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Atherosclerosis 271 (2018) 203e213

Contents lists available at ScienceDirect

Atherosclerosis
journal homepage: www.elsevier.com/locate/atherosclerosis

Review article

The gut microbiome and elevated cardiovascular risk in obesity and


autoimmunity
Lora J. Kasselman*, Nicholas A. Vernice, Joshua DeLeon, Allison B. Reiss
Winthrop Research Institute and Department of Medicine, NYU Winthrop Hospital, Mineola, NY, USA

a r t i c l e i n f o a b s t r a c t

Article history: Cardiovascular disease associated with obesity and autoimmunity is the leading cause of death in these
Received 5 January 2018 populations and significant residual risk remains despite current treatment approaches. Obesity, type 1
Received in revised form diabetes mellitus (T1DM), rheumatoid arthritis (RA), and systemic lupus erythematosus (SLE) are linked to
20 February 2018
chronic inflammation, and subjects with these disorders have characteristic shifts in their gut micro-
Accepted 28 February 2018
Available online 2 March 2018
biome 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
Keywords:
Microbiota
bacteria, such as Gram-positive Firmicutes to Gram-negative Bacteroidetes, as well as an overabundance
Atherosclerosis or depletion of certain species, including Prevotella copri. The consequent effects of these shifts include
Inflammation alterations in the metabolic composition of the gut, hyper-activation of toll-like receptor 4 (TLR-4),
Short-chain fatty acids upregulation of inflammatory pathways, e.g. c-Jun N-terminal kinase and nuclear factor-kappa B (NFkB),
Obesity increased intestinal permeability, increased C-reactive protein, and increased levels of trimethylamine N-
Type 1 diabetes mellitus oxide (TMAO). Differential microbiome compositions may also explain sex differences observed in
Rheumatoid arthritis autoimmunity, where a male gut microbiome promotes anti-inflammatory processes as compared to a
Systemic lupus erythematosus
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.
© 2018 Elsevier B.V. All rights reserved.

1. Introduction unknown, though it is likely that the pro-inflammatory environ-


ment plays a significant role [4]. Similarly, in obesity, metabolic
The risk of developing cardiovascular disease (CVD) is elevated derangements lead to inflammation that contributes to cardiovas-
in subjects who meet criteria for obesity as well as those diagnosed cular risk [67]. Interestingly, a commonality across different auto-
with a number of autoimmune disorders [55,67,106]. Despite immune diseases and obesity is a dysregulated gut microbiome.
adequate treatment to minimize damage from the autoimmune This review will focus on how an altered gut microbiome may be
disorder, as many as 30% of the autoimmune population will the proximate or underlying cause of elevated cardiovascular risk in
develop an adverse cardiovascular event and the leading cause of obesity and autoimmunity.
death among the autoimmune population is cardiovascular disease The human gut microbiome refers to the micro-organismal
[10,38]. Lipid lowering drugs fail to prevent CVD in autoimmune composition and corresponding environment of the human colon.
patients and modifications of the traditional Framingham risk In healthy individuals, the composition of the gut microbiome re-
factors also do not prevent adverse cardiovascular outcomes mains relatively stable, consisting mainly of a few phyla: the pre-
[86,121]. The mechanism of elevated CVD risk in autoimmunity is dominantly 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,
* Corresponding author. Winthrop Research Institute, NYU Winthrop Hospital,
101 Mineola Boulevard, Mineola, NY 11501, USA. Streptococcus, and Gram-negative bacteria such as Bacteroides,
E-mail address: lkasselman@nyuwinthrop.org (L.J. Kasselman). Prevotella, and Akkermansia [25,43,70]. Gut bacteria may engage

https://doi.org/10.1016/j.atherosclerosis.2018.02.036
0021-9150/© 2018 Elsevier B.V. All rights reserved.
204 L.J. Kasselman et al. / Atherosclerosis 271 (2018) 203e213

