Kymberleigh A. Romano

Untargeted metabolomics identifies trimethyllysine, a TMAO-producing nutrient precursor, as a predictor of incident cardiovascular disease risk

Using an untargeted metabolomics approach in initial (N = 99 subjects) and replication cohorts (N = 1,162), we discovered and structurally identified a plasma metabolite associated with cardiovascular disease (CVD) risks, N6,N6,N6-trimethyl-L-lysine (trimethyllysine, TML). Stable-isotope-dilution tandem mass spectrometry analyses of an independent validation cohort (N = 2,140) confirmed TML levels are independently associated with incident (3-year) major adverse cardiovascular event risks (hazards ratio [HR], 2.4; 95% CI, 1.7-3.4) and incident (5-year) mortality risk (HR, 2.9; 95% CI, 2.0-4.2). Genome-wide association studies identified several suggestive loci for TML levels, but none reached genome-wide significance; and d9(trimethyl)-TML isotope tracer studies confirmed TML can serve as a nutrient precursor for gut microbiota-dependent generation of trimethylamine (TMA) and the atherogenic metabolite trimethylamine N-oxide (TMAO). Although TML was shown to be abundant in both plant- and animal-derived foods, mouse and human fecal cultures (omnivores and vegans) showed slow conversion of TML to TMA. Furthermore, unlike chronic dietary choline, TML supplementation in mice failed to elevate plasma TMAO or heighten thrombosis potential in vivo. Thus, TML is identified as a strong predictor of incident CVD risks in subjects and to serve as a dietary precursor for gut microbiota-dependent generation of TMAO; however, TML does not appear to be a major microbial source for TMAO generation in vivo.

A common antimicrobial additive increases colonic inflammation and colitis-associated colon tumorigenesis in mice

The commonly used antimicrobial compound triclosan increases colonic inflammation and colon cancer in mice. Triclosan triggers inflammation Antimicrobials are ubiquitous in manufactured products beyond hand soap and exist in the environment as pollutants. Triclosan exposure is practically unavoidable in the United States, but little is known how ingestion may affect our health. Yang and colleagues used mouse models of colitis and colon cancer to see how brief exposures of triclosan could affect inflammation. They observed that triclosan altered mouse gut microbiota and increased inflammation in a TLR4-dependent manner. Triclosan increased the severity of colitis symptoms and spurred colitis-associated colon cancer cell growth. Although the study is limited to mouse models, this work suggests that the effects of triclosan on human health should be examined more closely. Triclosan (TCS) is a high-volume chemical used as an antimicrobial ingredient in more than 2000 consumer products, such as toothpaste, cosmetics, kitchenware, and toys. We report that brief exposure to TCS, at relatively low doses, causes low-grade colonic inflammation, increases colitis, and exacerbates colitis-associated colon cancer in mice. Exposure to TCS alters gut microbiota in mice, and its proinflammatory effect is attenuated in germ-free mice. In addition, TCS treatment increases activation of Toll-like receptor 4 (TLR4) signaling in vivo and fails to promote colitis in Tlr4−/− mice. Together, our results demonstrate that this widely used antimicrobial ingredient could have adverse effects on colonic inflammation and associated colon tumorigenesis through modulation of the gut microbiota and TLR4 signaling. Together, these results highlight the need to reassess the effects of TCS on human health and potentially update policies regulating the use of this widely used antimicrobial.

Is maternal microbial metabolism an early-life determinant of health?

