut bacteria to directly impact the brain and potentially cause neurological diseases. Manoj Thapa, a researcher at the Emory National Primate Research Center at Emory University, led an investigation to explore these physical pathways.

Thapa and a team of colleagues set out to determine if microbes could physically move from the digestive system directly into the brain. To test their ideas, the researchers used a specialized breed of laboratory mice that are prone to developing liver issues and gut bacterial changes. They fed these mice a high-fat, high-carbohydrate food called a Paigen diet for nine days.

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The research team then analyzed the fecal matter and intestinal tissue of the mice. They observed that the high-fat diet changed the bacterial makeup in the intestines, enriching bacteria like Staphylococcus while reducing beneficial bacteria like Lactobacillus. Alongside these bacterial changes, the high-fat diet caused the intestinal lining of the mice to weaken and leak.

To see if bacteria escaped the digestive tract, the researchers examined various organs, including the lungs, heart, kidneys, and blood. They found no bacteria in the blood or most other systemic organs. They did, however, discover small numbers of live bacteria within the brains of the mice fed the high-fat diet.

The researchers then used genetic sequencing to compare the bacteria found in the brain with those in the intestines. They discovered that the genetic codes matched almost perfectly, indicating the bacteria in the brain originated in the gut. Because they found no bacteria in the blood, the team needed to find the alternative route the microbes took to reach the brain.

They turned their attention to the vagus nerve, a long nerve pathway connecting the brainstem to the heart, lungs, and digestive organs. When the researchers tested the cervical branches of the vagus nerve in the mice, they found the exact same types of bacteria. To test if this nerve was the physical pathway, they performed a surgical procedure to sever the right cervical vagus nerve in some mice.

Because cutting the nerve on both sides of the body would be fatal, they only severed it on one side. These surgically altered mice had vastly lower levels of bacteria in their brains compared to mice with intact nerves. The researchers then wanted to know if the type of bacteria in the gut determined what ended up in the brain.

They gave a new group of mice a blend of common antibiotics to kill off their existing gut bacteria. They then introduced a specific, genetically modified strain of Enterobacter bacteria into the digestive tracts of these mice. This genetically modified strain contained a unique DNA barcode not found in nature.

After feeding these mice the high-fat diet to induce a leaky gut, the researchers searched the brain tissue for this specific bacterial DNA. Using highly sensitive laboratory techniques to copy and amplify the genetic material, they successfully detected the unique DNA barcode in the brain tissue. This proved that the specific bacteria placed in the gut had traveled directly to the brain.

To confirm the blood was truly free of bacteria, the researchers tested the blood for specific antimicrobial proteins. These proteins naturally spike when the immune system detects an infection in the bloodstream. The levels of these proteins remained completely normal, providing further evidence that the microbes did not use the circulatory system to travel.

To ensure these results were not limited to one specific mouse breed, they repeated the experiments using standard laboratory mice. When standard mice ate the high-fat diet, they also developed intestinal leakage and harbored gut bacteria in their brains. The team observed that bacteria appeared in the vagus nerve before showing up in the brain, supporting the idea of a transit route.

The researchers also tested whether this physical movement of bacteria was a permanent condition. They took mice that had been eating the high-fat diet and returned them to standard laboratory food. After returning to a normal diet, the intestinal lining of the mice healed and the leakage stopped.

Subsequently, the researchers could no longer detect bacteria in the brains of these mice. This indicated that the presence of bacteria in the brain is a reversible state, driven by the health of the gut lining.

The team then expanded their scope to look at mice engineered to mimic human neurological conditions. They examined mouse models designed to replicate Alzheimer’s disease, Parkinson’s disease, and autism spectrum disorder. Even when eating a normal diet, these particular mice exhibited weakened intestinal linings.

When the researchers examined the brains and vagus nerves of these diseased mice, they found gut bacteria present. Just like in the diet experiments, these mice had no bacteria in their bloodstreams. The blood-brain barrier, a protective filter separating the brain from the circulatory system, remained completely intact in all the tested animals.

This reinforced the idea that the microbes were bypassing the bloodstream entirely and using the nerves as a highway. The results suggested that a leaky gut might be a common feature allowing bacterial movement in these specific neurological conditions. The researchers took extreme precautions to ensure their samples were not contaminated during the collection process.

They performed all work in sterile environments and collected brain tissue before touching the digestive organs. They also confirmed that germ-free mice, which are raised in sterile bubbles without any natural bacteria, had no microbes in their brains. When the team gave these germ-free mice a single strain of bacteria and a normal diet, the microbes stayed in the gut.

The bacteria only traveled to the brain when the germ-free mice were fed the high-fat diet that caused intestinal leakage. This proved that their isolation methods were clean and that a weakened gut lining was absolutely required for the bacteria to relocate. To fully understand the link between gut leakage and the brain, the team also gave mice a chemical that aggressively destroys the intestinal lining.

Only at the absolute highest doses of this chemical did bacteria finally spill over into the bloodstream. This demonstrated that the moderate gut leakage caused by the high-fat diet was enough to send bacteria up the nerve, but not severe enough to cause a full-blown blood infection.

The study does have a few limitations that warrant further investigation by the scientific community. The research relied entirely on animal models, so it remains unknown if this exact physical transit of bacteria happens in humans. The number of bacterial cells found in the brain tissue was quite low, generally numbering in the hundreds.

Any differences in the exact amount of bacteria found in the brain across the different mouse models were not statistically significant, but the presence of the bacteria was consistent. The researchers have not yet been able to capture visual images of the bacteria inside the brain or the vagus nerve. The specific diet used to induce the leaky gut in the mice is an extreme formulation containing high levels of fat and specific acids.

This diet differs from typical human eating habits, though Western diets can also cause intestinal issues. It is not yet clear exactly where the bacteria reside once they reach the brain. Scientists also need to determine which specific brain cells come into contact with these translocated microbes.

Future research will focus on whether all types of gut bacteria have the ability to travel along the vagus nerve or if only certain species can make the journey. Investigators will also look into how long bacteria can survive in the brain after the intestinal lining heals. Understanding these pathways could eventually lead to new medical treatments.

If doctors can target the digestive system to prevent bacteria from escaping, they might be able to alter the course of some neurological conditions. “One of the biggest translational aspects of this study is that it suggests that the development of neurological conditions may be initiated in the gut,” said David S. Weiss, a corresponding author of the study. He noted that, “This may shift the focus of new interventions for brain conditions, with the gut as the new target of the therapy.”

The study, “Translocation of bacteria from the gut to the brain in mice,” was authored by Manoj Thapa, Anuradha Kumari, Chui-Yoke Chin, Jacob E. Choby, Elahe Akbari, Bikash Bogati, Fengzhi Jin, Elise Furr, Daniel M. Chopyk, Nitya Koduri, Andrew Pahnke, Theodore L. Burns, Elizabeth J. Elrod, Eileen M. Burd, David S. Weiss, and Arash Grakoui.