Human Milk Oligosaccharides Impact Cellular and Inflammatory Gene Expression and Immune Response.

Human milk harbors complex carbohydrates, including human milk oligosaccharides (HMOs), the third most abundant component after lactose and lipids. HMOs have been shown to impact intestinal microbiota, modulate the intestinal immune response, and prevent pathogenic bacterial binding by serving as decoy receptors. However, the direct effect of HMOs on intestinal function and immunity remains to be elucidated. To address this knowledge gap, 21-day-old germ-free mice (C57BI/6) were orally gavaged with 15 mg/day of pooled HMOs for 7 or 14 days and euthanized at day 28 or 35. A set of mice was maintained until day 50 to determine the persistent effects of HMOs. Control groups were maintained in the isolators for 28, 35, or 50 days of age. At the respective endpoints, intestinal tissues were subjected to histomorphometric and transcriptomic analyses, while the spleen and mesenteric lymph nodes (MLNs) were subjected to flow cytometric analysis. The small intestine (SI) crypt was reduced after HMO treatment relative to control at days 28 and 35, while the SI villus height and large intestine (LI) gland depth were decreased in the HMO-treated mice relative to the control at day 35. We report significant HMO-induced and location-specific gene expression changes in host intestinal tissues. HMO treatment significantly upregulated genes involved in extracellular matrix, protein ubiquitination, nuclear transport, and mononuclear cell differentiation. CD4+ T cells were increased in both MLNs and the spleen, while CD8+ T cells were increased in the spleen at day 50 in the HMO group in comparison to controls. In MLNs, plasma cells were increased in HMO group at days 28 and 35, while in the spleen, only at day 28 relative to controls. Macrophages/monocytes and neutrophils were lower in the spleen of the HMO group at days 28, 35, and 50, while in MLNs, only neutrophils were lower at day 50 in the 14-day HMO group. In addition, diphtheria toxoid and tetanus toxoid antibody-secreting cells were higher in HMO-supplemented group compared to controls. Our data suggest that HMOs have a direct effect on gastrointestinal tract metabolism and the immune system even in the absence of host microbiota.

Human Milk-Fed Piglets Have a Distinct Small Intestine and Circulatory Metabolome Profile Relative to That of Milk Formula-Fed Piglets.

The impact of human milk (HM) feeding compared with cow's milk formula (MF) feeding on small intestinal and circulatory metabolome patterns has not been fully investigated. Therefore, 2-day-old male piglets were fed HM or MF (n = 26/group) from postnatal day 2 (PND 2) through 21 and were weaned to a solid diet until PND 51. The small intestine (gastrointestinal [GI]) contents, serum, and urine were collected from subsets of piglets at PND 21 and PND 51. Samples were subjected to primary metabolomics analyses at the West Coast Metabolomics Center, UC Davis. The metabolome data assessment and the statistical analyses were performed with MetaboAnalyst software. Compared with MF feeding, at PND 21, HM feeding resulted in a higher abundance of fucose in the jejunum and urine and a greater concentration of myo-inositol in serum. In HM-fed piglets, 1,5-anhydroglucitol was higher in the duodenum, serum, and urine at PND 21. Additionally, the HM group had higher levels of urinary kynurenic acid at PND 21. Correlations between bacterial genera and altered metabolites in ileum revealed that Turicibacter sp. and Campylobacter sp. were positively correlated with maltotriose and panose at PND 21, while ileal Campylobacter sp. was negatively correlated with fumaric acid. At PND 51, no significant metabolites were identified between HM and MF diet groups. The metabolites associated with the neonatal diets may serve as the substrates and signals that contribute to the physiological effects in HM and MF during infancy, with a subset reflecting diet-associated differences in microbial metabolism and ecology.IMPORTANCE Exclusive HM feeding for newborns is recommended at least for the first 6 months of life. However, when breastfeeding is not possible, MF is recommended as a substitute. Due to the challenges associated with sample collection from infants fed HM or MF, their gut metabolism is poorly understood. Thus, an established piglet model from our team was used to determine the metabolite profile in relation to host, diet, and microbiota. The current study is the first to provide novel insights across the small intestine metabolism and its association with circulatory metabolites in the HM group relative to the MF group at the weaning and postweaning period. Data also demonstrate that during the neonatal period, diet, host, and microbial metabolism contribute to the lumen and circulatory metabolite profile. Furthermore, small intestinal lumen metabolome can be tracked in the urine as a biomarker of dietary differences, which would be a useful tool for clinical interventions.

Neonatal Diet Impacts the Large Intestine Luminal Metabolome at Weaning and Post-Weaning in Piglets Fed Formula or Human Milk.

