Insulin is an important hormone produced by our pancreas that allows our body to use glucose for energy. After a meal, our bodies break down carbohydrates from food into glucose molecules, which end up in our bloodstream. Insulin then prompts different types of cells, such as muscle, fat and liver cells, to take up glucose from the blood and use it as fuel or store it for later use.

This function of insulin comes in handy when we indulge our sweet tooth. Consuming a lot of sugary foods and drinks can raise our blood sugar to abnormal levels. If this persists for long periods, it can cause damage to vital organs and body parts, such as our blood vessels, kidneys and nerves. This is why diabetes is a serious health condition that needs to be addressed and managed promptly.

But under certain conditions, cells can become unresponsive to insulin. For instance, people who are overweight or obese usually undergo changes in metabolism that affect the way their cells respond to insulin. When cells become less sensitive to it, they don’t absorb glucose in the blood. This condition, commonly known as insulin resistance, leads to high blood sugar levels and is considered the precursor to Type 2 diabetes.

But while a number of studies have established a connection between insulin resistance and obesity, scientists are still unsure how the latter contributes to the former. In a recent study, researchers from Canada, Taiwan and the U.S. decided to investigate what makes obesity a risk factor for insulin resistance and diabetes. They found that the intestinal immune system is heavily involved in the series of reactions that eventually leads to cells become unresponsive to insulin.

The complex interactions between gut bacteria and the immune system

According to Daniel Peterson, an assistant professor of pathology at Johns Hopkins University School of Medicine, millions of bacteria live in the human gut, where a large portion of the immune system is actually located. These bacteria frequently interact with the immune system, and this interaction is marked by massive amounts of antibodies being produced by cells that make up your gut lining.

But how the immune system responds to these bacteria changes in different diseases, suggesting that gut bacteria play an important part in disease development. For instance, studies have found that gut microbiota composition directly affects the balance between Th17 and Treg cells, which are immune cells involved in our primary immune response. Certain bacteria in our gut, such as those that belong to the Clostridium and Bacteroides genera, have been found to trigger immune responses and the accumulation of Treg cells. An imbalance between TH17 and Treg cells has been linked to gut inflammation and inflammatory diseases like IBD.

But not all changes in microbial composition lead to undesirable consequences. In their 2014 study, Peterson and his colleagues found that a certain bacterium, Lactobacillus johnsonii, nearly doubles in number when mice develop colitis. But when the researchers transferred this bacterium in germ-free mice, they found that it did not trigger colitis, but instead made the mice a little healthier. This finding suggests that not all shifts in gut bacterial composition have adverse effects and that some changes may be allowed by the intestinal immune system in response to certain situations.

“There are a lot of data right now on these relationships between changes in the microbial community and different diseases. The next step is the hard step: trying to figure out all that data,” said Peterson.

Obesity-related changes in the intestinal immune system trigger insulin resistance

In their paper, which appeared in the journal Nature Communications, a team of Canadian, Taiwanese and American researchers wrote that “during [high-fat] diet feeding and obesity, a significant shift occurs in the microbial populations within the gut, known as dysbiosis, which interacts with the intestinal immune system.”

Animal studies also show that immune cells in the gut undergo changes that favor inflammation. For instance, in obese people, white blood cells known as T cells start producing signaling proteins that promote inflammation. But recently, researchers have begun proposing another possible link between the gut microbiota and the intestinal immune system, and it comes in the form of an antibody known as immunoglobulin A (IgA).

IgA can be found in mucous membranes, especially in our respiratory and digestive tracts. It is also found in our saliva, tears and breastmilk, and is often referred to as the body’s first line of defense against microbial infections. IgA is produced by immune cells called B cells that reside in the intestinal mucosa. Together with antimicrobial peptides and other immune-related molecules, IgA helps maintain homeostasis by protecting the gut from pathogens while tolerating the presence of commensal bacteria.

Research also reveals that IgA prevents gut bacteria from breaching the intestinal barrier and entering the bloodstream by binding to them. Because of its critical role in regulating the functions of the intestinal immune system, the researchers hypothesized that IgA may be involved in the development of obesity and insulin resistance.

Through their experiments on obese mice, the researchers found that obesity significantly decreases IgA production by reducing the number of intestinal B cells. This change allows bad bacteria to thrive and eventually leak through the intestines, triggering inflammation that affects intestinal cells and fat cells. At high levels, pro-inflammatory proteins can inhibit insulin signaling, messing up the ability of cells to respond to the hormone and absorb glucose. This series of events leads to insulin resistance and allows blood sugar levels to rise without regulation.

The researchers also found that putting IgA-deficient mice on a high-fat diet caused them to have dysfunctional glucose metabolism and made their insulin resistance worse. When the researchers collected gut bacteria from these mice and transferred them to germ-free mice, they noticed that the latter also developed insulin resistance. These findings show that IgA is important for keeping bad gut bacteria in check and preventing inflammation that causes insulin resistance.

For the last part of their experiment, the researchers collected stool samples from humans before and after they underwent bariatric (weight loss) surgery. The researchers analyzed the IgA content of these samples and found higher levels of IgA in the stools collected after surgery. This finding strongly suggests that IgA is linked to metabolic function and is influenced by the foods that we eat.

“IgA is naturally produced by our bodies and is crucial to regulating the bacteria that live in our gut,” explained Helen Luck, the lead author of the study. “It acts as a defense mechanism that helps neutralize potentially dangerous bacteria that take advantage of changes to the environment, such as when we consume an imbalanced or fatty diet.”

Luck and her team’s findings further cement the relationship not just between diet and obesity, but also between obesity, the intestinal immune system and insulin resistance. On the other hand, their results also suggest that boosting IgA levels could be an effective strategy for preventing metabolic disorders like diabetes. But the biggest takeaway from this study is that eating a well-balanced diet and reducing your consumption of fatty foods can help you fight obesity and avoid gut microbiota-related changes that could trigger the development of chronic disease.

Sources:

Healthline.com

KidsHealth.org

MedicineNet.com

MedicalNewsToday.com

HopkinsMedicine.org

MDPI.com

TAndFOnline.com

Nature.com

URMC.Rochester.edu

FEBS.OnlineLibrary.Wiley.com