Commensal microbiota-dependent tryptophan catabolism within the gastrointestinal tract is known to exert profound effects upon host physiology, including the maintenance of epithelial barrier and immune function. A number of abundant microbiota-derived tryptophan metabolites exhibit activation potential for the aryl hydrocarbon receptor (AHR). Gene expression facilitated by AHR activation through the presence of dietary or microbiota-generated metabolites can influence gastrointestinal homeostasis and confer protection from intestinal challenges. Utilizing untargeted mass spectrometry-based metabolomics profiling, combined with AHR activity screening assays, we identify four previously unrecognized tryptophan metabolites, present in mouse cecal contents and human stool, with the capacity to activate AHR. Using GC/MS and LC/MS platforms, quantification of these novel AHR activators, along with previously established AHR-activating tryptophan metabolites, was achieved, providing a relative order of abundance. Using physiologically relevant concentrations and quantitative gene expression analyses, the relative efficacy of these tryptophan metabolites with regard to mouse or human AHR activation potential is examined. These data reveal indole, 2-oxindole, indole-3-acetic acid and kynurenic acid as the dominant AHR activators in mouse cecal contents and human stool from participants on a controlled diet. Here we provide the first documentation of the relative abundance and AHR activation potential of a panel of microbiota-derived tryptophan metabolites. Furthermore, these data reveal the human AHR to be more sensitive, at physiologically relevant concentrations, to tryptophan metabolite activation than mouse AHR. Additionally, correlation analyses indicate a relationship linking major tryptophan metabolite abundance with AHR activity, suggesting these cecal/fecal metabolites represent biomarkers of intestinal AHR activity.

Background Observational evidence suggests higher nut consumption is associated with better glycemic control; however, it is unclear if this association is causal. Objectives We aimed to conduct a systematic review and meta-analysis of randomized controlled trials to examine the effect of tree nuts and peanuts on markers of glycemic control in adults. Methods A systematic review and meta-analysis of randomized controlled trials was conducted. A total of 1063 potentially eligible articles were screened in duplicate. From these articles, 40 were eligible for inclusion and data from these articles were extracted in duplicate. The weighted mean difference (WMD) between the nut intervention and control arms was determined for fasting glucose, fasting insulin, glycated hemoglobin (HbA1c), and homeostasis model assessment of insulin resistance (HOMA-IR) using the DerSimonian and Laird random-effects method. For outcomes where a limited number of studies were published, a qualitative synthesis was presented. Results A total of 40 randomized controlled trials including 2832 unique participants, with a median duration of 3 mo (range: 1–12 mo), were included. Overall consumption of tree nuts or peanuts had a favorable effect on HOMA-IR (WMD: −0.23; 95% CI: −0.40, −0.06; I2 = 51.7%) and fasting insulin (WMD: −0.40 μIU/mL; 95% CI: −0.73, −0.07 μIU/mL; I2 = 49.4%). There was no significant effect of nut consumption on fasting blood glucose (WMD: −0.52 mg/dL; 95% CI: −1.43, 0.38 mg/dL; I2 = 53.4%) or HbA1c (WMD: 0.02%; 95% CI: −0.01%, 0.04%; I2 = 51.0%). Conclusions Consumption of peanuts or tree nuts significantly decreased HOMA-IR and fasting insulin; there was no effect of nut consumption on HbA1c or fasting glucose. The results suggest that nut consumption may improve insulin sensitivity. In the future, well-designed clinical trials are required to elucidate the mechanisms that account for these observed effects.