The impact of human milk (HM) or dairy milk-based formula (MF) on the large intestine's metabolome was not investigated. Two-day old male piglets were randomly assigned to HM or MF diet (n = 26/group), from postnatal day (PND) 2 through 21 and weaned to a solid diet until PND 51. Piglets were euthanized at PND 21 and PND 51, luminal contents of the cecum, proximal (PC) and distal colons (DC), and rectum were collected and subjected to metabolomics analysis. Data analyses were performed using Metaboanalyst. In comparison to MF, the HM diet resulted in higher levels of fatty acids in the lumen of the cecum, PC, DC, and rectum at PND 21. Glutamic acid was greater in the lumen of cecum, PC, and DC relative to the MF group at PND 21. Also, spermidine was higher in the DC and rectal contents of HM relative to MF at PND 21. MF diet resulted in greater abundances of amino acids in the cecal lumen relative to HM diet at PND 21. Additionally, several sugar metabolites were higher in various regions of the distal gut of MF fed piglets relative to HM group at PND 21. In contrast, at PND 51, in various regions there were higher levels of erythritol, maltotriose, isomaltose in HM versus MF fed piglets. This suggests a post weaning shift in sugar metabolism that is impacted by neonatal diet. The data also suggest that infant diet type and host-microbiota interactions likely influence the lower gut metabolome.

Publisher Correction: Critical Southern Ocean climate model biases traced to atmospheric model cloud errors.

'In the original HTML version of this Article, ref.12 was incorrectly cited in the first sentence of the first paragraph of the Introduction. The correct citation is ref. 2. This has now been corrected in the HTML version of the Article; the PDF version was correct at the time of publication.'

Critical Southern Ocean climate model biases traced to atmospheric model cloud errors.

The Southern Ocean is a pivotal component of the global climate system yet it is poorly represented in climate models, with significant biases in upper-ocean temperatures, clouds and winds. Combining Atmospheric and Coupled Model Inter-comparison Project (AMIP5/CMIP5) simulations, with observations and equilibrium heat budget theory, we show that across the CMIP5 ensemble variations in sea surface temperature biases in the 40-60°S Southern Ocean are primarily caused by AMIP5 atmospheric model net surface flux bias variations, linked to cloud-related short-wave errors. Equilibration of the biases involves local coupled sea surface temperature bias feedbacks onto the surface heat flux components. In combination with wind feedbacks, these biases adversely modify upper-ocean thermal structure. Most AMIP5 atmospheric models that exhibit small net heat flux biases appear to achieve this through compensating errors. We demonstrate that targeted developments to cloud-related parameterisations provide a route to better represent the Southern Ocean in climate models and projections.

Guideline summary review: an evidence-based clinical guideline for the diagnosis and treatment of adult isthmic spondylolisthesis.

BACKGROUND CONTEXT: The North American Spine Society's (NASS) Evidence-Based Clinical Guideline for the Diagnosis and Treatment of Adult Isthmic Spondylolisthesis features evidence-based recommendations for diagnosing and treating adult patients with isthmic spondylolisthesis. The guideline is intended to reflect contemporary treatment concepts for symptomatic isthmic spondylolisthesis as reflected in the highest quality clinical literature available on this subject as of June 2013. NASS' guideline on this topic is the only guideline on adult isthmic spondylolisthesis accepted in the Agency for Healthcare Research and Quality's National Guideline Clearinghouse. PURPOSE: The purpose of the guideline is to provide an evidence-based educational tool to assist spine specialists when making clinical decisions for adult patients with isthmic spondylolisthesis. This article provides a brief summary of the evidence-based guideline recommendations for diagnosing and treating patients with this condition. STUDY DESIGN: This is a guideline summary review. METHODS: This guideline is the product of the Adult Isthmic Spondylolisthesis Work Group of NASS' Evidence-Based Clinical Guideline Development Committee. The methods used to develop this guideline are detailed in the complete guideline and technical report available on the NASS website. In brief, a multidisciplinary work group of spine care specialists convened to identify clinical questionsto address in the guideline. The literature search strategy was developed in consultation with medical librarians. Upon completion of the systematic literature search, evidence relevant to the clinical questions posed in the guideline was reviewed. Work group members utilized NASS evidentiary table templates to summarize study conclusions, identify study strengths and weaknesses, and assign levels of evidence. Work group members participated in webcasts and in-person recommendation meetings to update and formulate evidence-based recommendations and incorporate expert opinion when necessary. The draft guidelines were submitted to an internal peer review process and ultimately approved by the NASS Board of Directors. Upon publication, the Adult Isthmic Spondylolisthesis guideline was accepted into the National Guideline Clearinghouse and will be updated approximately every 5 years. RESULTS: Thirty-one clinical questions were addressed, and the answers are summarized in this article. The respective recommendations were graded according to the levels of evidence of the supporting literature. CONCLUSIONS: The evidence-based clinical guideline has been created using techniques of evidence-based medicine and best available evidence to aid practitioners in the diagnosis and treatment of adult patients with isthmic spondylolisthesis. The entire guideline document, including the evidentiary tables, literature search parameters, literature attrition flowchart, suggestions for future research, and all of the references, is available electronically on the NASS website at https://www.spine.org/ResearchClinicalCare/QualityImprovement/ClinicalGuidelines.aspx and will remain updated on a timely schedule.