A Lactobacillus strain worsens symptoms of autoimmune disease

• What is already known on this topic
  A common feature of Western diets is the intake of low amounts of fiber and high amounts of fat, which alter the gut microbiota make-up. These alterations have been linked to several autoimmune disorders, but whether diet influences autoimmunity through the gut microbiota is poorly understood.

• What this research adds
  The commensal Lactobacillus reuteri is enriched in mice prone to lupus, an inflammatory disease caused when the immune system attacks its own tissues, and worsens autoimmune symptoms. However, metabolites from a special starch diet can suppress the growth of L. reuteri and improve lupus manifestations.

• Conclusions
  The study uncovers a mechanism through which a lack of dietary fiber could favor the growth of bacteria that trigger the immune system of genetically predisposed people, which in turn could lead to systemic inflammatory disorders. Changes in diet could help restrain these potentially pathogenic bacteria.

A commensal Lactobacillus strain worsens the symptoms of the autoimmune disease systemic lupus erythematosus by triggering the host’s immune system, a study in mice has found. Daniel Zegarra-Ruiz and his colleagues at Yale University School of Medicine in New Haven reported these findings in the journal Cell Host & Microbe.

Western diets are characterized by low amounts of fiber and high amounts of fat, which alter the gut microbiota make-up. Changes in the microbiota composition have been linked to several autoimmune diseases, but whether diet influences autoimmunity through gut bacteria remains unclear.

To address this question, the researchers looked at mouse models of lupus and identified specific bacterial species that were linked to lupus development.

Commensal bacteria exacerbate lupus-related symptoms and mortality

The team first induced lupus in genetically prone mice, then suppressed the gut microbiota using broad-spectrum antibiotics or growing the rodents under germ-free conditions. In both situations, mice lived longer and showed fewer symptoms of autoimmune disease such as decreased levels of the inflammatory molecule type I IFN in the spleen and blood as well as reduced blood disorders and kidney injury.

To identify bacteria driving lupus manifestations, the researchers collected fecal samples from lupus-prone mice and sequenced the bacterial DNA.

Compared to wild-type mice, lupus-prone mice had an altered gut microbiota, which included bacterial species such as L. reuteri, Desulfovibrio, and Rikenellaceae. These mice also had an impaired gut epithelium that allowed Lactobacillus spp., and L. reuteri in particular, to leak into the blood. L. reuteri increased over time in the feces of lupus-prone mice as their disease progressed.

The researchers also found increased levels of L. reuteri in the feces of lupus patients compared to healthy people.

Bacteria enriched in lupus models are transferable

When lupus-prone mice were housed together with wild-type mice, the majority of bacterial species enriched in lupus-prone mice, including L. reuteri, were transferred to wild-type mice. Cohousing also increased gut leakiness in wild-type mice.

What’s more, the researchers observed increased gut leakiness and autoimmune symptoms such as an abnormal enlargement of the liver and spleen, worsened kidney disease and high levels of type I IFN in rodents that received the gut microbiota of lupus-prone mice.

Similar effects, as well as the worsening of lupus-related symptoms, occurred when wild-type mice were fed L. reuteri, but not when they were fed an unrelated gut bacterial species.

A special dietary starch modulates L. reuteri growth and improves autoimmune symptoms

To assess the role of diet in modulating bacteria in lupus-prone mice, the team fed them food enriched with resistant starch, a type of fiber that resists digestion and is fermented by gut bacteria.

Resistant starch decreased the amount of L. reuteri found in the feces and in the gut of mice fed with resistant starch. Resistant starch also tightened the gut epithelial barrier and reduced gut leakiness and L. reuteri translocation to the blood. Over time, resistant starch reduced lupus-related mortality and decreased the levels of inflammatory molecules in the spleen and gut.

The researchers discovered that L. reuteri growth was inhibited by short-chain fatty acids, in particular butyrate, which are the main metabolites of resistant starch fermentation by the gut microbiota.

In conclusion, these data suggest that a dietary intervention is sufficient to prevent the development of lupus-like disease, whose symptoms are exacerbated by the commensal L. reuteri strain. The findings could inform clinical approaches to restrain bacteria that contribute to autoimmune diseases.