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“Mini-Guts” Let Researchers Understand How Microbes Can Influence Our Brain

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The last decade has seen huge advances in our understanding of how the brain communicates with the bacteria that call our gut home. This so-called gut–brain axis sees chemical and electrical signals fly between the two areas, leading to alterations in both gut and brain function.

But these signals often arrive in furious flurries that are challenging to parse, leading to a stark lack of precise information about how individual bacterial species contribute to the axis. That gap may soon be filled, however, with the introduction of a new toolset that will help researchers listen in to these conversations between our brain and bacteria.

The new workflow, designed by a multi-institute team, was published in Nature Protocols.

“Currently, it is difficult to determine which microbial species drive specific brain alterations in a living organism. Here, we present a valuable tool that enables investigations into connections between gut microbes and the brain. Our laboratory protocol allows for the identification and comprehensive evaluation of metabolites – compounds microbes produce – at the cellular and whole-animal levels,” said first author, Dr. Thomas D. Horvath, instructor of pathology and immunology at Baylor College of Medicine and Texas Children’s Hospital.

Inside the microbiome

Our gastrointestinal tract is home to a vast community of microorganisms, called the microbiome. There are thought to be as many of these organisms in our bodies as there are human cells. These cells have important functions not only in maintaining gut health, but in communicating with body systems outwith the gut.

“Gut microbes can communicate with the brain through several routes, for example by producing metabolites, such as short-chain fatty acids and peptidoglycans, neurotransmitters, such as gamma-aminobutyric acid and histamine, and compounds that modulate the immune system as well as others,” said co-first author Dr. Melinda A. Engevik, assistant professor of regenerative and cellular medicine at the Medical University of South Carolina.

We now know much more about how microbes can talk to the brain. The presence of nerve cells in our gut, and the vagus nerve that acts as a superhighway between the brain and the body’s other organs, are the infrastructure that chemicals released by gut bacteria use to influence our brain health. But the scale of that influence, and its contribution to health and to conditions like schizophrenia and Parkinson’s disease, remains unclear.

Creating a mini-gut

One of the key innovations of the research team’s approach was to specify how to prepare systems that mimic how the gut and brain function in a body using test tubes and petri dishes. Engevik calls these systems “mini-guts”. The system, she explains, “is a laboratory model of human intestinal cells that retains properties of the small intestine and is physiologically active.”

Once they established these model systems, they then outlined a series of analytical steps that rely on liquid chromatography–tandem mass spectrometry-based metabolomic methods, to carefully study the chemical output of these bacterial species. The whole protocol takes up to five weeks of lab time, indicating how complex untangling gut–brain connections can be.

Horvath highlighted how the protocol was only able to succeed through researchers from multiple fields working together. “We were able to create this protocol thanks to large interdisciplinary collaborations involving clinicians, behavioral scientists, microbiologists, molecular biology scientists and metabolomics experts,” Horvath said. “We hope that our approach will help to create designer communities of beneficial microbes that may contribute to the maintenance of a healthy body. Our protocol also offers a way to identify potential solutions when miscommunication between the gut and the brain leads to disease,” he concluded.


Horvath TD, Haidacher SJ, Engevik MA, et al. Interrogation of the mammalian gut–brain axis using LC–MS/MS-based targeted metabolomics with in vitro bacterial and organoid cultures and in vivo gnotobiotic mouse models. Nat Protoc. Published online November 9, 2022:1-40. doi:10.1038/s41596-022-00767-7

This article is a rework of a press release issued by Baylor College of Medicine. Material has been edited for length and content.