Did you know that 70% of your immune system resides in your gut? In part 1 of this series, I discussed how exercise impacts the gut microbiota. Gut microbes are in constant communication with the immune system, so it’s really no wonder that exercise impacts the immune system as well. In this article, I’ll provide some background on how the gut immune system works, what we know about exercise and gut immunity, and the roles of exercise modality and butyrate in immune function.

Meet the GALT

The gut-associated lymphoid tissue, or GALT for short, lies throughout the small and large intestine, and covers an area of approximately 260-300 square meters. About 70% of all immune cells lie in the GALT. Many of these are found within dome-like structures called Peyer’s patches that are scattered along the gut mucosa.

Peyer’s patche contains a mixture of immune cells, including lymphocytes (B and T cells), macrophages, dendritic cells. Under normal conditions, macrophages and dendritic cells “sample” bacteria and dietary antigens in the gut lumen, and then “present” their findings to naive T cells, causing them to differentiate into regulatory T cells (Tregs). Tregs migrate into the tissue beneath the epithelial layer (the lamina propria) to release anti-inflammatory cytokines like IL-10, suppress immune responses, and promote tolerance to the particular bacteria or antigen.

During an intestinal insult, on the other hand, pro-inflammatory cytokines (IL-6, TNFα) and chemokines are released to aid in the recruitment of dendritic cells, which again “present” their findings to T cells, this time causing them to differentiate into effector T cells. Together with other cells, like neutrophils, these T cells help curb the potential invasion. (For a more visual representation of this process, I highly recommend this short 7 minute video by Nature Publishing Group.)

This delicate process of balancing tolerance and immune response has numerous implications for human disease. While researchers are constantly searching for drugs that might target this process to benefit those with gut pathology, many people (including myself) are much more interested in how we might modulate the immune response using lifestyle interventions like diet and exercise.

Exercise and gut mucosal immunity

Unfortunately, relatively few studies to date have looked at the effects of exercise on mucosal immunity, and it’s an area of active interest for my lab. Here, I’ll discuss the results from the few studies we do have.

Hoffman-Goetz et al. isolated lymphocytes (B and T cells) from the gut of animals that exercised or remain sedentary.^1–3 They found that exercise:

• Reduced pro-inflammatory cytokines (TNFα, IL-17)
• Increased antioxidant enzymes (glutathione peroxidase and catalase)
• Increased anti-inflammatory cytokines (IL-10)
• Decreased proteins involved in immune cell death (caspase 7)
• Improved intestinal immune function in older mice

Overall, these findings seem to suggest that exercise promotes greater immune tolerance. However, another study found that six weeks of voluntary wheel running increased T cell proliferation and cytokine production from Peyer’s patches when stimulated with an antigen known to produce T cell activation. The authors write:

“Since the Peyer’s patches are the inductive site in the mucosal immune system where immune cells first encounter antigen and initiate IgA production and mucosal T cell responses, an EX-induced enhancement of T cell responses in the Peyer’s patches may result in improved immunosurveillance against ingested pathogens and preneoplastic and/or neoplastic cell growth in the gastrointestinal tract.”

In other words, exercise may enhance appropriate immune responses, while maintaining a baseline of immune tolerance. More research in this area is needed to determine what type of exercise is best, and at what intensity.

Modality and microbiota transplants

Last week, I discussed two types of endurance exercise protocols in animal models (voluntary wheel running and forced treadmill running), and how they differentially impact the gut microbiota. Not surprisingly, these two modes of exercise also have differential effects on the gut immune system.

In a mouse model of colitis, forced treadmill running exacerbates, while voluntary wheel running attenuates, intestinal inflammation in the colon.⁴ In intestinal immune cells, even a single bout of forced treadmill running transiently increases production of the pro-inflammatory cytokine TNFα, though levels return to normal by 2 hours post-exercise and may even be reduced at 24 hours.²

A study performed by one of my labmates looked at the effects of transplanting an “exercised” microbiota into germ-free mice, which are raised in sterile isolators. The donor mice were exercised on wheels for six weeks before gut contents were collected, pooled, and given via feeding tube to recipient germ-free mice. Small sections of the colons of the recipient mice were stained and mounted onto slides. I was then blinded to treatment and tasked with scoring the mucosal health of each sample.

Our results were published in the journal Gut Microbes in 2017.⁵  Mice that received the “exercised” microbiota by fecal transplant had more goblet cells that were filled with mucus. This may indicate lower bacterial adherence to the epithelium, since microbial interaction with goblet cells has been shown to stimulate the release of mucus into the lumen and depletion of mucus stores. Mice receiving the “exercised” microbiota also had lower immune cell infiltrate in the submucosa. These observations also held true when mice were challenged with a chemical that causes acute colitis – but that’s a story for part 4 of this series!

Butyrate and the gut immune system

In my last article, I discussed several animal and human studies that suggest that exercise upregulates microbial butyrate production in the gut. This has multiple implications for the gut immune system. Butyrate has been shown to:

• Increase Tregs in the colon⁶
• Reduce pro-inflammatory cytokines⁷
• Promote intestinal barrier integrity,⁸ limiting the exposure of the gut immune system to microbes in the gut lumen

Despite these potential effects of increased butyrate, Tregs have never been directly measured in the gut in response to exercise. Additionally, studies looking at the effects of exercise on gut barrier function have some mixed and somewhat confusing results, though the intensity of exercise seems to play a major role. In Part 3 of this series, I’ll try to answer the question: what type of exercise is best for promoting optimal gut barrier function? For now, it’s clear that exercise does alter the gut microbiota and gut mucosal immunity – and in ways that seem to benefit our health.

That’s all for now! Be sure to subscribe so you don’t miss the next few articles in this series: how exercise impacts gut barrier function and diseases of the gut.

Sources:

1. Packer, N. & Hoffman-Goetz, L. Exercise training reduces inflammatory mediators in the intestinal tract of healthy older adult mice. Can. J. Aging Rev. Can. Vieil. 31, 161–171 (2012).
2. Hoffman-Goetz, L. Freewheel training decreases pro- and increases anti-inflammatory cytokine expression in mouse intestinal lymphocytes. Brain. Behav. Immun. 1105–1115 (2010).
3. Hoffman-Goetz, L., Pervaiz, N. & Guan, J. Voluntary exercise training in mice increases the expression of antioxidant enzymes and decreases the expression of TNF-alpha in intestinal lymphocytes. Brain. Behav. Immun. 23, 498–506 (2009).
4. Cook, M. D. et al. Forced treadmill exercise training exacerbates inflammation and causes mortality while voluntary wheel training is protective in a mouse model of colitis. Brain. Behav. Immun. 33, 46–56 (2013).
5. Allen, J. M. et al. Exercise training-induced modification of the gut microbiota persists after microbiota colonization and attenuates the response to chemically-induced colitis in gnotobiotic mice. Gut Microbes 0, 1–16 (2017).
6. Furusawa, Y. et al. Commensal microbe-derived butyrate induces the differentiation of colonic regulatory T cells. Nature 504, 446–450 (2013).
7. Chang, P. V., Hao, L., Offermanns, S. & Medzhitov, R. The microbial metabolite butyrate regulates intestinal macrophage function via histone deacetylase inhibition. Proc. Natl. Acad. Sci. U. S. A. 111, 2247–2252 (2014).
8. Kelly, C. J. et al. Crosstalk between Microbiota-Derived Short-Chain Fatty Acids and Intestinal Epithelial HIF Augments Tissue Barrier Function. Cell Host Microbe 17, 662–671 (2015).