Dataset Information

Alterations in the human gut microbiome in anti-N-methyl-D-aspartate receptor encephalitis.

ABSTRACT:

Objective

To explore the diversity and composition of the fecal microbiota in patients with anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis.

Methods

We enrolled 10 patients in the acute stage with naïve treatment, seven patients with relapse, 13 patients without relapse in the remission phase, and 12 paired healthy controls. The fecal microbiota in different groups was compared by 16S ribosomal DNA (rDNA) gene pyrosequencing.

Results

Prominent dysbiosis in the gut microbiome of patients with anti-NMDAR encephalitis was found. Our primary findings showed that the overall species richness (alpha diversity indexes) of the microbiota was higher in patients than in controls (P < 0.05). Distance-based community analysis revealed that the microbiota differed substantially within all subgroups of patients and controls (P < 0.05). The relative abundance of species heatmap showed a tendency toward depletion for some commensal genera, such as Prevotella_6, Bifidobacterium, Faecalibacterium, and other short-chain fatty acid (SCFA)-producing bacteria. Additionally, our results showed that all subgroups had a distinct bacterial species, with an increase in the genus Fusobacterium in the acute phase group and the genera Streptococcus and Parabacteroides in patients with relapse. However, the genus Bacteroides was very abundant in patients without relapse. Although the findings regarding the Firmicutes/Bacteroidetes (F/B) ratios across the four comparison groups were not statistically significant, the F/B ratio gradually increased in patients from the acute phase group (0.87), to the disease remission group with relapse (1.06), to the group without relapse (1.28), to the healthy group (1.63).

Interpretation

Patients with anti-NMDAR encephalitis exhibit a substantial alteration in fecal microbiota composition.

SUBMITTER: Gong X

PROVIDER: S-EPMC6764498 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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Publications

Alterations in the human gut microbiome in anti-N-methyl-D-aspartate receptor encephalitis.

Gong Xue X Liu Xu X Li Chen C Chen Chu C Lin Jingfang J Li Aiqing A An Dongmei D Zhou Dong D Hong Zhen Z

Annals of clinical and translational neurology 20190825 9

<h4>Objective</h4>To explore the diversity and composition of the fecal microbiota in patients with anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis.<h4>Methods</h4>We enrolled 10 patients in the acute stage with naïve treatment, seven patients with relapse, 13 patients without relapse in the remission phase, and 12 paired healthy controls. The fecal microbiota in different groups was compared by 16S ribosomal DNA (rDNA) gene pyrosequencing.<h4>Results</h4>Prominent dysbiosis in the gut m ...[more]

PMID: 31448571

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Project description:ObjectiveTo report the autoantigens of a new category of treatment-responsive paraneoplastic encephalitis.MethodsAnalysis of clinical features, neuropathological findings, tumors, and serum/cerebrospinal fluid antibodies using rat tissue, neuronal cultures, and HEK293 cells expressing subunits of the N-methyl-D-aspartate receptor (NMDAR).ResultsTwelve women (14-44 years) developed prominent psychiatric symptoms, amnesia, seizures, frequent dyskinesias, autonomic dysfunction, and decreased level of consciousness often requiring ventilatory support. All had serum/cerebrospinal fluid antibodies that predominantly immunolabeled the neuropil of hippocampus/forebrain, in particular the cell surface of hippocampal neurons, and reacted with NR2B (and to a lesser extent NR2A) subunits of the NMDAR. NR2B binds glutamate and forms heteromers (NR1/NR2B or NR1/NR2A/NR2B) that are preferentially expressed in the adult hippocampus/forebrain. Expression of functional heteromers (not single subunits) was required for antibody binding. Eleven patients had teratoma of the ovary (six mature) and one a mature teratoma in the mediastinum; five of five tumors examined contained nervous tissue that strongly expressed NR2 subunits and reacted with patients' antibodies. Tumor resection and immunotherapy resulted in improvement or full recovery of eight of nine patients (paralleled by decreased antibody titers); two of three patients without tumor resection died of neurological deterioration. Autopsies showed extensive microgliosis, rare T-cell infiltrates, and neuronal degeneration predominantly involving, but not restricted to, the hippocampus.InterpretationAntibodies to NR2B- and NR2A-containing heteromers of the NMDAR associate with a severe but treatment-responsive encephalitis. Our findings provide a diagnostic test and suggest a model of autoimmune NMDAR-related encephalitis with broad implications for other immune-mediated disorders of memory, behavior, and cognition.

Project description:ObjectiveSeizures develop in 80% of patients with anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis, and these represent a major cause of morbidity and mortality. Anti-NMDAR antibodies have been linked to memory loss in encephalitis; however, their role in seizures has not been established. We determined whether anti-NMDAR antibodies from autoimmune encephalitis patients are pathogenic for seizures.MethodsWe performed continuous intracerebroventricular infusion of cerebrospinal fluid (CSF) or purified immunoglobulin (IgG) from the CSF of patients with anti-NMDAR encephalitis or polyclonal rabbit anti-NMDAR IgG, in male C57BL/6 mice. Seizure status during a 2-week treatment was assessed with video-electroencephalography. We assessed memory, anxiety-related behavior, and motor function at the end of treatment and assessed the extent of neuronal damage and gliosis in the CA1 region of hippocampus. We also performed whole-cell patch recordings from the CA1 pyramidal neurons in hippocampal slices of mice with seizures.ResultsProlonged exposure to rabbit anti-NMDAR IgG, patient CSF, or human IgG purified from the CSF of patients with encephalitis induced seizures in 33 of 36 mice. The median number of seizures recorded in 2 weeks was 13, 39, and 35 per mouse in these groups, respectively. We observed only 18 brief nonconvulsive seizures in 11 of 29 control mice (median seizure count of 0) infused with vehicle (n = 4), normal CSF obtained from patients with noninflammatory central nervous system (CNS) conditions (n = 12), polyclonal rabbit IgG (n = 7), albumin (n = 3), and normal human IgG (n = 3). We did not observe memory deficits, anxiety-related behavior, or motor impairment measured at 2 weeks in animals treated with CSF from affected patients or rabbit IgG. Furthermore, there was no evidence of hippocampal cell loss or astrocyte proliferation in the same mice.SignificanceOur findings indicate that autoantibodies can induce seizures in anti-NMDAR encephalitis and offer a model for testing novel therapies for refractory autoimmune seizures.

Dataset Information

Alterations in the human gut microbiome in anti-N-methyl-D-aspartate receptor encephalitis.

Objective

Methods

Results

Interpretation

Publications

Alterations in the human gut microbiome in anti-N-methyl-D-aspartate receptor encephalitis.

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