Limosilactobacillus reuteri alleviates proinflammatory T-cell-mediated liver injury and transcriptomic changes in immunocompromised mice.

BACKGROUND: A deficiency of immunosuppressive regulatory T cells, as seen in scurfy (SF) mice or in IPEX syndrome in humans, can lead to multiorgan inflammation. Oral administration of the probiotic Limosilactobacillus reuteri Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH (DSM) 17938 prolongs survival and reduces Th1- and Th2-associated inflammation in SF mice. It remains unclear how DSM 17938-educated SF-CD4(+) T cells modulate T-cell-liver communication. METHODS: To characterize CD4(+) T cells from SF mice orally administered DSM 17938 (Prob-SF-CD4(+) T cells) and to compare them with CD4(+) T cells from SF mice (SF-CD4(+) T cells), cells isolated from SF spleens were adoptively transferred by intraperitoneal (IP) injection into lymphocyte-deficient Recombination-Activating Gene (RAG)-1-deficient (RAG1KO) mice. Liver histological inflammation and macrophages (MΦs), liver sample transcriptomes by RNAseq, and stool microbiota by 16S rRNA sequencing were then assessed in RAG1KO mice. RESULTS: Prob-SF-CD4(+) T cells reduced the incidence and severity of liver inflammation and F4/80(+)MΦ infiltration by SF-CD4(+) T-cell transfer. SF-CD4(+) T cells upregulated genes and altered RNA splicing factors and events involved in inflammatory pathways, including Toll-like receptor (TLR) cascades, inflammatory cytokines, and death receptor signals. SF-CD4(+) T cells downregulated genes linked to metabolism, including mitochondrial function, the TCA cycle, lipids, and liver detoxification. Prob-CD4(+) T-cell transfer reversed SF-CD4(+) T-cell-induced gene changes in inflammatory and metabolic interactive clusters while modulating distinct genes involved in TLR regulation and the cell cycle. CD4(+) T-cell transfer altered gut microbial diversity compared with RAG1KO mice without CD4(+) T-cell transfer. Prob-SF-CD4(+) T-cell transfer exclusively increased the relative abundance (RA) of Incertae_sedis and reduced the RA of Clostridia_vadinBB60_group in the stool of RAG1KO mice. CONCLUSIONS: Inflammatory lymphocytes (CD4(+) T cells) can perpetuate an exaggerated immune response in an immunologically naïve host. Feeding with DSM 17938 modulated T cells and allowed them to provide beneficial effects to the recipient. We observed activation of multiple genes and their interactions. These findings suggest that probiotics or probiotic-modulated T cells could be further explored as therapeutic options for autoimmune liver diseases.