Gut bacterial changes influence lupus treatment results in pregnancy

Lead authors Xin M. Luo, associate professor of immunology in the Department of Biomedical Sciences and Pathobiology, and Qinghui Mu, formerly a postdoctoral fellow in the department. Photo by Emily Koth.

The course of pregnancy, like that of true love, doesn’t always run smooth when you have lupus, correctly called systemic lupus erythematosus (SLE). This autoimmune disease is an occasionally violent, occasionally subdued, chronic inflammation that constantly smolders within multiple tissues in the body. Incurable by nature, it is caused by unnecessarily hostile immune reactions to innocent molecules found on the surface of the body’s own cells.

Now, a new study shows that pregnancy and breastfeeding could change the way the body reacts to conventional lupus treatment in women due to imbalances in the gut bacterial community, or dysbiosis.

Lupus is found nine times more frequently in females compared to males. The unpredictable occurrence of disease flares, or acute increases in severity, which can cause severe illness and tissue damage, have historically led to the recommendation that women with SLE avoid getting pregnant for fear of serious disease and death. This is especially so because many women experience more severe flares after childbirth. This can lead to damage to the heart, lungs, kidneys, skin and brain. Lupus nephritis is the Number 1 cause of death due to SLE in over 50% of patients.

The human gut contains about 38 trillion bacteria, from over a hundred species. Researcher Xin M. Luo says, “Disturbance of the gut microbiota exists in the pathogenesis of many autoimmune diseases, including lupus. Our work helps to uncover the mechanisms underlying pregnancy-induced disease flares and offers the possibility of developing new therapeutic strategies for pregnant women with lupus.”

Intensive research has been ongoing to find out more about what causes this ravaging disease. In the current study, researchers looked at the gut microbiome in pregnant and lactating mice, comparing it with controls, to see if it showed any changes that could help explain why it flared up in pregnancy. The results show that both the composition of the gut microflora, and the number of different species, show drastic differences depending on whether the patient is pregnant/breastfeeding or not. Strangely, the same treatments that improved the condition of mice without the disease worsened it in postpartum mice with lupus.

Pregnant mice with lupus show an increased number of Firmicutes, one of the predominant phyla in the gut, particularly Clostridia and Lactobacillus species. However, PP lupus mice had a notable jump in the number of Verrucomicrobia.

The study centered around the intriguing finding that administering the broad-spectrum gut antibiotic vancomycin improved lupus symptoms in mice that were not postpartum, but worsened them in postpartum (PP mice). Vancomycin effects reflect its effects on the gut microbiome since it is not absorbed by the gut. Vancomycin acted as expected in control mice, eliminating most of the bacteria but leaving behind Lactobacillus animalis which therefore became relatively abundant.

Vancomycin and inflammatory markers

Vancomycin reduced IL-6 and IL-7 levels in control non-PP mice, reducing inflammation, but not in PP mice. Instead, vancomycin in PP mice suppressed anti-inflammatory IL-10 responses, reduced T regulatory cell responses and reduced activity of B cells that produce IL-10. It also increased the production of IFNγ which is proinflammatory. Thus it produces a shift towards inflammation.

Vancomycin and kidney function

Lupus nephritis was measured by protein levels in urine, and this was shown to be improved following vancomycin treatment in control mice but not in PP. After delivery, the PP groups quickly went back to normal with or without vancomycin. The kidney lesions were worse in the PP vancomycin-treated group. Thus vancomycin harmed PP mice with lupus but benefited non-pregnant lupus mice.

L. animalis gavage vs vancomycin

The scientists tested naïve and PP mice with weekly oral gavage instead of vancomycin, or feeding the animal through a tube directly into the stomach, using the same organism. Again, feeding this organism directly worsened the symptoms in lupus PP mice but not in controls.

They found that L. animalis inhibited an enzyme called indoleamine 2,3-dioxygenase (IDO). This is known to activate Treg cells, and this could explain why vancomycin has such different effects on control mice compared to PP mice.

What they learned

This means, to the scientists, that they need to find new ways to specifically treat pregnant women with lupus. To begin with, they want to differentiate the gut bacteria that do good or harm to the gut.
Without knowing exactly which species are beneficial or otherwise, it is difficult to formulate the right strategy to modulate the gut microbiome’s composition in the right way. The bacteria in the gut form a highly complex community, with a multiplicity of interactions. Moreover, different individuals show differences in the type of gut microbiomes. The study concludes, “Together, these results provide a potential mechanism by which pregnancy and lactation may interfere with the response of autoimmunity to modulation of gut microbiota.”

In the future, the scientists want to look into how sex hormones and gut microbiota associate in the pathogenesis of SLE. Their investigation is focused on the role of female sex hormones in this condition since the condition is so much more rampant in women. Lupus nephritis, or kidney involvement in SLE, will be taken up as well, to identify the role of the gut bacteria in pregnancy-related worsening of kidney function.
The study was published in the online journal Microbiome on July 16, 2019.

Journal reference:

Pregnancy and lactation interfere with the response of autoimmunity to modulation of gut microbiota. Qinghui Mu, Xavier Cabana-Puig, Jiangdi Mao, Brianna Swartwout, Leila Abdelhamid, Thomas E. Cecere, Haifeng Wang, Christopher M. Reilly & Xin M. Luo. Microbiome volume 7, Article number: 105 (2019). https://doi.org/10.1186/s40168-019-0720-8., https://microbiomejournal.biomedcentral.com/articles/10.1186/s40168-019-0720-8|