Mounting evidence suggests that environmental stress experienced in utero (for example, maternal nutritional deficits) establishes a predisposition in the newborn to the development of chronic diseases later in life. This concept is often referred to as the “fetal origins hypothesis” or “developmental origins of health and disease”. Since its first proposal, epigenetics has emerged as an underlying mechanism explaining how environmental cues become gestationally “encoded”. Many of the enzymes that impart and maintain epigenetic modifications are highly sensitive to nutrient availability, which can be influenced by the metabolic activities of the intestinal microbiota. Therefore, the maternal microbiome has the potential to influence epigenetics in utero and modulate offspring’s long-term health trajectories. Here we summarize the current understanding of the interactions that occur between the maternal gut microbiome and the essential nutrient choline, that is not only required for fetal development and epigenetic regulation but is also a growth substrate for some microbes. Bacteria able to metabolize choline benefit from the presence of this nutrient and compete with the host for its access, which under extreme conditions may elicit signatures of choline deficiency. Another consequence of bacterial choline metabolism is the accumulation of the pro-inflammatory, pro-thrombotic metabolite trimethylamine-N-oxide (TMAO). Finally, we discuss how these different facets of microbial choline metabolism may influence infant development and health trajectories via epigenetic mechanisms and more broadly place a call to action to better understand how maternal microbial metabolism can shape their offspring’s propensity to chronic disease development later in life.Kymberleigh Romano and Federico Rey discuss the importance of the microbiome/choline interaction for in utero development.

INCREASED PLASMA TRIMETHYLAMINE-N-OXIDE (TMAO) IS ASSOCIATED WITH LOWER HIPPOCAMPAL BLOOD FLOW

were associatedwith driving performance and driving decline among cognitively normal older adults. Methods: Participants, 65 years of age or older, were enrolled from longitudinal studies at the Knight Alzheimer’s Disease Research Center at Washington University. Cox proportional hazards models evaluated whether a depression diagnosis, depressive symptoms (Geriatric Depression Scale [GDS]), antidepressant use, CSF biomarkers (}

THE GUT MICROBIOTA-DERIVED METABOLITE TRIMETHYLAMINE N-OXIDE (TMAO) IS ELEVATED IN ALZHEIMER’S DISEASE

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Diet-Microbiota Interactions Mediate Global Epigenetic Programming in Multiple Host Tissues.

^[fish 0,mfnt]>b42], tau, and phosphorylated tau181 [ptau181]), and amyloid imaging (Pittsburgh Compound B and Florbetapir) were associated with time to receiving a rating of marginal/ fail on the driving test. Interactions among the variables were tested. Age was adjusted in all models. Results:Data were available from 141 participants with ages ranging from 65.4 to 88.2 years with a mean follow up of 2.4 years. A depression diagnosis (p1⁄4.027) was associated with a faster time to receiving a marginal/fail rating on a road test while adjusting for age, and antidepressant use. Depression and all CSF and imaging AD biomarkers (p<.05) were associated with poor driving performance on the road test. In the model with CSF tau, both depression (p1⁄4.024) and antidepressant use (p1⁄4.019) usewere statistically significant predictors. However, there were no interaction effects between depression, antidepressant use and biomarker groups on driving performance. Depressive symptoms (GDS) were not a significant predictor of driving performance. Participants with depression and preclinical AD were faster to receive a marginal/fail rating on the road test compared to participants with no depression or abnormal biomarkers. Conclusions: While, as previously shown, preclinical AD alone predicts a faster time to receiving a marginal/fail rating, these results suggest that also having a diagnosis of depression accelerates the onset of driving problems in cognitively normal older adults (see Figure 1).

Metabolic, Epigenetic, and Transgenerational Effects of Gut Bacterial Choline Consumption

analysis, by using the PLV pre-condition average clusters in theta and beta bands together with the Direct digit span and the Delayed recall test, we obtained an accuracy of 79.25%. Besides, we achieved an accuracy of 96.23% by including the following parameters: PLV ratio average of the clusters in theta and beta bands, Inverse digit span and Trail making test (TMT, Part A). Conclusions: The decrease in functional connectivity in AD found in several studies may be considered as a relevant sign of network breakdown. This pattern, which was observed in the pMCI, may represent a loss of network robustness and a deviation from the optimal configuration for brain dynamic processing due to the progression of the disease. Finally, the classification analysis suggests that network disruption and neuropsychological scores, which were mainly related with memory, attentional and executive functions, are good factors to distinguish both groups.