Pediatric acute-onset neuropsychiatric syndrome (PANS) refers to a clinical spectrum of neuropsychiatric disorders triggered by environmental conditions, metabolic disorders and/or infections, which may increase children’s risk of sleep disturbances and mood disorders. A specific subset within the broader clinical spectrum of PANS includes pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections syndrome (PANDAS). An increasing amount of research is focusing on studying the bidirectional communication between the gut and the brain, with the aim of identifying new gut microbial biomarkers for brain-related diseases, though little is known about gut microbiota’s contribution in subjects affected by PANS/PANDAS.
A new study, led by Dr. Lorenza Putignani from the Bambino Gesù Children’s Hospital in Rome (Italy), has found that gut microbiota may promote gut inflammation and activation of an immune response in PANS/PANDAS patients.
The researchers collected three fecal samples over consecutive days and, using 16S ribosomal ribonucleic acid (rRNA)-based metagenomics, they analyzed the gut microbiota composition of a cohort of 30 PANS/PANDAS patients aged 4-16 years (20 males and 10 females), comparing them with 70 healthy controls.
An altered bacterial community structure was detected in PANS/PANDAS patients when compared to controls. As ecological analysis revealed the presence of two main clusters of subjects based on age range, the researchers split data from patients into two groups—4 to 8 years old and >9 years old—to remove possible age-related bias. A lower level of a-diversity was observed for PANS/PANDAS patients compared with control subjects, which seems to suggest a relationship between the disease and gut microbiota composition, regardless of the patients’ age.
The loss of biodiversity in the younger PANS/PANDAS group was limited and not so evident in all a-diversity indices, suggesting that this group of patients is characterized by a low degree of dysbiosis. At the phylum level, the younger PANS/PANDAS group had a reduction of Firmicutes and TM7 phyla and a major enrichment in Bacteroidetes compared with controls. The authors argue that this disequilibrium between Firmicutes and Bacteroidetes may be responsible for altered metabolic function in these patients as Bacteroidetes plays a relevant role in host physiology and changes in its relative abundance have been associated with metabolic disorders such as obesity. Specifically, this younger group was characterized by a strong increase in Bacteroides, Odoribacter and Oscillospira belonging to Bacteroidetes phyla and an absence of Erysipelotrichaceae species that have been found to attract more IgA molecules than other gut microbial families, thus possibly helping to explain the IgA deficiency usually detected in PANS/PANDAS patients. Furthermore, the 4 to 8 years old group exhibited an increase of several pathways involved in modulating the antibody response to inflammation within the gut, as well as a decrease in short-chain fatty acids, D-alanine, tyrosine and dopamine pathways involved in certain neuronal functions. Meanwhile, the metabolic profile was also characterized by a lack of important anti-inflammatory elements such as dioxin degradation and unsaturated fatty acids.
The older group of patients exhibited a less uniform bacterial profile and the researchers were unable to identify distinct biomarkers. They therefore argue that the high level of heterogeneity within this group could be explained by the repeated antibiotic treatments they have undergone during their lives.
Control subjects exhibited increased D-alanine metabolism and higher levels of Roseburia genus members, the latter being involved in gut homeostasis through preserving gut barrier function and promoting butyrate production with an anti-inflammatory effect.
Finally, in a subset of PANS/PANDAS patients with anti-streptolysin O titer (ASLOT) values higher than 500 units and time until detection <5 months from gut microbiota analysis, significant correlations were found between ASLOT—a measure of the blood plasma levels of antistreptolysin O antibodies used in tests for the diagnosis of a streptococcal infection—and bacterial genera. A negative correlation was found between genera belonging to Firmicutes phylum (Dehalobacterium, Corynebacteriu, Gemella and Lactobacillus) and ASLOT, which seems to be in agreement with the low percentage of this phylum among the younger group of PANS/PANDAS patients. Meanwhile, a positive correlation was observed with Odoribacter. Given the role of Streptococcus pyogenes infections in PANS/PANDAS etiology, these data suggest that streptococcal influence may influence gut microbiota composition and host inflammation, contributing to the development of disease.
In conclusion, these findings suggest that streptococcal infections alter gut microbiota composition, leading to a pro-inflammatory status by influencing specific gut bacterial communities. Further research is needed to explore the role of gut microbiota as a novel biomarker of the disease and its involvement in patients’ treatment.
Quagliariello A, Del Chierico F, Russo A, et al. Gut microbiota profiling and gut-brain crosstalk in children affected by pediatric acute-onset neuropsychiatric syndrome and pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections. Front Microbiol. 2018. doi: 10.3389/fmicb.2018.00675.