Ifnar gene variants influence gut microbial production of palmitoleic acid and host immune responses to tuberculosis

• DOI: 10.1038/s42255-022-00547-3
• Publication Date: 2022-03-14T17:12:40Z
• Authors: Lingming Chen; Guoliang Zhang; Guobao Li; Wei Wang; Zhenhuang Ge; Yi Yang; Xing He; Zhi Liu; Zhiyi Zhang; Qiongdan Mai; Yiwei Chen; Zixu Chen; Jiang Pi; Shuai Yang; Jun Cui; Haipeng Liu; Ling Shen; Lingchan Zeng; Lin Zhou; Xinchun Chen; Baoxue Ge; Zheng W. Chen; Gucheng Zeng
• Keywords: 0301 basic medicine; Immunity; Receptor, Interferon alpha-beta; Gastrointestinal Microbiome; 3. Good health; Fatty Acids, Monounsaturated; Mice; 03 medical and health sciences; Verrucomicrobia; Tumor Necrosis Factors; Animals; Humans; Tuberculosis; Disease Susceptibility

Both host genetics and the gut microbiome have important effects on human health, yet how host genetics regulates gut bacteria and further determines disease susceptibility remains unclear. Here, we find that the gut microbiome pattern of participants with active tuberculosis is characterized by a reduction of core species found across healthy individuals, particularly Akkermansia muciniphila. Oral treatment of A. muciniphila or A. muciniphila-mediated palmitoleic acid strongly inhibits tuberculosis infection through epigenetic inhibition of tumour necrosis factor in mice infected with Mycobacterium tuberculosis. We use three independent cohorts comprising 6,512 individuals and identify that the single-nucleotide polymorphism rs2257167 'G' allele of type I interferon receptor 1 (encoded by IFNAR1 in humans) contributes to stronger type I interferon signalling, impaired colonization and abundance of A. muciniphila, reduced palmitoleic acid production, higher levels of tumour necrosis factor, and more severe tuberculosis disease in humans and transgenic mice. Thus, host genetics are critical in modulating the structure and functions of gut microbiome and gut microbial metabolites, which further determine disease susceptibility.