The gut microbiome and elevated cardiovascular risk in obesity and autoimmunity

Highlights

• This review links altered microbiome to increased cardiovascular risk (ASCVD).

• Obesity, T1DM, RA, and SLE share ASCVD etiologies influenced by the microbiome, possibly modifiable by altering gut flora.

• It emphasizes the need for more research on the gut microbiome in ASCVD.

Abstract

Cardiovascular disease associated with obesity and autoimmunity is the leading cause of death in these populations and significant residual risk remains despite current treatment approaches. Obesity, type 1 diabetes mellitus (T1DM), rheumatoid arthritis (RA), and systemic lupus erythematosus (SLE) are linked to chronic inflammation, and subjects with these disorders have characteristic shifts in their gut microbiome composition. Recent data suggest that alterations in gut microbial and metabolic composition may be responsible, in part, for induction of chronic inflammation, thus promoting cardiovascular disease. Common microbiome changes observed in obesity, T1DM, RA, and SLE include a decrease in the ratio of bacteria, such as Gram-positive Firmicutes to Gram-negative Bacteroidetes, as well as an overabundance or depletion of certain species, including Prevotella copri. The consequent effects of these shifts include alterations in the metabolic composition of the gut, hyper-activation of toll-like receptor 4 (TLR-4), upregulation of inflammatory pathways, e.g. c-Jun N-terminal kinase and nuclear factor-kappa B (NFκB), increased intestinal permeability, increased C-reactive protein, and increased levels of trimethylamine N-oxide (TMAO). Differential microbiome compositions may also explain sex differences observed in autoimmunity, where a male gut microbiome promotes anti-inflammatory processes as compared to a female pro-inflammatory gut microbiome. Intervention at the level of the microbiota appears to attenuate symptoms in these inflammatory syndromes with probiotic treatment, such as Lactobacilli, playing a uniquely beneficial role in restoring intestinal health, decreasing inflammation, and reducing cardiovascular disease. This review will discuss obesity, T1DM, RA, and SLE in the context of how each unique microbiome profile contributes to elevated cardiovascular risk.

Introduction

The risk of developing cardiovascular disease (CVD) is elevated in subjects who meet criteria for obesity as well as those diagnosed with a number of autoimmune disorders [55,67,106]. Despite adequate treatment to minimize damage from the autoimmune disorder, as many as 30% of the autoimmune population will develop an adverse cardiovascular event and the leading cause of death among the autoimmune population is cardiovascular disease [10,38]. Lipid lowering drugs fail to prevent CVD in autoimmune patients and modifications of the traditional Framingham risk factors also do not prevent adverse cardiovascular outcomes [86,121]. The mechanism of elevated CVD risk in autoimmunity is unknown, though it is likely that the pro-inflammatory environment plays a significant role [4]. Similarly, in obesity, metabolic derangements lead to inflammation that contributes to cardiovascular risk [67]. Interestingly, a commonality across different autoimmune diseases and obesity is a dysregulated gut microbiome. This review will focus on how an altered gut microbiome may be the proximate or underlying cause of elevated cardiovascular risk in obesity and autoimmunity.

The human gut microbiome refers to the micro-organismal composition and corresponding environment of the human colon. In healthy individuals, the composition of the gut microbiome remains relatively stable, consisting mainly of a few phyla: the predominantly Gram-positive Firmicutes, the Gram-negative Bacteroidetes, and Gram-positive Actinobacteria [19]. The most abundant genera in the healthy gut are: Gram-positive bacteria such as Clostridium, Bifidobacterium, Lactobacillus, Ruminococcus, Streptococcus, and Gram-negative bacteria such as Bacteroides, Prevotella, and Akkermansia [25,43,70]. Gut bacteria may engage their host in either commensal, symbiotic, or pathogenic relationships [17,19]. The outer mucosal layer of the gut epithelium is responsible for the selective binding and nourishing of intestinal microbes, the clearing of pathogenic microbes, and is capable of altering the microbiota's composition [44,64]. Some bacteria, such as Prevotella and Akkermansia, members of the Bacteroidetes and Verrucomicrobia phyla, respectively, degrade mucin in the gut and thus their abundance in healthy individuals is an indication of upregulated mucin production and a healthy epithelial layer [16].

Metabolites produced by gut microbiota include short chain fatty acids (SCFAs) such as acetate, propionate, and butyrate. Acetate is present in the healthy gut in the highest concentrations and is readily absorbed for cholesterol production [21]. Propionate is exported to the liver via hepatic portal circulation for use in gluconeogenesis. Butyrate, unlike acetate and propionate, undergoes limited reabsorption, instead undergoing colonocyte oxidation [21]. Acetate and propionate are produced mainly by Bacteroidetes while butyrate is typically produced by Firmicutes [21]. Therefore, the ratio of fecal Firmicutes to Bacteroidetes is a useful proxy for classifying the metabolic composition of the microbiome of an individual since the actual microbiome metabolic composition is extremely difficult to measure [33]. In the healthy gut environment, a high ratio is normal, i.e. more Firmicutes, and, as a consequence, high levels of butyrate in the intestinal ileum and cecum result in low luminal pH [33]. Gut pH has an important role in the composition of the resident bacteria. For example, at pH 5.5, butyrate producing Firmicutes comprise 20% of the total bacterial population, whereas at pH 6.5, there is a decrease in the population of Firmicutes and an increase in acetate and propionate producing Bacteroidetes [21].

The composition of the human gut microbiome has changed dramatically over the past 70 years due to altered living conditions, antibiotic use, refrigeration, and the prevalence of processed food and water [62]. Rigorous study of the microbiota has demonstrated that there is a strong correlation between differential microbial composition and the etiology of certain diseases. This review will examine the contemporary microbiome in the context of obesity, type 1 diabetes mellitus (T1DM), rheumatoid arthritis (RA), and systemic lupus erythematosus (SLE) and the underlying increase in cardiovascular risk that accompanies these diseases.