Summary Dysfunction in host immune responses and pathologic alterations in the gut microbiota, referred to as dysbiosis, can both contribute to the development of inflammatory bowel disease (IBD). However, it remains unclear how specific changes in host immunity or the microbiota cause disease. We previously demonstrated that the loss of the innate immune receptor NLRP6 in mice resulted in impaired production of IL18 and increased susceptibility to epithelial-induced injury. Here, we show that NLRP6 is important for suppressing the development of spontaneous colitis in the IL10−/− mice model of IBD and that NLRP6-deficiency results in the enrichment of Akkermansia muciniphila. A. muciniphila was sufficient for promoting intestinal inflammation in both specific-pathogen free and germfree IL10−/− mice. Our results demonstrate that A. muciniphila can act as a pathobiont to promote colitis in a genetically-susceptible host and that NLRP6 is a key regulator of its abundance.

Highlights d Interpersonal human gut microbiome variation confers variable infection resistance d Microbiome-dependent infection resistance can be restored through co-transplantation d Colonization resistance is mediated through the bile salt hydrolase enzyme activity d Bile salt hydrolase abundance in human microbiomes correlates to final infection

Clonal hematopoiesis (CH), the clonal expansion of a blood stem cell and its progeny driven by somatic driver mutations, affects over a third of people, yet remains poorly understood. Here we analyze genetic data from 200,453 UK Biobank participants to map the landscape of inherited predisposition to CH, increasing the number of germline associations with CH in European-ancestry populations from 4 to 14. Genes at new loci implicate DNA damage repair (PARP1, ATM, CHEK2), hematopoietic stem cell migration/homing (CD164) and myeloid oncogenesis (SETBP1). Several associations were CH-subtype-specific including variants at TCL1A and CD164 that had opposite associations with DNMT3A- versus TET2-mutant CH, the two most common CH subtypes, proposing key roles for these two loci in CH development. Mendelian randomization analyses showed that smoking and longer leukocyte telomere length are causal risk factors for CH and that genetic predisposition to CH increases risks of myeloproliferative neoplasia, nonhematological malignancies, atrial fibrillation and blood epigenetic ageing.

No abstract

The likelihood ratio statistic, with its asymptotic χ 2 distribution at regular model points, is often used for hypothesis testing. At model singularities and boundaries, however, the asymptotic distribution may not be χ 2 , as highlighted by recent work of Drton. Indeed, poor behavior of a χ 2 for testing near singularities and boundaries is apparent in simulations, and can lead to conservative or anti-conservative tests. Here we develop a new distribution designed for use in hypothesis testing near singularities and boundaries, which asymptotically agrees with that of the likelihood ratio statistic. For two example trinomial models, arising in the context of inference of evolutionary trees, we show the new distributions outperform a χ 2 .MSC 2010 subject classifications: Primary 62E17; secondary 92D15.