One of the most exciting developments in the gut world is the new understanding of the key role the gut has in regulating immune system development and function, with implications for the health of every tissue in the body.
This actually shouldn't be a surprise, because the gut is loaded with immune cells. In fact, roughly 70% of all your immune cells are living or hanging out in your gut. And it turns out that the gut is one of the main places in the body where immune cells go to mature (Kumar 2018). There are many different varieties (phenotypes) of T cells (the "generals" of the immune system that initiate and coordinate systemic immune responses) and B cells (which produce antibodies after being activated by T cells). There are also a ton of "innate" immune cells (macrophages, dendritic cells, mast cells, neutrophils, and others) that live in the gut and serve as a first line of defense.
I am embarrassed that I was one of the people who was surprised (pleasantly so, of course), as I should have known better. During the 1980s and 1990s I was doing a lot of gut anatomy work. Whenever you want to report an anatomy finding, you need photographic evidence. And it is not enough to just show an image — it has to be artistic. I was studying mostly nerves and endocrine cells. I had nice findings but getting photos was challenging because every image would be photo-bombed by immune cells, which are not the beauty queens of the cellular world. They were everywhere.
In addition to these sorts of "free-range" immune cells, the gut contains fairly large masses of "lymphoid tissue" that are pretty much the same thing as lymph nodes, but are embedded within the gut. It is in these places that T and B cells mature and become activated. Depending on their experiences in the gut, they can become pro-inflammatory or regulatory (pro-tolerance). The types of experience that can influence this are interactions with microbes and microbial products, and possibly stress hormones such as cortisol. The innate immune cells in the gut are programmed in this way as well.
Although it is clear that we have a lot more to learn about the nuances of gut immune regulation, some very important themes have already emerged. One theme is that immune function in the gut contributes to autoimmunity.
Autoimmunity occurs when someone has a genetic background that predisposes them to having an overreactive or paranoid immune system, which gets triggered by environmental factors (Veauthier 2018; Pisetsky 2023).
Environmental factors can include stress and/or exposure to toxins, or having too many, or not enough, of certain kinds of gut microbes (Miyauchi 2017; Gavy 2023; Zeng 2026).
One key factor underlying these issues is "gut permeability," aka "Leaky Gut" (Mu 2017; Kinashi 2021). For autoimmune conditions of the gut, this is the key factor. When the gut is permeable, substances such as bacterial products or other "suspicious things" can pass from the lumen into the body. This sets off an inflammatory response in the gut that, because of genetics, is very hard to turn off, and can lead to catastrophic damage to the gut.
What is happening is that these environmental factors, in the context of a "leaky gut," can bias the balance of tolerance vs. inflammation/host defense in the gut towards inflammation. When this happens, immune cells maturing in the gut can adopt a pro-inflammatory, intolerant identity. This underlies gut autoimmune conditions such as Inflammatory Bowel Disorders (Crohn's Disease, ulcerative colitis, and microscopic colitis) and food allergies. It also contributes to "extra-gut" autoimmune conditions, such as type 1 diabetes, rheumatoid arthritis, lupus, and multiple sclerosis (Miyauchi 2023; Zhu 2025). More on this in Journal Club.
Are there modifiable ways to influence this balance?
Theoretically, yes! Clinical trials are so far thin on the ground, but reports of small clinical interventions and preclinical studies support the idea that lifestyle factors, particularly diet, can help improve gut barrier permeability and re-balance gut microbe populations (Aleman 2023).
Bacterial translocation, which means bacteria getting through the gut barrier and into the body, contributes to pro-inflammatory immune programming (Twardowska 2022). This usually occurs when gut microbes are imbalanced, so supporting beneficial microbes (the old friends) by eating lots of fiber, resistant starch, fresh fruits, and vegetables can help gut barrier integrity.
Overall, diet goals should focus on consuming whole, intact, fiber-containing foods that have undergone minimal processing and don't contain additives such as emulsifiers and dyes.
Aleman et al. (2023) also point out that stress can cause or exacerbate permeability. This means that lifestyle factors that promote resilience should also improve gut barrier function in autoimmune conditions. Such factors can include regular exercise, rewarding and meaningful activities and hobbies, social interaction, and mindfulness approaches.