their host in either commensal, symbiotic, or pathogenic relation- cardiac events; specifically, cardiac tissue undergoes a loss of con-
ships [17,19]. The outer mucosal layer of the gut epithelium is nexin and localized gap junction loss and remodeling resulting in
responsible for the selective binding and nourishing of intestinal the significantly slowed ventricular electrical conduction impli-
microbes, the clearing of pathogenic microbes, and is capable of cated in cardiac disease [87]. Similarly, the NFkB pathway has been
altering the microbiota's composition [44,64]. Some bacteria, such implicated in the pathogenesis of atherosclerosis and heart failure.
as Prevotella and Akkermansia, members of the Bacteroidetes and In atherosclerotic plaques, NFkB is known to promote gene
Verrucomicrobia phyla, respectively, degrade mucin in the gut and expression that recruits and activates inflammatory cells and
thus their abundance in healthy individuals is an indication of downstream molecules such as cytokines, inducible nitric oxide
upregulated mucin production and a healthy epithelial layer [16]. synthase, and leukocyte adhesion molecules, all of which are
Metabolites produced by gut microbiota include short chain associated with obesity [110].
fatty acids (SCFAs) such as acetate, propionate, and butyrate. Ace- Although obesogenic diets increase proliferation of Bacteroidetes,
tate is present in the healthy gut in the highest concentrations and Firmicutes still maintain a higher ratio compared to the Gram-
is readily absorbed for cholesterol production [21]. Propionate is negative LPS producing Bacteroidetes [69]. Interestingly, the obese
exported to the liver via hepatic portal circulation for use in microbiota may contain higher levels of Prevotellaceae, a member of
gluconeogenesis. Butyrate, unlike acetate and propionate, un- the Bacteroidetes phylum and an additional source of LPS, though
dergoes limited reabsorption, instead undergoing colonocyte this finding is inconsistent, depending on strain of bacteria measured
oxidation [21]. Acetate and propionate are produced mainly by [70,79]. Additionally, the high fat microbiome reduces the expression
Bacteroidetes while butyrate is typically produced by Firmicutes of host genes encoding the intestinal tight junction proteins zonula
[21]. Therefore, the ratio of fecal Firmicutes to Bacteroidetes is a occludens-1 (ZO-1) and occludin, thus increasing intestinal perme-
useful proxy for classifying the metabolic composition of the ability and permitting the absorption of the bacteria as well as their
microbiome of an individual since the actual microbiome metabolic metabolites into the bloodstream [50]. Increases in Gram-negative
composition is extremely difficult to measure [33]. In the healthy bacteria as well as a leaky intestinal epithelium are hallmarks of
gut environment, a high ratio is normal, i.e. more Firmicutes, and, as metabolic endotoxemia, defined by an LPS plasma concentration
a consequence, high levels of butyrate in the intestinal ileum and over three times the normal threshold [49]. Indeed, LPS infusion
cecum result in low luminal pH [33]. Gut pH has an important role alone was sufficient to increase energy uptake in murine models,
in the composition of the resident bacteria. For example, at pH 5.5, inducing obesity, inflammation, and insulin resistance [20]. Thus,
butyrate producing Firmicutes comprise 20% of the total bacterial metabolic endotoxemia resulting from an increase in Bacteroidetes
population, whereas at pH 6.5, there is a decrease in the population and consequent reduced expression of tight junction proteins ZO-1
of Firmicutes and an increase in acetate and propionate producing and occludin may play a major role in the onset of obesity, its
Bacteroidetes [21]. chronic inflammatory state, and insulin resistance.
The composition of the human gut microbiome has changed As the ratio of the gut microbiome shifts towards Bacteroidetes,
dramatically over the past 70 years due to altered living conditions, there is a subsequent increase in the production of acetate, which
antibiotic use, refrigeration, and the prevalence of processed food has been causally linked to increased adiposity [45]. A recent study
and water [62]. Rigorous study of the microbiota has demonstrated by Ref. [85] found that high-fat diet-fed rats showed an increase in
that there is a strong correlation between differential microbial the rate of acetate turnover as well as glucose-stimulated insulin
composition and the etiology of certain diseases. This review will secretion at rates proportional to the total calories consumed.
examine the contemporary microbiome in the context of obesity, Heightened acetate concentrations were concluded to derive from
type 1 diabetes mellitus (T1DM), rheumatoid arthritis (RA), and gut microbiota and drive parasympathetic nervous system activa-
systemic lupus erythematosus (SLE) and the underlying increase in tion, resulting in pancreatic b-cell stimulation and increased
cardiovascular risk that accompanies these diseases. secretion of ghrelin, an appetite-stimulating hormone. The result-
ing positive feedback loop results in hyperphagia, hyper-
2. Obesity triglyceridemia, increased lipid deposition, and insulin resistance,
all of which are risk factors associated with CVD [85]. Hyperphagia,
The Centers for Disease Control and Prevention classifies any overeating, and the subsequent increase in lipid deposition play a
individual with a body mass index (BMI) of 30 or higher as clinically role in inducing a chronic inflammatory state. Adipose tissue acts as
obese [32]. Obesity is a major risk factor for diseases such as hy- an endocrine gland and source of cytokines such as tumor necrosis
pertension, type 2 diabetes mellitus (T2DM), and metabolic syn- factor-a (TNF-a) and interleukin-6 (IL-6) [29,92]. High IL-6 levels
drome [21]. Additionally, obesity has been well established as a result in an increase in the blood concentrations of C-reaction
precursor to CVD [90]. protein (CRP), as IL-6 modulates CRP production in hepatic tissue
Obesity is related to the modern Western diet, characterized by [24,99]. CRP is an acute phase reactant associated with systemic
high levels of total fat, animal proteins, omega-6 polyunsaturated inflammation that is an important predictor of risk for cardiovas-
fatty acids, and refined sugars [7]. High fat diets alter the compo- cular events [94] such as acute coronary syndrome, an umbrella
sition of the microbiome to favor the proliferation of Gram- term referring to a sudden blockage of blood flow to the heart [90].
negative bacterial strains, namely Bacteroidetes resulting in An abundance of adipose tissue can also result in hyper-
increased production of, and intestinal permeability to, lipopoly- triglyceridemia and is characterized by increased flux of the
saccharides (LPS), a component of the Gram-negative cell mem- atherogenic lipoprotein very low density lipoprotein (VLDL) and
brane [50]. High LPS levels and SCFA production activate Toll-like cholesterol in the blood [47]. Additionally, insulin resistance results
receptor 4 (TLR-4) which selectively binds LPS and induces the low- in an inability to dilate blood vessels, leading to hypertension [73].
grade inflammation involved in the development of obesity [50]. In obese mice, high-fat diets supplemented with butyrate pre-
TLR-4 activation also results in upregulation of inflammatory vented and reversed insulin resistance, implicating an important
pathways such as the c-Jun N-terminal kinase and nuclear factor- role for microbiome-associated metabolites in the development
kappa B (NFkB) pathways in adipocytes and macrophages that and treatment of CVD [37]. Other microbial metabolites, including
contribute to insulin resistance and increased adiposity [3,105]. branched-chain amino acids (BCAA), are associated with insulin
Activation of the c-Jun N-terminal kinase pathway leads to upre- resistance in humans and the presence of Prevotella corpri and
gulation of stress response genes and is implicated in pathological Bacteroides vulgatus in the gut [83]. The introduction of P. corpri by
L.J. Kasselman et al. / Atherosclerosis 271 (2018) 203e213 205

