Metabolites’ Role in Autoimmune Arthritis

By Linda Rath | July 17, 2023

The microbiome is a vast, bustling ecosystem of bacteria, viruses, fungi and other microbes that live in and on the bodies of most living things. Many of the microorganisms in these complex communities are commensal, meaning they evolved a mutually beneficial relationship with their hosts. They protect against intruders, clean up messes and make essential vitamins. They also train the immune system to distinguish harmful organisms from beneficial ones.

In return, hosts provide microbes with nutrients – when we feed ourselves, we’re also feeding them – and a safe, stable place to live. We even have similar genes, though microbes have millions more of them. 

A tiny fraction of these microbes are pathogens that can cause serious illness, usually by manipulating the immune system. Sometimes the damage is self-inflicted, with the immune system overreacting to a pathogen and causing chronic inflammation or, in autoimmune conditions, mistakenly attacking its own tissue.  

In healthy people, commensals and pathogens peacefully co-exist. But when the elegant if somewhat tenuous balance of the microbiome is upset by poor diet, antibiotics, toxic chemicals, stress or early life trauma, pathogens may get the upper hand, potentially leading to a wide range of diseases. These include many chronic conditions – heart disease, type 2 diabetes, Alzheimer’s, cancer and nearly all autoimmune diseases, from inflammatory bowel disease to lupus and rheumatoid arthritis (RA).  

Although each person’s microbiome is unique and changes over time, the general makeup of a healthy microbiome is substantially different from an unhealthy one.

Intestinal inflammation starts before arthritis actually develops, so shifting the microbiome to a healthier state might help prevent the disease from taking hold. Mayo Clinic researchers found that patients who experienced improvements in their RA disease activity had more diversity in their microbiome makeup — indicating a healthier microbiome — than those patients whose RA did not improve. 

In June 2023, researchers at the University of Washington School of Medicine in St. Louis reported a similar finding in people with early-stage Alzheimer’s disease. They found striking changes in the gut microbiome long before cognitive symptoms appeared. This was the first time researchers looked at the earliest stages, when the disease might still be prevented, potentially by shifting the microbial makeup of the gut.

Metabolites Rule 

Scientists have a lot more to learn about the microbiome, but research suggests that certain parts of the microbial universe may have a greater influence on health than microbes themselves. These are small molecules called microbiota metabolites, gut-derived metabolites or postbiotic metabolites. They’re produced when microbes feast on fiber you can’t digest, such as fruit peels, beans, certain vegetables and whole grains, and they play a role in communication among microbes in the microbiome and the immune system.  

Short-Chain Fatty Acids

There are hundreds of thousands of metabolites. Among the most well-studied postbiotics are short-chain fatty acids (SCFAs), especially butyrate, secondary bile acids and byproducts of the essential amino acid tryptophan. Some SCFAs stick around in the gut, producing energy for microbes and hosts. Others travel through the bloodstream to tissues and organs, where they have a direct effect on the immune system and human health.

Short-chain fatty acids:

• Help maintain a strong intestinal barrier, preventing pathogenic bacteria from leaking into the bloodstream (often called leaky gut). Once in the bloodstream, pathogens can travel to distant sites like joints, where they trigger inflammation.
• Suppress inflammation in RA and other inflammatory diseases.
• Play a key role in the complex communication among gut microbes, the immune system and brain, and among different species of microbes. Communication can be positive or negative, defending against pathogens in some cases and contributing to inflammation in others.
• Regulate immune-related inflammatory diseases, including RA and lupus.
• Maintain normal cholesterol and blood sugar levels.
• Aid nutrient absorption.
• Stimulate the production of GLP-1, the hormone mimicked in the blockbuster weight loss drugs Ozempic and Wegovy.

Many experts consider butyrate the microbiome’s superhero because it is crucial for almost every aspect of health. Yet most patients with chronic inflammatory or autoimmune diseases have less butyrate and far fewer bacteria that produce SFCAs than normal. Some research in mice suggests that supplementing with these metabolites before symptoms develop may delay arthritis and reduce its severity.

