Introduction
The microbiota undergoes rapid changes during the first 3 to 4 years of life. A number of early childhood events that impact the microbiota are also associated with the risk for developing autoimmune diseases such as juvenile idiopathic arthritis (JIA). This editorial explores the role of the microbiota in the pathogenesis of JIA, as well as current research into therapeutic alterations of the microbiota.
Abnormalities of the microbiota in JIA
To date, there have been six studies on the intestinal microbiota of children with JIA (see Table 1). Despite substantial heterogeneity between these studies, several themes have emerged from this research. First, a decrease in the fecal abundance of Faecalibacterium prausnitzii was observed in our two studies of children with enthesitis-related arthritis (ERA) [1,2], and an Italian study of children with ERA [3]. This organism is generally considered to be anti-inflammatory through generation of short-chain fatty acids (SCFA) such as butyrate, and through direct action on regulatory T cells [4].
A second theme emerging from this research is increased fecal abundance of the Bacteroides genus, particularly B. fragilis. This was seen in both of our studies of ERA patients [1,2], in an Indian study of ERA patients [5], and in two Scandinavian studies of JIA patients [6,7].
Table 1. Summary of microbiota studies in JIA
Study | Population | Depleted bacteria | Enriched bacteria | Location |
Stoll (2014) [1] | New-onset and established ERA (n=25), HC (n=13) | F. prausnitzii Lachnospiraceae | Bacteroides Akkermansia muciniphila | Alabama, USA |
Stoll (20180 [2] | Newly diagnosed ERA (n=30), HC (n=19) | F. prausnitzii A2-165 | B. fragilis | Various sites in USA |
Di Paola (2016) [3] | Established JIA (n=29, ERA 19, pJIA 10), HC n=29 | Peptostreptococcaceae in ERA Faecalibacterium in ERA | Ruminococcaceae in both subsets Veillonellaceae and Clostridium cluster XIV in ERA | Florence, Italy |
Aggarwal (2017) [5] | ERA (n=33), HC (n=14) No medications prior 6 weeks | Prevotella | Bacteroides Enterococcus Klebsiella | Lucknow, India |
Muller (2017) [6] | RF- pJIA (n=8), HC (n=22) | Alistipes finegoldii, Prevotella multisaccharivorax | B. fragilis | Netherlands |
Tejesvi (2016) [7] | Newly diagnosed JIA* (n=30, HC (n=27) | Firmicutes | Bacteroidetes Bacteroides | Oulu, Finland |
*Mostly RF- polyarticular, oligoarticular. Abbreviations: ERA, enthesitis-related arthritis; HC, healthy controls; JIA, juvenile idiopathic arthritis; pJIA, polyarticular JIA; RF, rheumatoid factor.
Mechanisms by which an altered microbiota may be associated with JIA
There are numerous potential explanations linking an altered microbiota to a disease state such as JIA. The altered microbiota could very well represent an epiphenomenon induced by nonspecific factors such as an inflamed intestinal milieu. It may result from treatments of the underlying arthritis. There may also be dietary differences between JIA patients and controls, particularly if families have attempted to use dietary alteration as a treatment.
Alternatively, an altered microbiota may itself be a risk factor for JIA. There may be a loss of protective species and their byproducts, such as F. prausnitzii and SCFA, as discussed above. Another potential mechanism is that an altered microbiota may in fact reflect altered immunologic development.
Among the functions of the intestinal microbiota is education of the immune system. This has been best established in animal systems, in which multiple abnormalities are observed in germ-free mice (reviewed in [8]). Of relevance to children is that there appears to be a window of opportunity for the microbiota to impact immunologic development. Thus, alterations to the microbiota that take place during early childhood can have profound impacts on the development of the child’s immune system, and these alterations may become permanent.
Early childhood events, the microbiota, and JIA
It is of particular interest that several early childhood events are associated with alterations in the microbiota, and an increased risk for JIA. For example, delivery by Cesarean section results in dramatic alterations in the intestinal microbiota [9]. Likewise, the form of feeding – bottle versus breast – appears to impact the human intestinal microbiota [10]. Both of these factors are also associated with risk for JIA [11,12]. Finally, antibiotic exposure at any time clearly alters the microbiota, and is associated with a dose-dependent increased risk for JIA [13].
These exposures appear largely to be associated with pediatric autoimmune disease; however, ultimately proof of a causal association is lacking. It is possible that they result in the development of a microbiota that results in suboptimal immunologic development, thus priming the system for increased autoimmune disease risk. This was the conclusion of a recent study that showed that B. fragilis, compared with Escherichia coli, was less able to prevent inflammatory responses following toll-like receptor ligand activation or delay onset of a mouse model of diabetes [14]. These findings may explain the seemingly paradoxical observation that this anti-inflammatory organism is consistently present in increased abundance in children with JIA (see Abnormalities of the microbiota in JIA, above).
Therapeutic alterations of the microbiota in JIA
There are very little data on microbiota-altering therapies to treat JIA. A randomized trial of probiotics in children with ERA failed to show any differences compared with placebo [15]. However, the probiotic used in this study (VSL#3) contains organisms that are not typically depleted in ERA patients compared with controls, and this probiotic did not appear to alter the contents of the fecal microbiota [5]. This is not unexpected; a recent study indicated that probiotics are detected in the feces during the period of use, but do not have a lasting impact on the contents of the fecal microbiota [16].
Whether depleting the endogenous microbiota with antibiotics prior to offering probiotics would result in the latter having a more lasting impact, is a yet unanswered question. There have also been case reports describing the use of exclusive enteral nutrition to treat JIA [17]. Although alterations in the microbiota were observed, it is not known whether these alterations were responsible for the symptomatic improvement.
Recommendations: an ounce of prevention...
In general, changes in the development of the microbiota should be minimized, in particular, avoiding unnecessary use of antibiotics and the possible increased risk for immune-mediated diseases.
There are no data upon which to base recommendations regarding microbiota-based interventions in patients with established JIA. Targeted prebiotic or probiotic interventions designed to increase the abundance of butyrate-producing organisms may be worthy of study, but cannot be recommended in routine practice.
Conclusions
Research into the role of the fecal microbiota in the pathogenesis of JIA is in its infancy. Although differences between patients and controls are routinely and consistently observed, much work remains to explore the pathophysiologic and therapeutic implications of these findings.