A Short Look on Microbiome and Lipid Metabolism

Previously, I discussed how important gut microbiota is in disease condition and how it may contribute to TLR4 signaling pathway. In today’s post, I will discuss how gut microbiome can affect lipid metabolism.

Several studies supported a role for gut microbiota in the modulation of lipid metabolism1-3. In one of the early studies on this topic, Jeffrey Gordon group were able to show that conventialization of adult GF C57BL/6 mice with a normal microbiota resulted in a 60% increase in body fat content despite reduced food intake2. Further, they were able to demonstrate that Fasting-induced adipocyte factor (Fiaf) – also known as Angiopoietin-like 4 (ANGPTL4), a member of angiopoietin-like family of proteins, is suppressed in the intestine of normal mice after conventialization2. Their data from fiaf -/- mice also revealed that Fiaf is a LPL inhibitor and its suppression is needed for gut microbiota-induced deposition of triglyceride in adipose tissue. Continuing to further support the merging view of gut microbiota role in lipid metabolism, Backhed group compared the serum metabolome and the lipidomes of serum, adipose tissue and liver of CONV-R and GF mice3. CONV-R serum metabolome showed increased levels of energy metabolites while levels of fatty acids and cholesterol were reduced. Their results further showed that triglyceride levels were lower in the serum but higher in the adipose tissue and liver of CONV-R mice, consisted with increased lipid clearance3.

Although the aforementioned studies support the role of gut microbes and modulation of lipid levels, their study design did not allow identification of specific microbes responsible for the observed phenotype changes after conventialization. However, a recent novel study by Fu and her colleagues showed some of the very first human evidence that variations in gut microbiota are associated with blood lipid levels and what would the possible microbes involved1. By using a sub-cohort of LifeLines population based cohort, they investigated the impact of gut microbiome on BMI and blood lipid levels in 893 human subjects and determined the fecal microbial composition by assessing variations of bacterial 16S rRNA gene. The results of this study showed that microbial diversity was negatively correlated with body weight and triglyceride levels while positively correlated with HDL levels. Although most of the associated taxonomies were shared across BMI and lipid levels, they reported several specific taxa associated with lipids. The family Clostridiaceae/Lachnospiracease was specially associated with LDL, the family Pasteurellaceae (Proteobacteria), genus Coprococcus (Firmicutes) and genus Collinsella species Stercoris showed strong association to TG levels. Finally, they also demonstrated that microbiota contributes to lipid variations independent of age, gender and genetics. Notably, the findings of Fu et al. study are in line with previously described TwinUK population4 confirming lower abundance of families Christensenellaceae, Rikenellaceae, class Mollicutes, genus Dehalobacterium and kingdom Archaea that were associated to a high BMI. It is interesting to mention that several of the bacteria identified by Fu et al. study are also involved in BAs metabolism, thereby, it can be suggested that gut microbiota-associated changes in BA composition may play a partial role in the association of identified fecal taxa proportions and lipid levels. Although Fu et al. study supports the potential role of gut microbiota programming/modulation to improve dyslipidemia, the proof of causality for the presence of gut microbiome-lipids axis should be validated by functional studies.

With growing evidence for important role of gut microbiota in inflammation and lipid metabolism, an in-depth investigation of potential role of this commensal super organism on CVD is starting to emerge. A good example would be the role of trimethylamine N-oxide (TMAO), a gut microbiota-dependent metabolite that has been implicated in CVD, specifically in atherosclerosis development5. Recent lines of evidence show that “drugging the microbiome” to inhibit microbial TMAO production may serve as a potential therapeutic approach for prevention/treatment of CVD5,6. However, whether TMAO producing microbiota transplant into GF mice and whether TMAO administration to atherogenic mouse models will affect atherosclerosis development should be studied in far more details. Moreover, mono-specific gut microbiota manipulation by Akkermensia muciniphila recently showed antiatherogenic properties in atherosclerotic mouse model7 in agreement with results of a study in ApoE -/- mice that showed a sustained alteration of whole gut microbiota with antibiotics, improved lipoprotein profile and reduced atherosclerosis plaque development8.