Secondary Bile Acids

Primary bile acids are produced by the liver, stored in the gallbladder and released during meals to help digest fats. Secondary bile acids, modified by postbiotic metabolites, bind to certain receptors in the gut. There, they influence innate immunity – your body’s first line of defense against viruses and bacteria – and fight intestinal inflammation. In mouse studies of rheumatoid arthritis, secondary bile acids protected joints, improved the health of the gut microbiome and strengthened the intestinal wall.

Tryptophan Metabolites

Your body can’t make the essential amino acid tryptophan, so you must get it from food, mainly plant and animal proteins like chicken, eggs, cheese, tofu, seeds and nuts. It’s broken down into metabolites by gut microbes and through what’s called the kynurenine pathway, the main source of energy in the body. Tryptophan metabolites help maintain microbial balance in the gut and the integrity of the intestinal wall. They also trigger signaling that controls the function of many anti-inflammatory immune cells.

Studies have shown that tryptophan metabolites and the kynurenine pathway are different in people with RA than in those without RA, suggesting that these differences may contribute to autoimmune and inflammatory forms of arthritis.

Tryptophan metabolites are also involved in the microbiota gut-brain axis, the two-way conversation that constantly takes place between the gut and central nervous system. In these conversations, the gut sends signals to the brain that influence mood, and the brain sends signals to the gut that affect immunity and other functions. In mouse studies, altered tryptophan metabolites and bile acids seem to play a large role in many psychiatric disorders.

Experts Agree and Disagree

There is nearly universal agreement that bringing an unhealthy microbiome and its metabolites into a healthier state can prevent or improve RA and many other chronic diseases. But experts disagree on the best way to do that.

There are a couple of parts to the argument. One says that since each person’s microbiome is as unique as their fingerprints and can change on a dime, no one really knows what a healthy microbiome looks like. The counter to this is that decades of research have shown that a loss of microbial diversity and too many unfriendly microbes compared to friendly ones are sure signs of an unhealthy microbiome. 

The second part of the argument is whether it’s better to try to change the microbiome with probiotic supplements or diet, including fiber-rich plants and fermented foods like sauerkraut, miso and kimchee.

Pro-diet experts argue that flooding the gut with high doses of a few strains of bacteria in probiotics can have unintended consequences, throwing the microbiome off balance and creating the very problems probiotics were supposed to solve. They point to one study that found taking probiotics after a course of antibiotics (which kill microbes) led to a slow and half-hearted repopulation of the gut compared to what the body does naturally. Some experts also argue persuasively that since every microbiome is unique, it doesn’t make sense that an off-the-shelf probiotic would be effective for most people.

Yet hundreds of high-quality studies have shown that probiotics can shift the microbiome to a healthier state, helping improve or prevent chronic disease. In one study, probiotics prevented Type 1 diabetes in high-risk infants. In other research, a single probiotic called B. pseudocatenulatum prevented RA in mice. In human studies, probiotics have successfully treated irritable syndrome (IBS) and inflammatory bowel disease (IBD) in some people,  while significantly reducing disease activity in RA. Still other research has found that probiotics may reduce depression and anxiety when used alone or in combination with anti-depressants.

Personalized Probiotics

An ideal solution would be to create personalized probiotics for each person. Some researchers see these becoming available in the next few years. For now:

• Eat lots of fiber. Unless you have IBS, IBD or a diverticulitis flare, you should aim for about 25 to 30 grams of fiber a day. Most adults in the U.S. get half that. Keep in mind that different types of fiber feed different bacteria, so eat a wide range of fiber-containing fruits, veggies and whole grains.
• Eat more fermented foods; even raw fermented pickles count. Find them in your store’s refrigerated section, but check the label for cultures; not all pickles have them.
• Avoid highly processed and sugary foods that harmful bacteria love.
• Don’t take antibiotics unless necessary. According to the Centers for Disease Control and Prevention (CDC), at least one-third and up to half of antibiotics currently used aren’t needed.  
• If you have a chronic illness, especially inflammatory bowel disease or diverticulitis, consider butyrate supplements. You can find them in most natural food stores and online.