The gut microbiota has been linked to the emergence of obesity, metabolic syndrome and the onset of type 2 diabetes through decreased glucose tolerance and insulin resistance. Uncontrolled diabetes can lead to serious health consequences such as impaired kidney function, blindness, stroke, myocardial infarction and lower limb amputation. Despite a variety of treatments currently available, cases of diabetes and resulting complications are on the rise. One promising new approach to diabetes focuses on modulating the gut microbiota with probiotics, prebiotics, synbiotics and fecal microbial transplantation. Differences in gut microbiota composition have been observed in preclinical animal models as well as patients with type 2 diabetes and complications such as diabetic nephropathy, diabetic retinopathy, diabetic neuropathy, cerebrovascular disease, coronary heart disease and peripheral artery disease compared to healthy controls. Severity of gut microbiota dysbiosis was associated with disease severity and restoration with probiotic administration in animal models and human patients has been associated with improvement of symptoms and disease progression. Characterizing the gut microbiota dysbiosis in different diseases and determining a causal relationship between the gut microbiota and disease can be beneficial in formulating therapeutic interventions for type 2 diabetes and associated complications. In this review, we present the most important findings regarding the role of the gut microbiota in type 2 diabetes and chronic complications as well as their underlying mechanisms. 

Gut Microbiota and Complications of Type-2 Diabetes

Type 2 diabetes mellitus (T2DM) is one of the common metabolic diseases in the world. Due to the rise in morbidity and mortality, it has become a global health problem. To date, T2DM still cannot be cured, and its intervention measures mainly focus on glucose control as well as the prevention and treatment of related complications. Interestingly, the gut microbiota plays an important role in the development of metabolic diseases, especially T2DM. In this review, we introduce the characteristics of the gut microbiota in T2DM population, T2DM animal models, and diabetic complications. In addition, we describe the molecular mechanisms linking host and the gut microbiota in T2DM, including the host molecules that induce gut microbiota dysbiosis, immune and inflammatory responses, and gut microbial metabolites involved in pathogenesis. These findings suggest that we can treat T2DM and its complications by remodeling the gut microbiota through interventions such as drugs, probiotics, prebiotics, fecal microbiota transplantation (FMT) and diets.

/pdf/gut-microbiota-an-important-player-in-type-2-diabetes-225ekq1k.pdf

Gut Microbiota: An Important Player in Type 2 Diabetes Mellitus

OUP accepted manuscript

The gut microbiota plays a pivotal role in the onset and development of diabetes and its complications. Trimethylamine N-oxide (TMAO), a gut microbiota-dependent metabolite of certain nutrients, is associated with type 2 diabetes and its complications. Diabetic kidney disease (DKD) is one of the most serious microvascular complications. However, whether TMAO accelerates the development of DKD remains unclear. We tested the hypothesis that TMAO accelerates the development of DKD. A high-fat diet/low-dose streptozotocin-induced diabetes rat model was established, with or without TMAO in the rats' drinking water. Compared to the normal rats, the DKD rats showed significantly higher plasma TMAO levels at the end of the study. TMAO treatment not only exacerbated the kidney dysfunction of the DKD rats, but also renal fibrosis. Furthermore, TMAO treatment activated the nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3 (NLRP3) inflammasome and resulted in the release of interleukin (IL)-1β and IL-18 to accelerate renal inflammation. These results suggested that TMAO aggravated renal inflammation and fibrosis in the DKD rats, which provides a new perspective to understand the pathogenesis of DKD and a potential novel target for preventing the progression of DKD.

/pdf/trimethylamine-n-oxide-exacerbates-renal-inflammation-and-1z49rmwrkc.pdf

Trimethylamine N-Oxide Exacerbates Renal Inflammation and Fibrosis in Rats With Diabetic Kidney Disease

Since the introduction of the central dogma of molecular biology in 1958, various RNA species have been discovered. Messenger RNAs transmit genetic instructions from DNA to make proteins, a process facilitated by housekeeping non-coding RNAs (ncRNAs) such as small nuclear RNAs (snRNAs), ribosomal RNAs (rRNAs), and transfer RNAs (tRNAs). Over the past four decades, a wide array of regulatory ncRNAs have emerged as crucial players in gene regulation. In celebration of Cell's 50th anniversary, this Review explores our current understanding of the most extensively studied regulatory ncRNAs-small RNAs and long non-coding RNAs (lncRNAs)-which have profoundly shaped the field of RNA biology and beyond. While small RNA pathways have been well documented with clearly defined mechanisms, lncRNAs exhibit a greater diversity of mechanisms, many of which remain unknown. This Review covers pivotal events in their discovery, biogenesis pathways, evolutionary traits, action mechanisms, functions, and crosstalks among ncRNAs. We also highlight their roles in pathophysiological contexts and propose future research directions to decipher the unknowns of lncRNAs by leveraging lessons from small RNAs.