gavage into mice on a high-fat diet led to exacerbated glucose without an increase in food consumption when compared to mice
intolerance, increased serum BCAA, and reduced insulin sensitivity, receiving the human lean co-twin's transplant [93]. When obese-
indicating a causal role of P. corpri for the increase in BCAA and transplanted mice were co-housed with lean transplanted mice,
subsequent insulin resistance [83]. allowing exposure to a lean microflora phenotype, the obese-
Hyperphagia and adiposity, as well as hyperlipidemia, hyper- transplanted mice had reduced adiposity compared to non-co-
tension, and insulin resistance have also been linked to deficiencies housed obese transplanted mice, and they demonstrated a shift
in TLR-5, a receptor that binds flagellin, the structural protein of the in their gut composition towards a lean phenotype, which included
bacterial flagellum [112]. TLR-5 has been shown to activate IL-6 as higher levels of propionate and butyrate [93]. Alterations in me-
well as monocyte chemoattractant protein-1 (MCP-1), both of tabolites have also been seen in obese human males with metabolic
which are important factors contributing to atherosclerosis [40,92]. syndrome who received fecal transplants from lean donors [63].
MCP-1 enhances migration and infiltration of monocytes/macro- Fecal transplant recipients demonstrated altered gut microbiota
phages into the area of the atherosclerotic lesion and IL-6 partici- compositions, improved insulin sensitivity, and a small decrease in
pates in the vascular inflammatory cascade [52,76]. While the glycated hemoglobin (HbA1c) but these changes were dependent
knockout of TLR-5 in murine models did not alter the ratio of Fir- on the recipients' gut microbial composition at baseline and were
micutes to Bacteroidetes at the phylum level, there was a significant not maintained long-term [63]. Similar transient fecal trans-
correlation between the onset of the aforementioned symptoms plantation affects have been shown with microbial diet-associated
with differences in the gut microbial composition at the species atherogenic metabolites, e.g. trimethylamine N-oxide (TMAO), such
level [112]. Moreover, the transfer of the bacteria from the TLR-5 that transplantation of atherosclerosis-prone, high diet-related
knockout mice to healthy animals produced many of the features TMAO murine cecal contents conferred increased levels of TMAO
of metabolic syndrome. Therefore, the microbiota is also likely to initially, and larger diet-induced atherosclerotic plaque burdens in
contribute to metabolic syndrome through interactions with the recipient mice [51].
host immune system and response. In summary, altering the composition of the microbiota to
It is unclear if an altered gut composition is a pre-requisite factor contain an increased population of Bacteroidetes, obesogenic diets
for obesity or if consumption of a Western diet, and subsequent can aggravate an inflammatory response via LPS-induced TLR-4
changes in body composition and inflammation, leads to altered activation, resulting in increased adiposity and inflammation.
gut flora. Recent evidence in fecal transplantation research has Additionally, exposure to obese or atherogenic gut microflora
shown that obesity is transmissible by modulation of gut microbes. phenotypes can alter body composition, metabolism, and athero-
In one study, fecal samples from human female twins discordant for sclerotic plaque burden. Shifts in the microbiota can, therefore, be
obesity were transplanted into germ-free mice. Mice receiving the linked to the onset of obesity as well as the cardiovascular risks that
human obese twin's sample had a significant increase in adiposity accompany it (Fig. 1).

