A Novel Trimethylamine Oxide-Induced Model Implicates Gut Microbiota-Related Mechanisms in Frailty

Abstract

Frailty is a complicated syndrome that occurs at various ages, with highest incidence in aged populations, suggesting associations between the pathogenesis of frailty and age-related changes. Gut microbiota (GM) diversity and abundance change with age, accompanied by increased levels of trimethylamine oxide (TMAO), a systemic inflammation-inducing GM metabolite. Thus, we hypothesized that TMAO may be involved in the development of frailty. We successfully established and verified a novel model of frailty in adult mice based on a 4-week intraperitoneal injection regime of TMAO followed by LPS challenge. The frailty index significantly increased in TMAO-treated mice after LPS challenge. TMAO also decreased claudin-1 immunofluorescent staining intensity in the jejunum, ileum, and colon, indicating that the destruction of intestinal wall integrity may increase vulnerability to exogenous pathogens and invoke frailty. 16S sequencing showed that TMAO significantly reduced the GM Firmicutes/Bacteroidetes (F/B) ratio, but not α-diversity. Interestingly, after LPS challenge, more genera of bacterial taxa were differently altered in the control mice than in the TMAO-treated mice. We infer that a variety of GM participate in the maintenance of homeostasis, whereas TMAO could blunt the GM and impair the ability to recover from pathogens, which may explain the continuous increase in the frailty index in TMAO-treated mice after LPS challenge. TMAO also significantly increased serum imidazole metabolites, and led to different patterns of change in serum peptide and phenylpropanoid metabolites after LPS stimulation. These changes indicate that glucose metabolism may be one mechanism by which GM inactivation causes frailty. In conclusion, TMAO leads to frailty by destroying intestinal barrier integrity and blunting the GM response.

Genetically supported causality between gut microbiota and frailty: a two-sample Mendelian randomization study

“…This study represents the inaugural comprehensive, large-scale MR analysis examining the genetic basis for a causal relationship between gut microbiota and the FI. Prior research on this association predominantly utilized clinical trials and animal studies ( Chen et al, 2022 ), which involved collecting and analyzing fecal samples from patients with frailty using 16S rRNA gene sequencing ( Jackson et al, 2016 ; Margiotta et al, 2020 ; Lauretani et al, 2021 ). However, these approaches often faced challenges due to confounding factors such as age and smoking habits, complicating the establishment of a direct causal link.…”

“…The Clostridium innocum group , part of the Clostridium genus, consists of Gram-positive bacteria adapted to hypoxic or microaerobic conditions. An increase in Clostridium abundance correlates with higher levels of trimethylamine (TMA) ( Chen et al, 2022 ), which may contribute to an increased risk of frailty. In a recent investigation by Lim et al (2021) , they examined the correlation between gut microbiota and frailty in a cohort of 176 elderly Korean individuals.…”

“…In recent years, a new hypothesis regarding the origin of inflammation in the digestive tract, especially the imbalance of intestinal homeostasis, has attracted the attention of the aca demic community ( de Jong et al, 2016 ). Notably, intestinal inflammation is linked to disruptions in gut microbiota, emphasizing its significance in health and disease ( Willing et al, 2010 ; Chen et al, 2022 ). The gut, as the primary interface with external microorganisms, plays a key role in managing chronic inflammation associated with frailty.…”

“…Consequently, it is plausible to suggest a link between the gut microbiota and frailty. Recent investigations have also elucidated potential mechanisms through which gut microbiota may contribute to the aging and frailty processes ( Chen et al, 2022 ). These effects can manifest directly via the gut microbiota itself or its metabolites.…”

Oxidative stress bridges the gut microbiota and the occurrence of frailty syndrome

“…It has also been reported that TMAO can promote inflammatory hepatocellular carcinoma by inducing ROS and activating ILK/AKT/mammalian target of rapamycin (mTOR) signaling via POSTN[ 42 ]. Our previous studies showed that administration of TMAO produced a novel model of frailty in mice[ 43 ]. In this TMAO-induced frailty model, the abundance of Firmicutes was decreased slightly, while the abundance of Bacteroidetes was significantly increased in the gut.…”