Small and long non-coding RNAs: Past, present, and future

To determine the relationship between plasma levels of trimethylamine-N-oxide (TMAO) and odds of diabetic retinopathy (DR). A cross-sectional study was conducted. Blood samples were obtained from 122 type 2 diabetes mellitus (T2DM) patients with or without DR. Multivariable logistic regression analyses were performed to identify the association between plasma TMAO and DR. The diagnostic value of plasma TMAO was assessed by the area under the receiver operating characteristic curve (AUROC) and integrated discrimination improvement (IDI). In the T2DM patients, plasma levels of TMAO were significantly higher in patients with DR compared with those without DR (P = 0.001). As logarithmic (ln) transformation of TMAO increased per standard deviation (SD), there was higher probability to have DR [odds ratio (OR) = 2.31; P = 0.005]. As ln-transformed TMAO increased per SD, the severity of DR was more likely to get worse (OR = 2.05; P = 0.004). In the diagnostic model, the addition of TMAO contributed to the improvement in AUROC from 0.646 to 0.734 (P = 0.043), and the IDI was 10.7% (P < 0.001). Elevated levels of plasma TMAO were associated with higher odds and worse severity of DR in T2DM patients, and further investigation is required for the causality of this association.

/pdf/elevated-plasma-trimethylamine-n-oxide-levels-are-associated-4c2l5ew751.pdf

Elevated plasma trimethylamine-N-oxide levels are associated with diabetic retinopathy.

LincRNA‐EPS is an important regulator in inflammation. However, the role of lincRNA‐EPS in the host response against viral infection is unexplored. Here, we show that lincRNA‐EPS is downregulated in macrophages infected with different viruses including VSV, SeV, and HSV‐1. Overexpression of lincRNA‐EPS facilitates viral infection, while deficiency of lincRNA‐EPS protects the host against viral infection in vitro and in vivo. LincRNA‐EPS−/− macrophages show elevated expression of antiviral interferon‐stimulated genes (ISGs) such as Mx1, Oas2, and Ifit2 at both basal and inducible levels. However, IFN‐β, the key upstream inducer of these ISGs, is downregulated in lincRNA‐EPS−/− macrophages compared with control cells. RNA pulldown and mass spectrometry results indicate that lincRNA‐EPS binds to PKR and antagonizes the viral RNA–PKR interaction. PKR activates STAT1 and induces antiviral ISGs independent of IFN‐I induction. LincRNA‐EPS inhibits PKR‐STAT1‐ISGs signaling and thus facilitates viral infection. Our study outlines an alternative antiviral pathway, with downregulation of lincRNA‐EPS promoting the induction of PKR‐STAT1‐dependent ISGs, and reveals a potential therapeutic target for viral infectious diseases.

https://onlinelibrary.wiley.com/doi/pdfdirect/10.15252/embr.202153937

LincRNA‐EPS impairs host antiviral immunity by antagonizing viral RNA–PKR interaction

Rapid and robust induction of antiviral genes is essential for the host to clear the invaded viruses. In addition to the IRF3/7-IFN-I-STAT1 signaling axis, the XAF1-IRF1 positive feedback loop synergistically or independently drives the transcription of antiviral genes. ABSTRACT XIAP-associated factor 1 (XAF1) is an interferon (IFN)-stimulated gene (ISG) that enhances IFN-induced apoptosis. However, it is unexplored whether XAF1 is essential for the host fighting against invaded viruses. Here, we find that XAF1 is significantly upregulated in the host cells infected with emerging RNA viruses, including influenza, Zika virus (ZIKV), and SARS-CoV-2. IFN regulatory factor 1 (IRF1), a key transcription factor in immune cells, determines the induction of XAF1 during antiviral immunity. Ectopic expression of XAF1 protects host cells against various RNA viruses independent of apoptosis. Knockout of XAF1 attenuates host antiviral innate immunity in vitro and in vivo, which leads to more severe lung injuries and higher mortality in the influenza infection mouse model. XAF1 stabilizes IRF1 protein by antagonizing the CHIP-mediated degradation of IRF1, thus inducing more antiviral IRF1 target genes, including DDX58, DDX60, MX1, and OAS2. Our study has described a protective role of XAF1 in the host antiviral innate immunity against RNA viruses. We have also elucidated the molecular mechanism that IRF1 and XAF1 form a positive feedback loop to induce rapid and robust antiviral immunity. IMPORTANCE Rapid and robust induction of antiviral genes is essential for the host to clear the invaded viruses. In addition to the IRF3/7-IFN-I-STAT1 signaling axis, the XAF1-IRF1 positive feedback loop synergistically or independently drives the transcription of antiviral genes. Moreover, XAF1 is a sensitive and reliable gene that positively correlates with the viral infection, suggesting that XAF1 is a potential diagnostic marker for viral infectious diseases. In addition to the antitumor role, our study has shown that XAF1 is essential for antiviral immunity. XAF1 is not only a proapoptotic ISG, but it also stabilizes the master transcription factor IRF1 to induce antiviral genes. IRF1 directly binds to the IRF-Es of its target gene promoters and drives their transcriptions, which suggests a unique role of the XAF1-IRF1 loop in antiviral innate immunity, particularly in the host defect of IFN-I signaling such as invertebrates.

XAF1 Protects Host against Emerging RNA Viruses by Stabilizing IRF1-Dependent Antiviral Immunity

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Elevated plasma trimethylamine-N-oxide levels are associated with diabetic retinopathy.

LincRNA‐EPS impairs host antiviral immunity by antagonizing viral RNA–PKR interaction

XAF1 Protects Host against Emerging RNA Viruses by Stabilizing IRF1-Dependent Antiviral Immunity