Can gut bacteria control inflammatory diseases?

Patients with these diseases may one day have their gut bacteria closely catalogued and be given poo transplants to improve their condition.

---

Doctors may one day order a catalogue of their rheumatic patient’s gut bacteria and order them a poo transplant, if evidence linking the microbiome to symptoms continues to grow.

With management of inflammatory disease symptoms having progressed greatly in recent years through drug therapy, research is increasingly turning to the pathogenesis of these diseases – and the gut microbiome has come under the spotlight.

“There’s really been an explosion in this in this field,” says Associate Professor Tony Kenna, inflammatory arthritis researcher at Queensland University of Technology. “I think that across health disciplines there’s a realisation that the microbiome plays a role in health and disease.”

Professor Kenna says much of this awareness has been spearheaded by oncology research, particularly in melanoma, and by the inflammatory bowel disease community, but that it’s still early days for inflammatory disease research.

Because many people with inflammatory disease have very complex diseases, Professor Kenna says good research demands a study design with enormous complexity and a substantial enough population.

“We just haven’t got the statistical power to be able to determine a causal relationship with the microbiome,” he says of research so far.

But the early research hints at some alluring links between inflammatory and autoimmune diseases, and a breakdown in a healthy gut microbiome.

Hand osteoarthritis

This year, researchers in China found people with symptomatic hand osteoarthritis had a different microbiome to healthy individuals. Specifically, those with the condition had a higher relative abundance of bacteria such as Bilophila and Desulfovibrio and a lower relative abundance of Roseburia.

Reactive arthritis and undifferentiated peripheral spondyloarthritis

Likewise, research from Kalinga Institute of Medical Sciences in India, which was presented at APLAR 2021, found that the diversity of gut bacteria found in the 55 patients with reactive arthritis (ReA) and undifferentiated peripheral spondyloarthritis (upSpA) differs was different to the level of diversity found in the guts of healthy controls.

Interestingly, despite their differing aetiology, Associate Professor Sakir Ahmed and his colleagues found no significant difference between patients with ReA and upSpA.

Systemic sclerosis

An imbalance in gut bacteria, known as dysbiosis, also appears to be a common marker of systemic sclerosis, according to a literature review presented at APLAR 2021 by Singaporean rheumatologist Dr Andrea Low from Singapore General Hospital.

Researchers are still unclear about whether dysbiosis contributed to disease progression or was a consequence of it. To properly understand the evolution of this relationship, and create better therapies, scientists need to undertake long-term studies into the early stages of the disease, says Dr Low.

Rheumatoid arthritis

One growing field of research is in analysing the microbiomes of patients with RA. Researchers at Shanxi Medical University in China analysed the individual level of gut microbe diversity of 108 RA patients, and compared that to the level of microbiome diversity in sex matched healthy controls. The research, also presented at APLAR 2021, found RA patients had less diversity compared to their healthy peers, as well as an over- and underabundance of multiple types of gut bacteria.

In the US, a small Mayo Clinic study published in Genome Medicine found certain features of the gut microbiome of RA patients could predict improvements in disease activity.  

Artificial intelligence could accurately predict the minimum clinically important improvement in RA patients based on the microbiota found in stool samples. 

According to the researchers, using a microbiome prognosis would address “a steep challenge” in the clinical practice of RA and enable more precise drug treatment for patients. 

Interestingly, Chinese research also suggests that when RA patients are treated for their disease, their microbiome dysfunction appears to partially return to normal.

The study, which was published in Nature Medicine, also suggested that the bacteria Haemophilus spp. was depleted in individuals with RA and that the more it was affected, the higher the levels of serum autoantibodies found in the patients. In contrast, Lactobacillus salivarius was overabundant in RA patients’ faecal, dental and salivary samples and was especially high in patients with very active RA.

In trying to narrow down a causal link between microbiome composition and RA, other studies have reported that Prevotella copri correlates with enhanced susceptibility to RA, as the bacteria often dominates microbiota of patients.

However, an editorial about P. copri in the Journal of Clinical Medicine identified additional bacterial clusters as potential key players; Collinsella, Erghetella, the oral P. gingivalis and others such as the segmented filamentous bacteria (SGB), or a particular strain of Lactobacillus bifidus.

Genes affect gut microbiome

The immune system and gut microbiome seem to go hand in glove, according to Professor Kenna.

He pointed to an animal study that showed rats who expressed the HLA-B27 gene had a different gut microbiome to rats who didn’t.

“The genetics of HLA-B27 delta – an immune system gene – shapes the immune system in a particular way,” Says Professor Kenna.

“We think that gene correspondingly influences the microbiome to be an inflammatory microbiome which then drives disease development.”

Another study published in Arthritis & Rheumatology showed that the changes in intestinal microbiome in ankylosing spondylitis and RA patients are at least partially due to effects of genes.

Certain HLA alleles have been known to strongly influence predisposition to ankylosing spondylitis and RA. This research suggested that the risk of these diseases is caused or increased by the interaction between these HLA alleles and intestinal microbiome.

Can you change the gut microbiome to fix the disease?

Sadly, a small Danish trial published in Annals of the Rheumatic Diseases found that faecal matter transplant did not improve outcomes for PsA patients. In fact, symptoms got worse for some patients who tried the experimental therapy. Rather than proving the therapy is useless though, the authors suggested that the worsening of symptoms actually bolstered the idea that intestinal microbiota played a role in the immune effects of PsA.

And more faecal matter transplants are on their way. Speaking at APLAR 2021, Dr Low said a larger randomised controlled trial was planned.

Microbiome consortia

The growing enthusiasm for the gut microbiome has led to exciting collaboration and resource sharing.

Dr Lara Bereza-Malcolm is a part of the Australian Arthritis and Autoimmune Biobank Collaborative (A3BC), which recruits patients with different inflammatory arthritis disorders and obtains and stores the patients’ blood, tissue, stool and oral samples.

Dr Bereza-Malcolm says she’s excited that the biobank will facilitate more microbiome studies using Australian cohorts.

“There are so many confounding factors in microbiome research,” she says. “By collecting as much data as possible it increases our potential to derive significant associations between microbiota and disease features.”

“I believe we are on the cusp of increasing microbiome research in rheumatology in Australia,” says the University of Sydney postdoctoral fellow.

In addition to A3BC, the UNSW Microbiome Research Centre provides support to researchers interested in undertaking any microbiome research.

Consortia further afield includes the Human Microbiome Project of the US National Institutes of Health and the European Metahit project which ran from 2008 to 2012.

The future

Professor Kenna looks forward to novel clinical options for doctors and patients.

“Ultimately, I think the progress in this area will give us an opportunity for fairly standardised treatment approaches in the future,” he says.

“Some Australian biotech companies are heading towards a scenario where they will use cutting-edge science to design treatments that are as simple as taking a probiotic,” he says. “It’s a really exciting space.”