The dynamics of the tripartite relationship between the host, gut bacteria and diet in the gut is relatively unknown. An imbalance between harmful and protective gut bacteria, termed dysbiosis, has been linked to many diseases and has most often been attributed to high-fat dietary intake. However, we recently clarified that the type of fat, not calories, were important in the development of murine colitis. To further understand the host-microbe dynamic in response to dietary lipids, we fed mice isocaloric high-fat diets containing either milk fat, corn oil or olive oil and performed 16S rRNA gene sequencing of the colon microbiome and mass spectrometry-based relative quantification of the colonic metaproteome. The corn oil diet, rich in omega-6 polyunsaturated fatty acids, increased the potential for pathobiont survival and invasion in an inflamed, oxidized and damaged gut while saturated fatty acids promoted compensatory inflammatory responses involved in tissue healing. We conclude that various lipids uniquely alter the host-microbe interaction in the gut. While high-fat consumption has a distinct impact on the gut microbiota, the type of fatty acids alters the relative microbial abundances and predicted functions. These results support that the type of fat are key to understanding the biological effects of high-fat diets on gut health.

Individuals with clonal hematopoiesis of indeterminate potential (CHIP) are at increased risk of aging related health conditions and all-cause mortality, but whether CHIP affects risk of infection is much less clear. Using UK Biobank data, we revealed a positive association between CHIP and incident pneumonia in 438,421 individuals. We show that inflammation enhanced pneumonia risk, as CHIP carriers with a hypomorphic IL6 receptor polymorphism were protected. To better characterize the pathways of susceptibility, we challenged hematopoietic Tet Methylcytosine Dioxygenase 2– knockout ( Tet2 ^–/– ) and floxed control mice ( Tet2 ^fl/fl ) with Streptococcus pneumoniae . As with human CHIP carriers, Tet2 ^–/– mice had hematopoietic abnormalities resulting in the expansion of inflammatory monocytes and neutrophils in peripheral blood. Yet, these cells were insufficient in defending against S . pneumoniae and resulted in increased pathology, impaired bacterial clearance, and higher mortality in Tet2 ^–/– mice. We delineated the transcriptional landscape of Tet2 ^–/– neutrophils and found that, while inflammation-related pathways were upregulated in Tet2 ^–/– neutrophils, migration and motility pathways were compromised. Using live-imaging techniques, we demonstrated impairments in motility, pathogen uptake, and neutrophil extracellular trap (NET) formation by Tet2 ^–/– neutrophils. Collectively, we show that CHIP is a risk factor for bacterial pneumonia related to innate immune impairments.

Somatic mutations in the TET2 gene occur more frequently with age, imparting an intrinsic hematopoietic stem cells (HSCs) advantage and contributing to a phenomenon termed clonal hematopoiesis of indeterminate potential (CHIP). Individuals with TET2-mutant CHIP have a higher risk of developing myeloid neoplasms and other aging-related conditions. Despite its role in unhealthy aging, the extrinsic mechanisms driving TET2-mutant CHIP clonal expansion remain unclear. We previously showed an environment containing tumor necrosis factor (TNF) favors TET2-mutant HSC expansion in vitro. We therefore postulated that age-related increases in TNF also provide an advantage to HSCs with TET2 mutations in vivo. To test this hypothesis, we generated mixed bone marrow chimeric mice of old wild-type (WT) and TNF–/– genotypes reconstituted with WT CD45.1+ and Tet2–/– CD45.2+ HSCs. We show that age-associated increases in TNF dramatically increased the expansion of Tet2–/– cells in old WT recipient mice, with strong skewing toward the myeloid lineage. This aberrant myelomonocytic advantage was mitigated in old TNF–/– recipient mice, suggesting that TNF signaling is essential for the expansion Tet2-mutant myeloid clones. Examination of human patients with rheumatoid arthritis with clonal hematopoiesis revealed that hematopoietic cells carrying certain mutations, including in TET2, may be sensitive to reduced TNF bioactivity following blockade with adalimumab. This suggests that targeting TNF may reduce the burden of some forms of CHIP. To our knowledge, this is the first evidence to demonstrate that TNF has a causal role in driving TET2-mutant CHIP in vivo. These findings highlight TNF as a candidate therapeutic target to control TET2-mutant CHIP.

Human milk is the best nutritional choice for infants. However, in instances where breastfeeding is not possible, infant formulas are used as alternatives. While formula manufacturers attempt to mimic the performance of human breast milk, formula-fed babies consistently have higher incidences of infection from diarrheal diseases than those breastfed. Differences in disease susceptibility, progression and severity can be attributed, in part, to nutritional fatty acid differences between breast milk and formula. Despite advances in our understanding of breast milk properties, formulas still present major differences in their fatty acid composition when compared to human breast milk. In this review, we highlight the role of distinct types of dietary fatty acids in modulating host inflammation, both directly and through the microbiome-immune nexus. We present evidence that dietary fatty acids influence enteric disease susceptibility and therefore, altering the fatty acid composition in formula may be a potential strategy to improve infectious outcomes in formula-fed infants.

Background & AimsLong chain omega-3 polyunsaturated fatty acids (n-3 PUFA), such as docosahexaenoic acid (DHA) are widely considered beneficial for infant health and development. The aim of this meta-analysis was to summarize the evidence related to the clinical outcomes of long chain n-3 PUFA supplementation maternally and in fortified formula/taken directly. Additionally, we investigate if the addition of arachidonic acid (AA) alters the effects caused by n-3 PUFA supplements.MethodsWe searched the Cochrane Central Register of Controlled Trials (CENTRAL), EMBASE (1974 to June 2015) CINAHL (1990 to June 2015), PubMed (1966–2015), Web of Science (1864–2015), MEDLINE (1974 to June 2015), and hand searches for randomized and semi-randomized controlled trials on term infants evaluating the effects of long chain n-3 PUFA supplementation taken maternally and in milk based formula or directly.ResultsWe identified 39 formula and 39 breastmilk studies on the clinical outcomes of long chain n-3 PUFA supplementation, with or without AA, on infant immunity and development. Of these studies, 32 formula and 37 breastmilk studies were deemed appropriate resulting in a total of 2443 formula fed infants and 4553 breastfed infants exposed to n-3 PUFA supplementation. This meta-analysis shows that n-3 PUFA supplementation in infants delivered either maternally or in formula/directly, does not improve visual acuity, language development, or cognition. However, some aspects of growth, motor development, behavior and cardiovascular health are differentially altered in the summary effects of certain studies with the more desired effect occurring often in breastfed infants compared to formula fed infants. Moreover, this meta-analysis shows that n-3 PUFA supplements affects infant immune development and reduces pro-inflammatory responses in the supplemented breastfed and fortified formula fed/directly supplemented infants.ConclusionOverall, the evidence does not support the continued supplementation of infant formula with long chain n-3 PUFA considering the negative impact on the developing immune responses