  1. Fu J, Bonder MJ, Cenit MC, Tigchelaar E, Maatman A, Dekens JAM, Brandsma E, Marczynska J, Imhann F, Weersma RK, Franke L, Poon TW, Xavier RJ, Gevers D, Hofker MH, Wijmenga C, Zhernakova A. The gut microbiome contributes to a substantial proportion of the variation in blood lipids. Circulation research. 2015
  2. Backhed F, Ding H, Wang T, Hooper LV, Koh GY, Nagy A, Semenkovich CF, Gordon JI. The gut microbiota as an environmental factor that regulates fat storage. Proc Natl Acad Sci U S A. 2004;101:15718-15723
  3. Velagapudi VR, Hezaveh R, Reigstad CS, Gopalacharyulu P, Yetukuri L, Islam S, Felin J, Perkins R, Boren J, Oresic M, Backhed F. The gut microbiota modulates host energy and lipid metabolism in mice. J Lipid Res. 2010;51:1101-1112
  4. Goodrich JK, Waters JL, Poole AC, Sutter JL, Koren O, Blekhman R, Beaumont M, Van Treuren W, Knight R, Bell JT, Spector TD, Clark AG, Ley RE. Human genetics shape the gut microbiome. Cell. 2014;159:789-799
  5. Wang Z, Klipfell E, Bennett BJ, Koeth R, Levison BS, Dugar B, Feldstein AE, Britt EB, Fu X, Chung YM, Wu Y, Schauer P, Smith JD, Allayee H, Tang WH, DiDonato JA, Lusis AJ, Hazen SL. Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease. Nature. 2011;472:57-63
  6. Wang Z, Roberts AB, Buffa JA, Levison BS, Zhu W, Org E, Gu X, Huang Y, Zamanian-Daryoush M, Culley MK, DiDonato AJ, Fu X, Hazen JE, Krajcik D, DiDonato JA, Lusis AJ, Hazen SL. Non-lethal inhibition of gut microbial trimethylamine production for the treatment of atherosclerosis. Cell. 2015;163:1585-1595
  7. Li J, Lin S, Vanhoutte PM, Woo CW, Xu A. Akkermansia muciniphila protects against atherosclerosis by preventing metabolic endotoxemia-induced inflammation in apoe-/- mice. Circulation. 2016;133:2434-2446
  8. Rune I, Rolin B, Larsen C, Nielsen DS, Kanter JE, Bornfeldt KE, Lykkesfeldt J, Buschard K, Kirk RK, Christoffersen B, Fels JJ, Josefsen K, Kihl P, Hansen AK. Modulating the gut microbiota improves glucose tolerance, lipoprotein profile and atherosclerotic plaque development in apoe-deficient mice. PLoS ONE. 2016;11:e0146439

Shayan Mohammad Moradi Headshot

Shayan is a caffeine-dependent Ph.D. Candidate at the Saha Cardiovascular Research Center, University of Kentucky. His research area is focused on vascular biology and lipid metabolism. He tweets @MoradiShayan, blogs at shayanmoradi.com and he is the Winner of World’s Best Husband Award (Category: nagging).


Lipid-lowering Therapy In Young Adults: Do We Need To Re-invent The Wheel Or Just Align It?

Elevated cholesterol levels or hypercholesterolemia can be found for years or even decades, before individuals present with cardiovascular disease and complications such as myocardial infarction, stroke, or sudden cardiac death. The diagnosis of hypercholesterolemia and its treatment along with healthy lifestyle changes including a healthy diet and exercise as well as blood pressure control, are cornerstones of long-term cardiovascular health.1

There has been a substantial decline in cardiovascular disease mortality in the last decade due to improved awareness, therapy for established cardiovascular disease and primary and secondary preventive interventions.1 However, this observation is absent in young adults.2 Over the last decade, unfavorable trends in coronary heart disease and related mortality in younger individuals, i.e. 35-55 year-old, have emerged.2

We have previously shown that there is a phenotype of young adults with premature hypertension and development of resistant hypertension in their 30s.3 This phenotype has been characterized in a cross-sectional study of 2068 patients seen in a university referral clinic for resistant hypertension. In this study 45% of consecutively seen patients were younger than 55 years of age. Amongst them, 23% had high lipids, 25% were obese, 19% had diabetes, and 13% had obstructive sleep apnea. Cardiovascular events such a s history of myocardial infarction, stroke, or heart failure were prevalent were found in >20%. The majority of these predominately obese, resistant hypertensive individuals have excessive aldosterone, cortisol and sodium levels, conditions that are associated with increased cardiovascular morbidity and mortality, independent of blood pressure levels.

Lipid-lowering drugs, so-called statins, have been shown to reduce cardiovascular disease and mortality. Lipid lowering with statins in patients with hypercholesterolemia has a proven survival benefit for both primary prevention (ie, in patients without clinical evidence of coronary disease) and secondary prevention (ie, in patients with established coronary disease), even when serum cholesterol concentrations are “normal” for the population or borderline high. The mechanisms by which lipid-lowering therapy is beneficial are incompletely understood since absolute levels of cholesterol before or during treatment only explain parts while cholesterol-independent effects have been also described.1 Among the non-lipid mechanisms that may be involved are plaque stabilization, reduced inflammation, improvement of endothelial and arterial function, and decreased blood clotting.
In 2013 the American College of Cardiology and American Heart Association developed a new guideline for the management of hyperlipidemia. While previous guidelines recommended to initiate or adjust predominantly in response to lipid values these 2013 ACC/AHA guidelines target patients to fixed dose of statin therapy corresponding to atherosclerotic cardiovascular disease (ASCVD) or other risk factors. The four at-risk populations of individuals that are thought to benefit from statin therapy based on this guideline include:

  1. Adult patients with clinical ASCV
  2. Adult patients with primary elevations of LDL–C ≥190 mg/dL
  3. Patients 40-75 years of age with diabetes and LDL–C 70 to 189 mg/dL without clinical ASCVD
  4. Patients 40-75 years of age without clinical ASCVD or diabetes with LDL–C 70 to 189 mg/dL and have an estimated 10-year ASCVD risk of 7.5% or higher

In our cohort half of obese young patients under the age of 40 would per se not qualify to be treated with a statin. Patients between the ages of 40-55 are in the majority of cases not considered “eligible” since age is one of the most powerful nominators in the risk calculator and, anecdotally, when we evaluate these patients for statin eligibility for primary prevention, we usually calculate an estimated 10-year CVD risk score of <5%.

