Elucidation of an anaerobic pathway for metabolism of
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            -carnitine–derived γ-butyrobetaine to trimethylamine in human gut bacteria

Rajakovich, Lauren J.; Fu, Beverly; Bollenbach, Maud; Balskus, Emily P.

doi:10.1073/pnas.2101498118

Cited by 42 publications

(22 citation statements)

References 71 publications

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“…On the other hand, l -carnitine is metabolized by gut bacteria and liver to produce TMAO 98 . Nonetheless, the responsible biochemical pathway(s) and required genetic components in gut bacteria to metabolize l -carnitine to TMAO is not yet fully understood 98 , 99 . TMAO was our reference metabolite to assure the germ-free status of the mice used in the study, as it is a metabolite with microbial origin 100 .…”

Section: Discussionmentioning

confidence: 99%

Tissue-wide metabolomics reveals wide impact of gut microbiota on mice metabolite composition

Zarei

Koistinen

Kokla

et al. 2022

Sci Rep

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The essential role of gut microbiota in health and disease is well recognized, but the biochemical details that underlie the beneficial impact remain largely undefined. To maintain its stability, microbiota participates in an interactive host-microbiota metabolic signaling, impacting metabolic phenotypes of the host. Dysbiosis of microbiota results in alteration of certain microbial and host metabolites. Identifying these markers could enhance early detection of certain diseases. We report LC–MS based non-targeted metabolic profiling that demonstrates a large effect of gut microbiota on mammalian tissue metabolites. It was hypothesized that gut microbiota influences the overall biochemistry of host metabolome and this effect is tissue-specific. Thirteen different tissues from germ-free (GF) and conventionally-raised (MPF) C57BL/6NTac mice were selected and their metabolic differences were analyzed. Our study demonstrated a large effect of microbiota on mammalian biochemistry at different tissues and resulted in statistically-significant modulation of metabolites from multiple metabolic pathways (p ≤ 0.05). Hundreds of molecular features were detected exclusively in one mouse group, with the majority of these being unique to specific tissue. A vast metabolic response of host to metabolites generated by the microbiota was observed, suggesting gut microbiota has a direct impact on host metabolism.

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Section: Discussionmentioning

confidence: 99%

Tissue-wide metabolomics reveals wide impact of gut microbiota on mice metabolite composition

Zarei

Koistinen

Kokla

et al. 2022

Sci Rep

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“…6 ). We note that a recent preprint by Rajakovich et al recently identified the same 6-membered gene cluster in E. timonensis in catalyzing TMA generation from γBB 27 . Their independent characterization of the microbial biochemical pathway was highly aligned with our findings, further validating the role of the gbu gene cluster in gut microbial γBB→TMA transformation reported herein.…”

Section: Discussionmentioning

confidence: 57%

The microbial gbu gene cluster links cardiovascular disease risk associated with red meat consumption to microbiota l-carnitine catabolism

et al. 2021

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The heightened cardiovascular disease (CVD) risk observed with omnivores is thought to be linked, in part, to gut microbiota-dependent generation trimethylamine-N-oxide (TMAO) from L-carnitine, a nutrient abundant in red meat. Gut microbial transformation of L-carnitine into trimethylamine (TMA), the precursor of TMAO, occurs via the intermediate γ-butyrobetaine (γBB). However, the relationship between γBB, red meat ingestion and CVD risks, as well as the gut microbial genes responsible for the transformation of γBB to TMA, are unclear. Here we show plasma γBB levels in individuals from a clinical cohort (n=2,918) are strongly associated with incident CVD event risks. Culture of human fecal samples and microbial transplantation studies in gnotobiotic mice with defined synthetic communities showed that the introduction of Emergencia timonensis, a human gut microbe that can metabolize γBB into TMA, is sufficient to complete the carnitine→γBB→TMA transformation, elevate TMAO levels, and enhance thrombosis potential in recipients following arterial injury. RNAseq analyses of E. timonensis identified a 6 gene cluster, herein named g amma-butyro b etaine u tilization gene cluster ( gbu ), which is upregulated in response to γBB. Combinatorial cloning and functional studies identified 4 genes ( gbuA , gbuB , gbuC , and gbuE ) that are necessary and sufficient to recapitulate the conversion of γBB to TMA when co-expressed in E. coli . Finally, reanalysis of samples (n=113) from a clinical randomized diet intervention study showed that the abundance of fecal gbuA correlates with plasma TMAO and a red meat-rich diet. Our findings reveal a microbial gene cluster that is critical to dietary carnitine→γBB→TMA→TMAO transformation in hosts and contributes to CVD risk.

