A quasi-paired cohort strategy reveals the impaired detoxifying function of microbes in the gut of autistic children

Abstract

30Growing evidence suggests that autism spectrum disorder (ASD) is highly associated with 31 dysbiosis in the gut microbiome. However, results of metagenome-based microbiome 32 studies are not always consistent due to great individual diversity that overwhelms 33 disease-associated alterations. Here, we proposed a novel analysis strategy-quasi-paired 34 cohort and applied it to a metagenomic study of ASD microbiomes. By comparing the 35 paired samples of ASD and neurotypical subjects, we identified significant deficiencies in 36 ASD children in detoxifying enzymes and pathways, which showed strong correlations to 37 mitochondrial damage. Diagnostic models with these detoxifying enzymes accurately 38 discriminated ASD individuals from controls, and the dysfunction score inferred from the 39 model increased with the clinical rating scores of ASD. Conclusively, our findings suggest 40 a previously undiscovered mechanism in which impaired microbial detoxification leads to 41 toxicant accumulation and mitochondrion damage contributes to the pathogenesis of ASD. 42 This novel mechanism points to future therapeutic strategies of rebuilding microbial 43 detoxification for ASD. 44 45 MAIN TEXT 46 47 131 Hs37 human genomes by BWA (mem module with default parameters) (http://bio-132

Intestinal butyrate-metabolizing species contribute to autoantibody production and bone erosion in rheumatoid arthritis

“…To avoid bias, we selected multiple parallel boundary samples for both sides and then compared the abundance or presence/ absence of each species across twinned samples to identify candidate species for each of the two phenotypes (see Materials and Methods for details). This approach allowed us to transform the original group cohort into a paired cohort, which not only controls for individual diversity but also increases statistical power (10).…”

“…This concept has been extended into metagenomics research on “paired” animal studies, in which paired samples are acquired from cohoused animals of distinct phenotypes or from longitudinal sampling ( 6 , 9 ). On the basis of this concept, we previously described a novel strategy for metagenomic analysis, the “quasi-paired cohort,” in which we paired samples that displayed a similar species profile but distinct phenotypes ( 10 ). Briefly, this method begins with a matrix containing species abundance inferred from sequencing-based metagenome data of samples exhibiting a binary phenotype (e.g., diseased versus healthy control).…”

“…Making the assumption that two samples sharing a similar species profile yet with opposite phenotypes should theoretically reside near the boundary that delineates the two phenotype states in the Euclidean space ( 11 ), we recruited the concept of “boundary samples”—samples whose nearest neighbors are of the opposite phenotype, and paired each boundary sample with one of its nearest neighbors of the opposite side to form a “twin.” To avoid bias, we selected multiple parallel boundary samples for both sides and then compared the abundance or presence/absence of each species across twinned samples to identify candidate species for each of the two phenotypes (see Materials and Methods for details). This approach allowed us to transform the original group cohort into a paired cohort, which not only controls for individual diversity but also increases statistical power ( 10 ).…”

Gene variations in Autism Spectrum Disorder are associated with alternation of gut microbiota, metabolites and cytokines

“… 52 Toxin exposure has been epidemiologically demonstrated as one of the main etiological factors of ASD, and deficiencies in toxicant-degradation pathways were reported in ASD. 53 These results implicated the possible genetic factors that were underlying the microbial detoxification deficiency. Besides, a couple of gene variations were associated with the immune system.…”

The gut microbiota affects the social network of honeybees

“…Bacterial metabolites and signals produced in the gut can reach the brain and elicit local host responses that affect the host nervous system (6)(7)(8). There is also accumulating evidence linking the gut microbiome to social behavior and its dysfunctions (9)(10)(11)(12). However, effects on social behavior have typically been investigated during one-to-one encounters between gnotobiotic animals, and in model organisms that do not naturally express complex social structure (7,8,(13)(14)(15)(16)(17).…”