Fig. 1. Etiology of cardiovascular risk in obesity due to microbiota shift.


The ingestion of foods high in animal fat, protein, and refined sugar favors the proliferation of the Gram-negative Bacteroidetes, hypothesized to be the incident event resulting in
the inflammatory state. Concentrations of LPS upregulate TLR-4 activity, inducing the obese inflammatory state that often results in CVD.
206 L.J. Kasselman et al. / Atherosclerosis 271 (2018) 203e213

Dietary treatments can mitigate the pathogenic impact of from those of biobreeding diabetes-resistant rats (BB-DR), with BB-
obesity. For example, in an animal model of obesity, the ingestion of DR hosting higher populations of Lactobacillus and Bifidobacterium,
fiber-rich common beans (Phaseolus vulgaris) can alter the obese both probiotic-like Firmicutes, whereas BB-DP rats had higher
microbiome composition by increasing levels of the mucin- numbers of Bacteriodetes such as Bacteroides, as well as the Fir-
degrading Akkermansia and Prevotellaceae, leading to increased micutes Eubacterium and Ruminococcus [95]. Moreover, the treat-
tight junction expression, upregulated mucin production, increased ment of BB-DP mice with probiotics prevented the development of
SCFA production, and reduced serum LPS levels [78]. In a similar T1DM, further strengthening this link [95].
animal model, ingestion of anthocyanins, present in black currants, A common metabolite of Firmicutes, butyrate, is regarded as an
has been demonstrated to decrease weight gain and adipocyte size anti-inflammatory SCFA integral to colon health. Butyrate induces
and improve glucose metabolism through phenolic acid, an mucin synthesis, decreases bacterial transport across the intestinal
anthocyanin-derived metabolite of bacteria in the jejunum [42]. In epithelial wall, and increases the rate of tight junction formation. In
obese humans, treatment with probiotics such as Lactobacilli or healthy individuals, the abundance of the mucin-degrading Pre-
fecal transplants have been shown to reduce body weight, improve votella and Akkermansia bacteria indicates upregulated mucin
insulin sensitivity, and reduce blood glucose and triglyceride levels production [107]. In individuals with T1DM, these two strains are
[59,75,113]. Dietary supplementation with specific species such as noticeably absent, suggesting a lack of mucin on the epithelial layer
Akkermansia muciniphila, which has a good safety profile in of intestines and consequent increase in gut permeability [16,122].
humans, leads to a decrease in fat mass, lower glucose intolerance It has also been hypothesized that breast feeding may decrease the
and insulin concentration, resulting in a lower insulin resistance risk of T1DM in children via key early exposure to human milk
index in high fat diet-fed mice [15,89]. oligosaccharides, which are similar in structure to the mucins
Surgical intervention in obese individuals has also been produced by the intestinal epithelium [122]. Additionally, lactic
demonstrated to alter the host microbiome, often resulting in acid fermentation, as a result of human milk oligosaccharide
increased microbial diversity, as bacteria quickly adapt to a “star- exposure produces acetate, which can then be used for butyrate
vation-like state” and readily proliferate [1,23]. Roux-en-Y gastric production [122]. While the number of lactic acid and butyrate
bypass (RYGB) surgery is a popular treatment option to reduce producing bacteria is higher in healthy individuals, the T1DM
cardiovascular risk in obese individuals. RYGB surgery has also been microbiota contains a larger proportion of Bacteroides, Veillonella,
demonstrated to increase facultative anaerobic bacteria pop- and Alistipes, which ferment glucose and lactate into propionate,
ulations, resulting in an increase of fermentation products associ- acetate, and succinate. These SCFAs do not induce mucin synthesis,
ated with weight loss, namely butyrate [56]. Decreased suggesting decreased mucin levels and increased gut permeability
concentrations of Bacteroidetes, as a result of pH changes in the [16]. Thus, the host may be leaking a greater quantity of substrates
biliopancreatic limb of the stomach after surgery, are also associ- into the gut [16]. Increased intestinal permeability has been shown
ated with weight loss [1]. Additionally, transfer of gut bacteria from to result in a higher intestinal inflammatory state, including
RYGB-treated mice to non-operated, germ-free mice resulted in a increased concentrations of IL-1 and IL-4. IL-1 is a pro-
decrease in fat mass and weight loss, further suggesting the ability inflammatory cytokine that has been linked to atherogenesis, pla-
of surgery to alter the obese microbiome [1]. que destabilization, plaque rupture, and thrombosis [18]. IL-4 is an
anti-inflammatory cytokine that activates collagen synthesis,
3. Type 1 diabetes mellitus leading to inflammatory fibrosis related to myocarditis and chronic
heart failure [96]. The inflammatory state of patients with T1DM is
Type 1 diabetes mellitus (T1DM) results from T cell-mediated detectable before the onset of T1DM, which suggests that gut mi-
autoimmune destruction of pancreatic b-cells [11]. The risk for crobial composition plays a role in the pathogenesis of the disease
developing T1DM is higher in people with a first-degree relative [13]. Additionally, the composition of healthy gut microbiota has
diagnosed with T1DM and with the presence of susceptibility genes been found to be more diverse than the T1DM microbiome. The
such as certain human leukocyte antigen (HLA) haplotypes, though healthy microbiome harbors a higher proportion of unclassified
these factors do not confer 100% susceptibility, suggesting an organisms, which suggests that they are nonpathogenic, as pre-
environmental component to T1DM [5]. Although T1DM is dominantly pathogenic organisms are classified [48].
manageable, one of the long term side effects of the disease is CVD, Women with T1DM are more likely to experience cardiovascular
which has become a major and increasingly incident cause of events such as myocardial infarction, coronary revascularizations,
mortality in T1DM patients [102]. T1DM patients exhibit arterial and stroke than men with diabetes. Differential microbiome com-
lesions that are more laden with lipids, macrophages, and thrombi positions may play a role in establishing this sex bias. The presence
with larger necrotic cores and more calcification than non-diabetic of hormone receptors on immune cells links hormone levels to the
individuals [115]. Patients diagnosed with T1DM have an elevated etiology of autoimmunity, including T1DM. While estrogen and
risk of developing CVD, namely coronary heart disease (CHD), ce- prolactin act as enhancers of humoral immunity, testosterone and
rebrovascular disease, peripheral artery disease, and atheroscle- progesterone serve as immunosuppressants, thereby reducing
rosis, due in part to chronic inflammation [30]. inflammation and its adverse cardiovascular effects [28,31]. It is
Emerging research has implicated a dysregulated microbiome as possible that a male-specific microbiome is responsible for pro-
a pathogenic factor in the development of autoimmune disorders, ducing testosterone in the gut, thus offering greater protection
including T1DM. As children with T1DM develop islet autoimmu- against the development and pathology of autoimmunity, whereas
nity, their gut microbiota show a correlative decline in the pop- the converse may be true for an estrogen-producing female-spe-
ulations of Firmicutes and increase in Bacteroidetes at the phylum cific microbiome. While further research is needed to determine
level [48]. More specifically, within the Bacteroides genus, more causality, several studies have corroborated the differential com-
than one-fifth of the changes that occur are in the species B. ovatus. positions between male and female gut microbiome as well as the
This is in contrast to non-diabetic children who demonstrated protective effect of increased testosterone levels [81]. The
increased abundance of the Firmicutes species human intestinal postepubescent male microbiome demonstrates differential com-
firmicute CO19 [48]. Similar changes are seen in animal models. The positions of Lactobacilli, Porphyromonadaceae of the Bacteroidetes
gut microbial composition of biobreeding diabetes-prone rats phylum, Enterobacteriacae of the Proteobacteria phylum, and
susceptible to the effects of T1DM (BB-DP) differed significantly segmented filamentous bacterium (SFB). Both Enterobacteriacae
L.J. Kasselman et al. / Atherosclerosis 271 (2018) 203e213 207

