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Gut Biome Altered in Inflammatory Arthritis, but Causal Direction Unclear

— Authors of new study ready to exonerate intestinal flora as a cause of joint disease

MedpageToday
A computer rendering of the intestinal microbiome

Another study has confirmed that the intestinal microbiome's composition in people with inflammatory arthritis differs from that in other people, and in potentially unhealthy ways -- but whether the microbiome alterations actually cause arthritis is less clear.

In fact, the investigators believe it's probably the other way around.

Stool samples from 221 patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA), or ankylosing spondylitis (AS) were compared to samples from 219 control individuals who were either healthy (n=165) or had non-inflammatory joint pain (n=54). The former group had "increased carriage of typically oral and inflammatory taxa and decreased abundance and prevalence of typical gut clades" relative to controls, according to Curtis Huttenhower, PhD, of the Harvard T.H. Chan School of Public Health in Boston, and colleagues.

Moreover, the patterns seen in the inflammatory arthritis patients were associated with metabolic pathways that would alter "vitamin B salvage and biosynthesis" and foster "enrichment of iron sequestration," the researchers reported.

"Our study contributes to the growing body of evidence that the gut microbiome and inflammation throughout the body are tightly coupled, likely both casually and responsively, because the gut microbiome serves as a mediator of environmental triggers and then also changes in response to immune activity," the group . "We hypothesize that this occurs in part because of a functional 'echo' of systemic inflammation in the gut microbiome, due to the similarity in the specific processes that are altered in IBD [inflammatory bowel disease] and in arthritis."

Connections between the gut microbiome and rheumatologic conditions have been hypothesized and confirmed in numerous studies, which began almost immediately after it was recognized that intestinal flora are not parasites, but are crucial to healthy metabolism. (In fact, Huttenhower and colleagues cited one publication from the 1890s suggesting that arthritis could stem from Mycobacterium infections.) Not surprisingly, alterations in biome composition were quickly found in IBD patients, and this work was then extended to more distant inflammatory conditions. These associations were strong enough to prompt speculation that perhaps such alterations could actually trigger diseases such as RA.

Evidence for a causal role was limited, however -- largely circumstantial with some support from rodent experiments, and without much insight into the exact pathways by which the intestinal biome could generate joint pathology. And the case for causation going in the other direction is also highly plausible: systemic inflammation would make the intestinal wall more porous and thus alter the habitat for microorganisms.

"[A] comprehensive understanding of the role of the gut microbiome in arthritis development and persistence is still lacking," Huttenhower's group observed.

Patients for their study came from three clinics in England; just over half of the inflammatory group had RA, 67 had AS, and 35 had PsA. The controls with non-inflammatory joint pain mostly had been diagnosed with fibromyalgia.

Microbe types that were substantially more common in the arthritis patients versus controls included Streptococcus species, Escherichia coli, and Ruminococcus gnavus. Many of the Streptococcus species are normally found in the oral cavity but not typically in the intestine. Increases in Prevotella copri, however, were not seen, in contrast to some previous studies.

However, the functional implications of these alterations don't add up to a one-way causal arrow, Huttenhower's group concluded. For example, they suggested that their finding of increased expression of iron sequestration genes is likely due to "anemic conditions" in the arthritis patients.

"[W]e hypothesize that they are mainly positive feedback responses to changes in host physiology and immune homeostasis," they wrote.

At the same time, they acknowledged that their functional analyses were based only on genomic data and presumptions of how that would translate physiologically. "[I]t is impossible to establish the causality or mechanism of these gut microbial changes from an observational human study, and we fully expect our own and others' longitudinal human and model system research to clarify these," the investigators wrote.

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    John Gever was Managing Editor from 2014 to 2021; he is now a regular contributor.

Disclosures

The study was funded by nonprofit foundation grants. Huttenhower reported relationships with Seres Therapeutics, Empress Therapeutics, and ZOE Nutrition. One co-author reported being a founder of Vedanta Biosciences; another author reported relationships with Bristol Myers Squibb, Abbvie, and Sanofi.

Primary Source

Science Translational Medicine

Thompson KN, et al "Alterations in the gut microbiome implicate key taxa and metabolic pathways across inflammatory arthritis phenotypes" Sci Transl Med 2023; DOI: 10.1126/scitranslmed.abn4722.