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“…Although SCFAs derive from dietary fibre, these observations were independent of dietary fibre intake suggesting that other factors may influence the availability of SCFAs. Recent data suggest that SCFAs may derive from the metabolism of l ‐carnitine to trimethylamine, a pathway highlighted by Suzuki at the symposium (Suzuki et al., 2021) and discussed below in relation to the atherogenic phenotype (Rajakovich et al., 2021 ). In their talk, Swann further demonstrated that in contrast to IBS‐C patients, IBS patients with diarrhoea (IBS‐D) present higher levels of tryptophan and its indoleamine microbial metabolite, tryptamine, which again acts locally to regulate intestinal motility by interacting with serotonin receptor‐4 (Swann et al., 2020 ).…”

Section: Microbial Components Cell Signalling and Disease Stratificationmentioning

confidence: 99%

“…The metabolism of choline to TMA seems to involve the direct choline‐TMA lyase pathway (Day‐Walsh et al., 2021 ). However, the metabolism of l ‐carnitine involves the formation of an obligate intermediate, γ‐butyrobetaine, which is further metabolised in a multistep process involving several gene clusters to produce TMA and other metabolites including SCFAs, such as acetate and butyrate, which have been shown to be the end‐products in this process (Day‐Walsh et al., 2021 ; Rajakovich et al., 2021 ). The factors that regulate the formation of TMA from carnitine are yet to be understood although it seems that this pathway may be more important in the production of the atherogenic TMA than that involving choline.…”

Section: Stratifying Disease Outcomes and Clinical Decisions Based On...mentioning

confidence: 99%

Microbiomes in physiology: insights into 21st‐century global medical challenges

Shehata

Parker

Suzuki

et al. 2022

Experimental Physiology

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New Findings What is the topic of this review?The role of the gut microbiome in physiology and how it can be targeted as an effective strategy against two of the most important global medical challenges of our time, namely, metabolic diseases and antibacterial resistance. What advances does it highlight?The critical roles of the microbiome in regulating host physiology and how microbiome analysis is useful for disease stratification to enable informed clinical decisions and develop interventions such as faecal microbiota transplantation, prebiotics and probiotics. Also, the limitations of microbiome modulation, including the potential for probiotics to enhance antimicrobial resistance gene reservoirs, and that currently a ‘healthy microbiome’ that can be used as a biobank for transplantation is yet to be defined. Abstract The human gut microbiome is a key factor in the development of metabolic diseases and antimicrobial resistance, which are among the greatest global medical challenges of the 21st century. A recent symposium aimed to highlight state‐of‐the‐art evidence for the role of the gut microbiome in physiology, from childhood to adulthood, and the impact this has on global disease outcomes, ageing and antimicrobial resistance. Although the gut microbiome is established early in life, over time the microbiome and its components including metabolites can become perturbed due to changes such as dietary habits, use of antibiotics and age. As gut microbial metabolites, including short‐chain fatty acids, secondary bile acids and trimethylamine‐N‐oxide, can interact with host receptors including G protein‐coupled receptors and can alter host metabolic fluxes, they can significantly affect physiological homoeostasis leading to metabolic diseases. These metabolites can be used to stratify disease phenotypes such as irritable bowel syndrome and adverse events after heart failure and allow informed decisions on clinical management and treatment. While strategies such as use of probiotics, prebiotics and faecal microbiota transplantation have been proposed as interventions to treat and prevent metabolic diseases and antimicrobial resistance, caution must be exercised, first due to the potential of probiotics to enhance antimicrobial resistance gene reservoirs, and second, a ‘healthy gut microbiome’ that can be used as a biobank for transplantation is yet to be defined. We highlight that sampling other parts of the gastrointestinal tract may produce more representative data than the faecal microbiome alone.

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Elucidation of an anaerobic pathway for metabolism of l -carnitine–derived γ-butyrobetaine to trimethylamine in human gut bacteria

Cited by 42 publications

References 71 publications

Tissue-wide metabolomics reveals wide impact of gut microbiota on mice metabolite composition

Tissue-wide metabolomics reveals wide impact of gut microbiota on mice metabolite composition

The microbial gbu gene cluster links cardiovascular disease risk associated with red meat consumption to microbiota l-carnitine catabolism

Microbiomes in physiology: insights into 21st‐century global medical challenges

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