and SFB demonstrated an ability to support the gender bias of been seen with a decrease in concentrations of probiotic-like bac-
T1DM [117]. However, since the sex-specific differences in the teria such as Lactobacilli.
microbiome do not arise until after puberty, it is also possible that Increasing the population of Lactobacilli via ingestion of pro-
the endocrine production of sex hormones influences the compo- biotic treatments may play a beneficial role in the attenuation of
sition of the microbiome [81]. T1DM. Some lactobacilli strains have shown modulation of host
Males also produce greater quantities of interferon (IFN)g, a bacteria, inhibiting the formation of norepinephrine transporters,
molecule hypothesized to play a role in inhibiting the inflammatory improving antioxidant status, and increasing the expression of
pathway, which may protect against cardiac events arising from genes encoding junction and adhesion proteins, specifically claudin
chronic low-grade inflammation [81]. While IFNy is typically [80]. Lactobacilli can act as a physical barrier inhibiting the passage
associated with pro-inflammatory pathways [116], one possible of pro-inflammatory antigens and signaling molecules such as ni-
mechanism by which IFNg provides protection against T1DM is tric oxide, degradation of toxic compounds, release of nutrients,
through its negative regulation of the helper T cells integral in increased concentration of mucus-producing goblet cells, and
activating the B cells necessary for the onset of T1DM [117]. In male production of anti-inflammatory compounds [111]. Additionally,
T1DM mice with a knockout for IFNg, the sex bias in T1DM dis- dietary fiber hydrolysis by Lactobacilli releases antioxidant species
appeared [117]. Male gut microbiota transplantation via fecal that are critical in T1DM patients with increased oxidative stress
transplant to female mice ameliorated T1DM and increased [111].
testosterone in female cases [80]. Additionally, in murine models,
germ-free female mice demonstrated enhanced activity of the type
4. Rheumatoid arthritis
I IFN signaling pathway, which has been shown to regulate intes-
tinal homeostasis. Deletion of the type I IFN receptor IFNAR1 in
Rheumatoid arthritis (RA) is a chronic inflammatory autoim-
intestinal epithelial cells resulted in alternation in the microbiota
mune disease in which severe progressive joint destruction,
composition, epithelial hyperproliferation, and colitis-associated
swelling, functional disability, and pain occur due to responsive
cancer [46]. Thus, it has been postulated that the increase in type
thickening of the synovium [100]. Over time, the disease can induce
1 IFN production in the female intestinal tract may contribute to the
cartilage loss as well as joint deformity ([114]). CVD is the leading
differentiation of the gender-specific gut microbiota resulting in
cause of mortality in RA patients, accounting for nearly 40% of
the sex bias observed in T1DM [46].
deaths of individuals with RA [53]. RA patients have a twofold
Overall, the effects of an increase in Bacteroidetes and subse-
increased risk of suffering from myocardial infarction and stroke,
quent decrease in Firmicutes populations, namely, a decrease in the
with the risk increasing threefold 10 years after the initial RA
intestinal concentration of butyrate, results in decreased mucin
diagnosis [65]. The increased cardiovascular risk associated with RA
synthesis. The lack of sufficient mucin on the intestinal membrane
is not fully explained by the risk factors traditionally associated
leads to an increase in intestinal permeability, which induces a
with CVD [35,103].
chronic inflammatory state and the cardiovascular risks that
Microbial dysbiosis in the periodontium, the lung, and the gut
accompany it, thereby posing a potentially strong causal link to the
have been implicated in the pathogenesis of RA. In the gut, Pre-
elevated risk of CVD in T1DM patients (Fig. 2). Similar effects have
votella copri, a unique species of Gram-negative anaerobic bacterial

