Autoimmune Liver Disease and the Leaky Gut Hypothesis

Evaluating the Evidence for Gut-Based Treatments in Autoimmune Liver Disease

Autoimmune liver diseases may be rare [1 Trusted SourcePubMedGo to source], but occurrences are on the rise [2]. And while immunosuppressive drugs like prednisone and azathioprine are helpful and prevent worst-case outcomes like liver failure and liver transplants [3 Trusted SourcePubMedGo to source], these treatments come with significant side effects. Patients with autoimmune liver diseases report significant negative impacts on their quality of life, including depression and anxiety [4 Trusted SourcePubMedGo to source].

Studies have shown an association between autoimmune conditions, including autoimmune liver disease, and dysbiosis, or imbalance in the gut microbiota. In the case of more common autoimmune diseases such as Hashimoto’s thyroiditis or rheumatoid arthritis, gut treatment protocols are increasingly recognized as effective treatments and are backed by research.

Can patients with autoimmune liver disease benefit from gut-directed therapies? We decided to take a deep dive into the research to see what support we could find. First, we’ll look at the overall research that suggests gut health may play a significant role in autoimmune disease in general. Then, we’ll explore research specific to gut health and autoimmune liver disease.

autoimmune liver disease: diagram of internal organs

The Leaky Gut Hypothesis of Autoimmune Disease

There are currently over 100 recognized autoimmune diseases [5], including autoimmune liver diseases. One hypothesis suggests that a condition known as “leaky gut” may play a significant role in the development of all autoimmune diseases [6 Trusted SourcePubMedGo to source, 7, 8 Trusted SourcePubMedGo to source, 9, 10, 11 Trusted SourcePubMedGo to source, 12 Trusted SourcePubMedGo to source, 13 Trusted SourcePubMedGo to source].

What Is Leaky Gut?

Leaky gut, medically known as intestinal permeability, takes place when gaps develop between the cells that line your small intestine. This allows bacterial fragments and undigested food particles to enter your bloodstream, causing inflammation and a chronic immune response.

Leaky gut generally develops as a result of gut dysbiosis, an unhealthy imbalance in the population of microorganisms that live in the digestive tract [14].

autoimmune liver disease: leaky gut illustration

While the leaky gut hypothesis is an exciting and growing area of research, results are not conclusive for all autoimmune diseases, and more research is needed.

There is more research for the most common autoimmune diseases, like Hashimoto’s thyroiditis and inflammatory bowel disease. So, we’ll start with these common autoimmune conditions to get an overview of what we know about the gut-autoimmune connection:

Hashimoto’s Thyroiditis and the Gut

Some of the strongest evidence for a gut-autoimmune connection relates to Hashimoto’s thyroiditis. Research shows that thyroid autoimmunity is more prevalent in patients with gut infections like SIBO (small intestinal bacterial overgrowth and H. pylori [15 Trusted SourcePubMedGo to source, 16 Trusted SourcePubMedGo to source, 17].

Research also shows that gut treatments can be very helpful for Hashimoto’s patients:

Type 1 Diabetes and the Gut

In one clinical trial, 58 patients with type-1 diabetes and 40 healthy controls were tested for leaky gut [32 Trusted SourcePubMedGo to source]. All of the type-1 diabetes patients had results indicating leaky gut. Researchers hypothesize that changes in the health of the small intestine contribute to the development of autoimmune diabetes.

In a large study of 7,473 children at risk for type 1 diabetes, early probiotic supplementation (before the age of 27 days) was shown to reduce the risk of autoimmunity when compared to children who had not taken probiotics or had been given probiotics more than 27 days after birth [33].

Inflammatory Bowel Disease (IBD) and the Gut

Approximately one-third of Crohn’s patients were found to have pathogenic E. coli bacteria in their gut lining [34 Trusted SourcePubMedGo to source, 35 Trusted SourcePubMedGo to source].

Nearly 42% of ulcerative colitis patients treated with a fecal microbiota transplant (FMT) were able to achieve clinical remission [36], and more than 65% of patients reached clinical response. FMT doubled rates of clinical remission in patients with ulcerative colitis compared with controls [37 Trusted SourcePubMedGo to source].

Probiotics have been shown to work as well as the anti-inflammatory drug, mesalamine, in maintaining remission for Crohn’s disease [38 Trusted SourcePubMedGo to source]. The best results were with a combination of probiotics and mesalamine.

Similar studies have found probiotics to be equally effective for ulcerative colitis as anti-inflammatory drugs like mesalamine [39 Trusted SourcePubMedGo to source, 40]. However, at least one systematic review has found the evidence for using probiotics to treat ulcerative colitis to be unclear [41 Trusted SourcePubMedGo to source].