At their first visits we always discuss life style changes, since younger patients may be more motivated to eat healthier, exercise, and lose weight, but consistent, successful lifestyle changes are often difficult to accomplish.

When we consider statin treatment for primary prevention even if the ASCVD risk score is <7.5%, there are a lot of unknowns. Aside from statins being contraindicated in young women who are or want to become pregnant or are breastfeeding, it is not known if there are short-term benefits of therapy. There are few data on the safety of statins over decades of therapy and possible side effects of statin therapy could outweigh potential benefits.

Furthermore, we don’t know whether long-term treatment leads to better outcomes and who are the individuals who are going to benefit. With evolving advances in precision medicine, we may be able to “customize” primary prevention especially for this group and identify young individuals in whom premature cardiovascular events can be prevented.

However, the question remains: how can we prevent cardiovascular events in young adults?

Data of young adults who suffered a cardiovascular event will help to elucidate underlying mechanisms and optimal therapy regimens. 

Premature CHD in young adults versus CHD 02012018

This problem has been recognized and resulted in the YOUNG-MI Registry, a retrospective study examining a cohort of young adults age ≤50 years with a first-time MI.  The study uses electronic health records of 2 large academic centers, as well as detailed chart review of all patients, to generate high-quality longitudinal data regarding the clinical characteristics, management, and outcomes of patients who experience a myocardial infarction at a young age. Findings are thought to provide important insights regarding prevention, risk stratification, treatment, and outcomes of cardiovascular disease in this understudied population, as well as identify disparities which, if addressed, can lead to further improvement in patient outcomes.  

In a recent study from this registry, Singh et al. analyzed retrospectively the statin eligibility of young adults after a myocardial infarction. In this study the statin eligibility, based on the 2013 ACC/AHA guidelines and 2016 USPSTF recommendations, for primary prevention in adults <50 years who experienced a first-time type 1 myocardial infarction were evaluated. The median age of analyzed patients was 45 years, 20% were women, the majority had at least 1 traditional cardiovascular risk factor and 57% had experienced a ST-segment elevation myocardial infarction. Surprisingly, the median estimated 10-year atherosclerotic cardiovascular disease risk score was only 4.8% (interquartile range 2.8-8.0%). Only 49% and 29% would have met criteria for statin eligibility as per the 2013 ACC/AHA guidelines and 2016 USPSTF recommendations, respectively. These findings were even more noticeable in women where 63% were not eligible for statins according to either one of the guidelines as opposed to 46% of men only. To summarize these findings, the majority of young adults who present with a heart attack would not have met current guideline-based treatment thresholds for statin therapy prior to their myocardial infarction.

It highlights the need for better risk assessment tools for young adults.  Further, much more needs to be known about risk profiles, optimal prevention, and treatment to improve outcomes in these young understudied adults.


  1. Stone NJ, Robinson JG, Lichtenstein AH, Bairey Merz CN, Blum CB, Eckel RH, Goldberg AC, Gordon D, Levy D, Lloyd-Jones DM, McBride P, Schwartz JS, Shero ST, Smith SC, Jr., Watson K, Wilson PW, Eddleman KM, Jarrett NM, LaBresh K, Nevo L, Wnek J, Anderson JL, Halperin JL, Albert NM, Bozkurt B, Brindis RG, Curtis LH, DeMets D, Hochman JS, Kovacs RJ, Ohman EM, Pressler SJ, Sellke FW, Shen WK, Smith SC, Jr., Tomaselli GF and American College of Cardiology/American Heart Association Task Force on Practice G. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2014;129:S1-45.
  2. Ghazi L, Oparil S, Calhoun DA, Lin CP and Dudenbostel T. Distinctive Risk Factors and Phenotype of Younger Patients With Resistant Hypertension: Age Is Relevant. Hypertension. 2017;69:827-835.
  3. Ghazi L, Dudenbostel T, Xing D, Ejem D, Turner-Henson A, Joiner CI, Affuso O, Azuero A, Oparil S, Calhoun DA, Rice M and Hage FG. Assessment of vascular function in low socioeconomic status preschool children: a pilot study. J Am Soc Hypertens. 2016.

Tanja Dudenbostel Headshot

Tanja Dudenbostel is an Internist, Hypertension Specialist within Cardiology at the University of Alabama at Birmingham where I divide my time as an Assistant Professor between clinical research and seeing patients in cardiology.