Fig. 2. Etiology of cardiovascular risk in T1DM due to microbiome shift.


A decrease in butyrate-producing Firmicutes is hypothesized to be the incident event decreasing mucin synthesis and subsequently increasing intestinal permeability endemic in
patients with T1DM. This intestinal permeability results in the chronic inflammation associated with CVD in T1DM patients.
208 L.J. Kasselman et al. / Atherosclerosis 271 (2018) 203e213

member of the Bacteriodetes phylum, defined the microbiome of system, increasing macrophage activity and phagocytosis. It is
RA patients and has recently been implicated in a number of other possible that the abundance of the Gram-negative P. copri con-
autoimmune diseases including inflammatory bowel disease and tributes to heightened levels of LPS and consequently CRP in RA
colitis [12,88]. Even in healthy subjects, P. copri was correlated with patients [98]. CRP is a known biomarker of CVD. Otherwise healthy
adverse health effects predictive of cardiovascular events, namely individuals with heightened CRP levels demonstrated a 2-fold in-
an increase of the microbial byproduct trimethylamine N-oxide crease in risk of stroke, a 3-fold increase in risk of myocardial
(TMAO; [17]). TMAO, previously established as a byproduct infarction (MI), and a 4-fold increase in the development of pe-
resulting from an increase in dietary choline found in egg yolks and ripheral vascular disease [94]. Whether CRP activity directly in-
meats, increases platelet responsiveness and thus plays a direct role duces cardiovascular events or is simply a biomarker of their advent
in increasing the incidence of thrombotic events such as heart is unknown [94]. However, studies have also established a correl-
attack and stroke [120]. Increased levels of Bacteriodetes, such as ative link between CRP levels and proteinuria [57]. Proteinuria has
Bacteroides, can also interfere with the effectiveness of common been shown to correlate with coronary artery calcification, hyper-
disease modifying anti-rheumatic drugs through alterations in tension, hyperlipidemia, and inflammation [6,91]. Thus, the abun-
microbial metabolism, such as methotrexate, an anti-inflammatory dance of P. copri in RA patients may increase the risk of cardiac
drug that confers survival benefit due to reduced CV mortality incidents via an LPS-CRP-proteinuria axis.
[8,22,97]. Along with heightened CRP levels, RA patients tend to exhibit
P. copri presents LPS on its cell wall and binds TLR-4. TLRs have other inflammatory markers that correlate with increased risk of
been demonstrated to not only play a role in microbial recognition heart disease, including erythrocyte sedimentation rate, rheuma-
of LPS but also serve as a link between innate and adaptive im- toid factor, and anti-citrullinated and anti-carbamylated protein
munity, as they regulate the expression of costimulatory molecules antibodies [14,104]. Additionally, the chronic inflammation result-
on antigen-presenting cells (APCs) to induce T cell activation and ing from RA can result in hypertension, yet another risk factor in
also create a cytokine cascade to differentiate T cells into the CVD [26].
desired subset. Failure of T cell differentiation and regulation is a In short, the physiological response to high levels of LPS from
hallmark of the development of autoimmunity [98]. Since the the prevalence of the Gram-negative P. copri in RA patients,
ligand of TLR-4 is LPS, the sensing of LPS from Gram-negative including TLR-4 activation and subsequent IL-17 proliferation,
bacteria such as P. copri may be responsible for triggering cyto- could result in increased platelet mobilization, T cell activation, and
kines such as IL-17 and driving T cell-mediated pathogenesis of increased proteinuria leading to a chronic inflammatory state and
arthritis [2,72,108]. Further, LPS has been shown to increase platelet associated elevated cardiovascular risk (Fig. 3).
aggregation [118]. Studies have shown that treatment with the commensal Gram-
When compared to patients with psoriatic arthritis, those with negative Prevotella histicola bacterium attenuated symptoms of RA
RA demonstrate elevated levels of CRP [34]. The bacterial ligand for in murine models [74]. Treatment with P. histicola led to increased
CRP is phosphocholineda common component of the bacterial cell expression of the tight junction protein ZO-1 and consequently
wall, namely LPS. Once bound to LPS, CRP activates the complement decreased intestinal permeability in the ileum, jejunum, and colon.