Rheumatoid Arthritis (RA) and the Gut

Gut infections have also been associated with rheumatoid arthritis. A 2020 meta-analysis involving 5,052 patients suggests that more virulent strains of H. pylori can increase the risk of rheumatoid arthritis, as well as lupus, autoimmune gastritis, and autoimmune pancreatitis [42].

Preliminary research suggests that dysbiosis in fecal, dental, and saliva samples is commonly seen in RA patients [43 Trusted SourcePubMedGo to source, 44 Trusted SourcePubMedGo to source].

A 2017 meta-analysis found that probiotics lowered inflammatory markers in patients with rheumatoid arthritis [45 Trusted SourcePubMedGo to source]. However, probiotics had no effect on disease activity scores when compared with placebo.

A clinical trial of 60 Danish patients with rheumatoid arthritis found that a multi-strain probiotic reduced disease activity of 28 joints and improved markers of inflammation and insulin resistance [46 Trusted SourcePubMedGo to source]. Another clinical trial found reduced inflammatory activity in RA patients who followed an anti-inflammatory, Mediterranean diet when compared with controls [47 Trusted SourcePubMedGo to source].

What About Autoimmune Liver Diseases?

autoimmune liver disease: jaundiced eyes

Autoimmune liver diseases represent at least 5% of all chronic liver diseases [48]. There are three types of autoimmune liver disease. Each of them involves immune system attacks on different parts of the liver. A minority of patients may experience overlap syndrome, which is a combination of two types of autoimmune liver disease [49].

Autoimmune Hepatitis (AIH)

In autoimmune hepatitis, the body’s immune system attacks the liver cells, leading to inflammation (hepatitis). Over time, the inflammatory process can scar and damage the liver (cirrhosis) and lead to reduced liver function [50].

AIH is rare: Just over 17 people per 100,000 live with the condition [51 Trusted SourcePubMedGo to source]. AIH is more likely to occur in women, in older people, and in Europeans and Americans [52 Trusted SourcePubMedGo to source].  Type 1, or classic autoimmune hepatitis, mostly affects young women. Type 2 autoimmune hepatitis is less common and generally affects girls between the ages of 2 and 14 [53].

Symptoms of autoimmune hepatitis vary from person to person and may not be evident at early stages. Symptoms may include:

  • Fatigue
  • Yellowing of the skin
  • Yellowing of whites of the eyes
  • Swelling in the liver
  • Abdominal discomfort
  • Spider angiomas (a cluster of dilated blood vessels visible on the skin)
  • Skipped menstrual cycles
  • Rashes
  • Joint pain

Primary Biliary Cholangitis (PBC)

PBC is a progressive autoimmune liver disease characterized by inflammation of the portal vein and gradual destruction of the liver’s internal bile ducts [54]. PBC mostly affects women between 40 and 60 years of age

Patients at early stages of PBC may not have symptoms or they may experience:

  • Fatigue
  • Itching
  • Darkening of the skin
  • White bumps under the skin

Primary Sclerosing Cholangitis (PSC)

PSC is a chronic, progressive autoimmune liver disorder characterized by inflammation, fibrosis, and abnormal narrowing of the liver’s interior and exterior bile ducts [55 Trusted SourcePubMedGo to source]. Unlike PBC and AIH, it is twice as common in men and is most frequently seen in patients between 25 and 40 years of age [56].

PBC patients are often diagnosed with other autoimmune disorders, including Sjögren’s syndrome, Hashimoto thyroiditis, and celiac disease [57]. As many as 70% of PSC patients also have ulcerative colitis [58].

Symptoms of PSC may not be present at early stages of the disease. Patients may also experience:

  • Itching
  • Fatigue
  • Yellowing of the skin and eyes (jaundice)
  • Fever, chills, and abdominal discomfort

Why Early Diagnosis Is Important

Comparison of healthy liver vs. liver with cirrhosis

Early diagnosis of autoimmune liver diseases is important. Diagnosis is generally based on blood tests for liver function and the presence of specific autoantibodies, such as antimitochondrial antibodies, antinuclear antibodies, anti-smooth muscle antibody and/or atypical perinuclear antineutrophil cytoplasmic antibodies.

Untreated, autoimmune liver diseases progress from liver inflammation to fibrosis (mild scarring) and cirrhosis (severe scarring and damage). Cirrhosis is a significant risk factor for liver cancer, liver transplantation, or liver failure.

When it comes to the management of autoimmune hepatitis and other autoimmune liver diseases, taking steps to slow the progression of the disease is critical. For autoimmune hepatitis, treatment with immunosuppressive drugs is effective in most cases but can result in significant side effects.

Can Better Gut Health Slow the Progression of Autoimmune Liver Disease?

