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.
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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 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).
Shayan is a caffeine-dependent Ph.D. Candidate at the Saha Cardiovascular Research Center, University of Kentucky. His research area is focused on inflammation, aortic aneurysms and atherosclerosis. He tweets @MoradiShayan, blogs at shayanmoradi.com and always gives his 100% to science, unless he is donating blood.