Fig. 3. Etiology of cardiovascular risk in RA due to microbiota shift.


The overabundance of a single Gram-negative bacterial strain, P. copri (Firmicute), is implicated in the pathogenesis of RA. An increase in P. copri is accompanied by an increase in
LPS concentrations, which activate TLR-4. TLR-4 activation has been linked to the proliferation of IL-4 and the failure of T cells to properly differentiate, both of which result in the
chronic inflammatory state associated with CVD in RA patients. This inflammatory state is accompanied by an increase in CRP levels and subsequent risk of proteinura.
L.J. Kasselman et al. / Atherosclerosis 271 (2018) 203e213 209

Moreover, P. histicola induces the differentiation of T cells into T Hypothesis states that as incidence of bacterial infection have
regulatory cells in muscosal membranes and increases the con- decreased with increased hygiene standards and practices, both
centration of anti-inflammatory cytokines such as IL-10 [74]. These pathogenic and non-pathogenic colonization of the gut have also
potent probiotic properties suggest that this single species might be decreased [80]. Evidence of a connection between environmental
valuable as adjunct treatment for the symptoms of RA via mucosal sanitation and autoimmunity was demonstrated in murine models,
regulation. However, the inflammatory response triggered by TLR-4 with the level of sanitation of the cages of mice correlating directly
remains unaffected by treatment with P. histicola, and further with the onset of T1DM, for example. It was concluded that the
research must be conducted to examine the relative levels of serum lower the burden of disease, the higher the incidence of autoim-
CRP before and after treatment with P. histicola to draw a more munity [82]. In the case of SLE, seronegativity of Helicobacter pylori
comprehensive conclusion about the bacterium's ability to atten- correlated to increased risk and earlier onset of SLE, suggesting that
uate the symptoms of RA. H. pylori plays a protective immunosuppressant role against T cell
hyperactivity. Of course, heightened levels of H. pylori have long
5. Systemic lupus erythematosus been associated with the formation of peptic ulcers, and thus the
benefit of its immunosuppressant role should not be overestimated
Systemic lupus erythematosus (SLE) is an autoimmune disease [60,66]. More broadly, T cell activation and subsequent exhaustion
that triggers an inflammatory response in different tissues of the resulting from chronic infection by bacterial pathogens may explain
body, including internal organs [71]. According to the Lupus the ability of pathogenesis to down-regulate inflammation and
Foundation of America, approximately 2,000,000 Americans suffer attenuate SLE symptoms [80].
from the disease. SLE affects both women and men but is most SLE patients demonstrate a decrease in Firmicutes levels,
prevalent among pre-menopausal women [80]. The chronic exhibiting a 2.5-fold decrease in the ratio of Firmicutes to Bacter-
inflammation seen in lupus is also associated with the development oidetes at the phylum level [54]. Butyrate, produced by Firmicutes,
of atherosclerotic lesions. SLE patients show elevated rates of plays a role in the differentiation of regulatory T cells in the colon,
atherosclerosis, thrombosis, arteritis, embolization, and vascular spleen, and lymphatic system that suppress inflammation, the
spasm, which often manifest in coronary artery disease (CAD) or dysfunction of which is a hallmark of SLE and a precursor to car-
coronary heart disease (CHD). CVD is the leading cause of death in diovascular incidents [82]. Therefore, a decrease in Firmicutes and
SLE patients symptomatic for more than five years [101]. consequent decrease in butyrate levels may contribute to inflam-
The incidence of SLE in the American population has increased mation in SLE patients [119]. This hypothesis is further supported
threefold in the latter half of the 20th century [109]. The “Hygiene by evidence demonstrating that antibiotics, which diminish pop-
Hypothesis” is a popular hypothesis accounting for the role of the ulations of butyrate-producing Firmicutes such as
contemporary microbiome in the pathogenesis of SLE. The Hygiene trimethoprimesulfamethoxazole (Septra), minocycline, and