Research into autoimmune liver disease and the gut is very preliminary, and studies are small. However, the preliminary evidence does imply that an association between autoimmune liver disease and gut health may be present:

There is even less research that explores how gut treatments may affect patients with autoimmune liver disease:

  • A 2018 case study of one 20-year-old female with PSC and ulcerative colitis (UC) was put on a Specific Carbohydrate Diet (SCD) for UC [66]. At the start of the diet and after following it for two weeks, her stool samples were compared with stool samples from three healthy controls. In that early stage, her microbial composition was markedly less diverse than and higher in pathogenic species than controls. A follow-up test found the pathogenic bacterium had decreased two- to threefold. Furthermore, her overall species diversity increased to levels near the controls, suggesting a possible therapeutic effect of the SCD in PSC.
  • A small clinical trial in Spain gave a probiotic mixture to 12 patients with cirrhosis of the liver and ascites (fluid accumulation causing abdominal swelling) [67 Trusted SourcePubMedGo to source]. After six weeks on probiotics, patients had increased blood flow through the liver and portal vein, suggesting that probiotics may provide therapeutic effects to patients with cirrhosis.
  • However, an earlier pilot study assessed the potential benefits of probiotics on serum liver tests, itching, and fatigue in patients with primary sclerosing cholangitis [68 Trusted SourcePubMedGo to source] and found no significant health benefits.

If you are a patient with autoimmune liver disease and considering natural and complementary treatments for your condition, where does this slim amount of research leave you?

Most important is to continue your standard medication regimen, as there is no evidence that gut-directed therapies can cure or resolve autoimmune liver diseases.

However, it’s also important to consider that an absence of research evidence does not disprove a hypothesis. It just means we don’t have enough information. Basic gut health treatments, such as dietary improvements and probiotic supplementation, are safe [69 Trusted SourcePubMedGo to source, 70]  and beneficial for many inflammatory and immune conditions.

If you want to try some simple steps to improve your gut health, follow these Basic Gut Health Guidelines.

Basic Gut Health Guidelines

It’s best to implement these changes in a step-by-step fashion, starting with the most fundamental changes (diet and lifestyle) first. Monitor your symptoms for 2-3 weeks after making each change and before trying the next step. For more detailed information about this process, see my book, Healthy Gut, Healthy You.

Lifestyle

The foundation of good gut health lies in diet and lifestyle changes. Research shows that lack of sleep, stress, and over-exercise can contribute to leaky gut [71 Trusted SourcePubMedGo to source, 72 Trusted SourcePubMedGo to source, 73 Trusted SourcePubMedGo to source, 74 Trusted SourcePubMedGo to source, 75 Trusted SourcePubMedGo to source].

Regular moderate exercise has been shown to decrease inflammation and intestinal permeability [76 Trusted SourcePubMedGo to source, 77 Trusted SourcePubMedGo to source]. Strive for a full 7-8 hours of sleep a night, and prioritize relaxing activities such as spending time in nature or a relaxing hobby.

Diet

Diet is also critical for good gut health. A whole foods diet that is low in processed foods, sugars, and trans fats helps to reduce inflammation [78 Trusted SourcePubMedGo to source, 79 Trusted SourcePubMedGo to source, 80 Trusted SourcePubMedGo to source, 81 Trusted SourcePubMedGo to source, 82 Trusted SourcePubMedGo to source]. You can choose to incorporate more fresh, whole foods into your diet or adopt an anti-inflammatory diet such as the Paleo diet or Whole 30 diet.

Eating a lower-carb diet can be helpful for some patients with gut dysbiosis. The paleo diet tends to be lower in carbs as it restricts grains and sugars.

Probiotics

Research shows that probiotics can be very helpful for treating microbial gut imbalances and reducing inflammation [83 Trusted SourcePubMedGo to source, 84 Trusted SourcePubMedGo to source, 85 Trusted SourcePubMedGo to source, 86 Trusted SourcePubMedGo to source]. In general, multistrain probiotics perform better than single strain probiotics [87 Trusted SourcePubMedGo to source].

For more guidance on which probiotic strains to choose and what to look for in a probiotic supplement, see our Probiotic Starter Guide.

Treating Gut Infections

Some patients struggle with hidden gut infections, such as SIBO (small intestinal bacterial overgrowth) or an H. pylori infection, and may need to take additional steps to improve their gut health.

Testing for and treating gut infections is best done with the help of an experienced health practitioner.

The Bottom Line

While there’s not enough evidence to recommend gut-based therapies for autoimmune liver disease, we know that simple improvements to gut health can reduce inflammation and improve leaky gut.

Patients may wish to try gut-based therapies, along with standard medication, as a potential route for optimizing immune health.

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