Background It is unclear whether the favorable effects of walnuts on the gut microbiota are attributable to the fatty acids, including α-linolenic acid (ALA), and/or the bioactive compounds and fiber. Objective This study examined between-diet gut bacterial differences in individuals at increased cardiovascular risk following diets that replace SFAs with walnuts or vegetable oils. Methods Forty-two adults at cardiovascular risk were included in a randomized, crossover, controlled-feeding trial that provided a 2-wk standard Western diet (SWD) run-in and three 6-wk isocaloric study diets: a diet containing whole walnuts (WD; 57–99 g/d walnuts; 2.7% ALA), a fatty acid–matched diet devoid of walnuts (walnut fatty acid–matched diet; WFMD; 2.6% ALA), and a diet replacing ALA with oleic acid without walnuts (oleic acid replaces ALA diet; ORAD; 0.4% ALA). Fecal samples were collected following the run-in and study diets to assess gut microbiota with 16S rRNA sequencing and Qiime2 for amplicon sequence variant picking. Results Subjects had elevated BMI (30 ± 1 kg/m2), blood pressure (121 ± 2/77 ± 1 mmHg), and LDL cholesterol (120 ± 5 mg/dL). Following the WD, Roseburia [relative abundance (RA) = 4.2%, linear discriminant analysis (LDA) = 4], Eubacterium eligensgroup (RA = 1.4%, LDA = 4), LachnospiraceaeUCG001 (RA = 1.2%, LDA = 3.2), Lachnospiraceae UCG004 (RA = 1.0%, LDA = 3), and Leuconostocaceae (RA = 0.03%, LDA = 2.8) were most abundant relative to taxa in the SWD (P ≤ 0.05 for all). The WD was also enriched in Gordonibacter relative to the WFMD. Roseburia (3.6%, LDA = 4) and Eubacterium eligensgroup (RA = 1.5%, LDA = 3.4) were abundant following the WFMD, and Clostridialesvadin BB60group (RA = 0.3%, LDA = 2) and gutmetagenome (RA = 0.2%, LDA = 2) were most abundant following the ORAD relative to the SWD (P ≤ 0.05 for all). Lachnospiraceae were inversely correlated with blood pressure and lipid/lipoprotein measurements following the WD. Conclusions The results indicate similar enrichment of Roseburia following the WD and WFMD, which could be explained by the fatty acid composition. Gordonibacter enrichment and the inverse association between Lachnospiraceae and cardiovascular risk factors following the WD suggest that the gut microbiota may contribute to the health benefits of walnut consumption in adults at cardiovascular risk. This trial was registered at clinicaltrials.gov as NCT02210767.

Background Walnuts have beneficial effects on cardiovascular risk factors, but it is unclear whether these effects are attributable to the fatty acid ( FA ) content, including α‐linolenic acid ( ALA ), and/or bioactives. Methods and Results A randomized, controlled, 3‐period, crossover, feeding trial was conducted in individuals at risk for cardiovascular disease (n=45). Following a 2‐week standard Western diet run‐in (12% saturated FAs [ SFA ], 7% polyunsaturated FAs, 12% monounsaturated FAs), participants consumed 3 isocaloric weight‐maintenance diets for 6 weeks each: a walnut diet ( WD ; 7% SFA , 16% polyunsaturated FAs, 3% ALA , 9% monounsaturated FAs); a walnut FA ‐matched diet; and an oleic acid–replaced‐ ALA diet (7% SFA , 14% polyunsaturated FAs, 0.5% ALA , 12% monounsaturated FAs), which substituted the amount of ALA from walnuts in the WD with oleic acid. This design enabled evaluation of the effects of whole walnuts versus constituent components. The primary end point, central systolic blood pressure, was unchanged, and there were no significant changes in arterial stiffness. There was a treatment effect ( P =0.04) for central diastolic blood pressure; there was a greater change following the WD versus the oleic acid–replaced‐ALA diet (−1.78±1.0 versus 0.15±0.7 mm Hg, P =0.04). There were no differences between the WD and the walnut fatty acid‐matched diet (−0.22±0.8 mm Hg, P =0.20) or the walnut FA‐matched and oleic acid–replaced‐ALA diets ( P =0.74). The WD significantly lowered brachial and central mean arterial pressure. All diets lowered total cholesterol, LDL (low‐density lipoprotein) cholesterol, HDL (high‐density lipoprotein) cholesterol, and non‐ HDL cholesterol. Conclusions Cardiovascular benefits occurred with all moderate‐fat, high‐unsaturated‐fat diets. As part of a low‐ SFA diet, the greater improvement in central diastolic blood pressure following the WD versus the oleic acid–replaced‐ALA diet indicates benefits of walnuts as a whole‐food replacement for SFA . Clinical Trial Registration URL : https://www.clinicaltrials.gov . Unique identifier: NCT 02210767.

Abstract Clusters of bacterial species within the gut microenvironment, or gut enterotype, have been correlated with cardiometabolic disease risk. The metabolic products and metabolites that bacteria produce, such as short-chain fatty acids, secondary bile acids, and trimethylamine, may also affect the microbial community and disease risk. Diet has a direct impact on the gut microenvironment by providing substrates to and promoting the colonization of resident bacteria. To date, few dietary patterns have been evaluated for their effect on the gut microbiome, but the Mediterranean diet and Vegetarian diets have shown favorable effects for both the gut microbiome and cardiometabolic disease risk. This review examines the gut microbiome as a mediator between these dietary patterns and cardiometabolic disease risk.