Fig. 4. Etiology of cardiovascular risk in SLE due to microbiome shift.


A decrease in the population of butyrate-producing Firmicutes leads to a decrease in butyrate production. This decreased production of butyrate has been postulated to be the
incident event leading to the failure of T cells to properly differentiate in patients with SLE, resulting in the induction of the chronic inflammatory state representative of the disease.
210 L.J. Kasselman et al. / Atherosclerosis 271 (2018) 203e213

amoxicillin have been shown to trigger lupus flares [80]. The car- lupus-prone MRL/lpr mice [119]. In this same model, retinoic acid
diovascular risk associated with SLE has been strongly suggested to protected the mice from glomerulonephritis [84]. Retinoic acid is a
be caused by this active inflammatory and immunological metabolite of vitamin A and increased vitamin A ingestion has also
response, and not the long-term lipid buildup along the arterial been shown in a very small study to ameliorate lupus nephritis and
walls as previously thought [77]. proteinuria [61,80]. Finally, increases in Lactobacilli in SLE murine
Additionally, female lupus patients demonstrated reduced levels models have been shown to suppress pro-inflammatory responses
of Lactobacillaceae and increased levels of Lachnospiraceae, both by increasing the production of IL-10, an anti-inflammatory cyto-
members of the Firmicutes phylum [119]. The same held true for kine, as well as regulatory T cells [41,119].
female lupus-presenting murine models, in which there were de-
creases in the levels of Lactobacilli and increases in those of Lach- 6. Conclusion
nospiraceae as well as increased diversity when compared to
healthy subjects [80]. It is worth noting that Lachnospiraceae, a The disease states associated with obesity, T1DM, RA, and SLE
butyrate-producing bacterium of the Firmicutes phylum, are pre- each are accompanied by a high cardiovascular risk. Additionally,
sent in higher numbers in SLE patients than in their healthy each disease state demonstrates a characteristic microbiome that
counterparts. Therefore, it is possible that Lachnospiraceae, or any deviates in some way from that of healthy individuals. The impli-
butyrate-producing bacteria, may not be able to suppress inflam- cation of the microbiota in the pathogenesis of obesity, T1DM, RA,
mation in SLE cases [119]. and SLE demonstrates a putative link between alterations in the
The relative increase in Bacteroidetes in the SLE microbiome composition of the host microbiome and the cardiovascular risks
results in heightened TLR-4 activity that has been associated with associated with each of the aforementioned diseases. Further
spontaneous lupus development. TLR-4 activation by LPS has been research should investigate the therapeutic potential of alteration
shown to increase CD40 levels in macrophages and microglia in in disease-specific microbiomes, with potential therapies including
liver and kidney tissue, among others [36]. Increases in CD40 increasing the concentration of Lactobacilli or other probiotic
expression in macrophages have been directly implicated in the strains as well as the concentration of butyrate.
pathogenesis of atherosclerosis and atherothrombosis [58]. Liga-
tion of CD40 on pro-inflammatory M1 macrophages activates the Conflict of interest
release of TNFa, IL-1 (a and b), IL-6, IL-8, IL-12, and chemokine li-
gands (CCL) 2, 3, 4, and 5 [58]. Pro-inflammatory cytokines such as The authors declared they do not have anything to disclose
TNFa and IL-1 induce the expression of cell-surface leukocyte regarding conflict of interest with respect to this manuscript.
adhesion proteins such as E-selectin, vascular cell adhesion
molecule-1 (VCAM-1), and inter-cellular adhesion molecule-1 Financial support
(ICAM-1) along the endothelial wall. Upon binding, the leuko-
cytes migrate through the endothelium and into the intima. This work was supported by the American Heart Association
Therefore, the adhesion of immune cells such as monocytes and T under grant number 16GRNT26430041 and by The Elizabeth
cells to the arterial endothelium marks the beginning of an Daniell Research Fund. We thank Janet and Robert Buescher for
atherosclerotic lesion [68,77]. their generous support.
Further, SLE patients demonstrate heightened levels of soluble
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