Application of IgA-Seq in schizophrenia to identify key gut bacteria that promote abnormal behavior in mice

ABSTRACT Schizophrenia (SCZ) has a complex etiology, and growing evidence implicates the microbiota-gut-brain axis. Because abundance-based profiling does not identify taxa closely engaged by mucosal immunity, we used immunoglobulin A (IgA)-based bacterial sorting to prioritize candidate SCZ-associated gut bacteria and evaluated cultured consortia in mouse models. Fecal samples were collected from participants with SCZ, other mental disorders, and healthy controls, which underwent 16S rRNA gene sequencing before and after magnetic separation of IgA-coated (IgA+) and non-IgA-coated (IgA−) bacteria. Taxa prioritized by the IgA coating index were anaerobically cultured, pooled into defined IgA+ and IgA− consortia, and administered to germ-free (GF) C57BL/6J, antibiotic-pretreated Rag1 −/− SPF, and conventional SPF C57BL/6J mice. In the bacterial treatment groups, MK-801 was introduced only during the final 7 days of consortium gavage; the GF NaCl control received intraperitoneal saline during the corresponding final 7-day period. Behavioral, serological, colonic, and hippocampal outcomes were assessed according to the endpoints specified for each experiment. Candidate IgA+ taxa included Streptococcus , Pseudomonas , and Parabacteroides , whereas IgA− candidates included Collinsella , Eggerthella , Bifidobacterium , Bacteroides , Enterococcus , and Clostridium . In experiment 1, the GF IgA+ and GF IgA− groups differed in open-field center-zone time ( P = 0.032). Marble-burying behavior showed a significant overall difference among the five groups ( P = 0.040), with a significant pairwise difference between GF IgA+ and GF IgA− mice ( P = 0.022). Y-maze spontaneous alternation showed no overall group difference ( P = 0.81). Forced-swim immobility showed a significant overall group effect ( P = 0.020), with significant pairwise differences between GF IgA+ and GF IgA− mice ( P = 0.020) and between GF IgA− and Rag1 −/− IgA− mice ( P = 0.030). IL-6 was frequently undetectable and was not compared statistically; TNF-α showed a significant overall analysis of variance group effect ( P = 0.040), but no Tukey-adjusted pairwise comparison was significant. Colon length also showed a significant overall group effect ( P = 0.010), with shorter colons in the GF IgA+ group than in the GF saline and GF IgA− groups (both pairwise P = 0.016), although colonic histology was largely normal. Descriptive hippocampal alterations were observed in GF IgA+ consortium mice. In conventional specific pathogen-free mice, MK-801 was introduced after the first 7 days of consortium gavage and continued during the final 7 days; under this exposure schedule, the IgA+ consortium was associated with greater colonic mucosal injury than the IgA− consortium. IgA-based prioritization identified candidate SCZ-associated taxa, and the resulting consortia were associated with distinct, context-dependent host responses. Individual-taxon causality remains unproven and requires validation in larger cohorts and rigorously matched animal studies. IMPORTANCE Schizophrenia (SCZ) is a severe psychiatric disorder with incompletely understood biological mechanisms. Although gut microbial alterations have been reported in SCZ, abundance alone does not show which bacteria are most closely recognized by the intestinal immune system. Here, IgA-based sorting was used to prioritize immune-targeted bacterial taxa, and cultured IgA+ and IgA− consortia were evaluated in mouse experiments. The two consortia were associated with different behavioral and tissue outcomes under specific experimental conditions. In both animal experiments, bacterial gavage preceded MK-801, which was introduced during the final 7 days of gavage as a late pharmacological challenge. These findings provide a hypothesis-generating framework for studying mucosal immune-microbiota interactions in SCZ, but they do not support diagnostic, therapeutic, or strain-specific causal claims.