July 01, 2022 5 min read
A recent study published in the prestigious journal Nature Medicine entitled “Microbiome and metabolome features of the cardiometabolic disease spectrum” characterized the microbiome signatures of
To assess the impact of the microbiome on disease progression.
In fact, the microbiome signatures across groups are so striking that they may be even more effective clinically, than conventional risk markers.
Cardiovascular and metabolic diseases, also known as cardiometabolic diseases (CMDs), are the top cause of death in the world.
This is a heterogenous group of conditions that includes:
CMDs primarily result from unhealthy lifestyles characterized by physical inactivity, smoking, and poor diet. Researchers in the field also acknowledge the multifaceted nature of CMD progression.
Indeed, it is widely accepted that genetics, age, sex, and environmental exposures including dietary intake and physical activity play a major role in cardiometabolic health status.
Interestingly, it is now understood that genetics, diet, and physical activity also directly influence the composition of the gut microbiome. Thus, the microbiome may play an instrumental role in directly shaping disease progression.
However, the signal may be confounded by factors like pharmaceutical drugs, many of which are known to modulate the gut microbiome and could, therefore, mask or mimic pathological microbiome signatures.
In this study, the researchers sought to establish signatures within the gut microbiome and metabolome (the global collection of all low molecular weight metabolites that are produced by cells during metabolism) that correspond to the onset and progression of ischemic heart disease (IHD).
Previous work in this area failed to account for major confounding factors like pharmaceutical drugs and extent of metabolic dysfunction.
The research team stratified their cohorts into discrete groups: healthy controls, untreated metabolically matched controls (i.e. i.e. individuals with obesity or diabetes that were not diagnosed with IHD and not administered pharmaceuticals), metabolically matched controls (i.e. individuals with obesity or diabetes that were not diagnosed with IHD but were administered pharmaceuticals), heart failure, chronic ischemic heart disease, and acute coronary syndrome.
In total, 1,241 middle-aged individuals were recruited with all participants falling into one of the six cohorts. This study design allowed the researchers to assess changes to the microbiome and metabolome that occur not only before disease onset but also from early to late disease progression.
With this strategy, early onset microbiome and metabolic signatures could be identified that would allow clinicians to identify patients at high risk of developing IHD.
With regards to the analytical framework, the team assessed the levels of gut microbial diversity and species present, gut microbial function, and metabolites in fasting serum and urine.
After using computational methods to remove features that were the result of confounding factors like pharmaceutical drug intake, key readouts were obtained including:
As reported by other groups, both the taxonomy and functional outputs of the gut microbiome were significantly different between the healthy control group and the group with IHD. Surprisingly, even more differences were observed between healthy controls and metabolically matched controls.
A significant shift was observed from the Bacteroides 1 and Ruminococcus populations to a Bacteroides 2 enterotype as disease worsened. The Bacteroides 2 enterotype is characterized by high levels of Bacteroides relative to Faecalibacterium, and is associated with guts that have a low bacterial cell count.
In other words, worsening of disease was closely associated to serious loss of microbial density as well as loss of microbial gene richness.
A total of 121 species emerged as markers of metabolic dysfunction and 85% of these were depleted in IHD. Of these, 23 unique species were identified as markers specific to IHD, some of which were depleted in IHD and other which were enriched. Specifically, depleted levels of Acinetobacter, Turcimonas, and Acetobacter were tightly linked to IHD.
Conversely, eight species showed enrichment in IHD including two, which were Betaproteobacteria within the Burkholderiales order. This was an intriguing observation as Burkolderia pseudomallei has been reported as a potential cause of endocarditis.
One species, an uncharacterized member of the Ruminococcus family, was identified that served as a marker of escalation when depleted. Ruminococcus include butyrogenic bacteria (i.e. butyrate producers). Thus, depletion of these bacteria are associated with insufficient production of short chain fatty acids—molecules essential for gut energy metabolism, gut barrier integrity, and immune regulation.
There were six species identified as de-escalation markers or, in other words, six species whose abundances were associated with improvements in health status.
All of these species were within the order Clostridales and all but one, Eubacterium siraeum, were uncharacterized. Previous reports suggest that Eubacterium are depleted in patients with atherosclerosis.
Importantly, Clostridales are known butyrate producers, reaffirming the critical role of short chain fatty acids like butyrate in health.
In addition to the markers for IHD, there were 31 species markers identified within the heart failure cohort, which indicates that microbiome composition shifts continue throughout disease progression.
The creation of multiple cohorts ranging from disease-free healthy controls to individuals across the spectrum of CMD progression facilitated microbial characterization and comparison between groups.
Importantly, this study identified that most of the species markers previously believed to correspond to IHD are actually markers of metabolic dysfunction broadly. In other words, the bacterial signatures associated with IHD are also present in individuals with type 2 diabetes and obesity.
To this end, the Bacteroides 2 enterotype emerged as a biomarker of both metabolic dysfunction and IHD. Overall, the microbiome signatures identified within this study were more effective at identifying health status than the conventionally used risk markers.
This work also confirmed previous research that identified reduced bacterial biomass and shifts in the bacterial composition and functional abilities in response to CMD.
Individuals who received treatment for IHD showed recovery of a healthy bacterial biomass, indicating that bacterial cell count may be a useful clinical marker to assess disease severity and treatment efficacy.
Interestingly, the commonly prescribed statin drugs, used to manage cholesterol levels, appeared to help with the restoration of bacterial biomass in the setting of CMD.
Finally, depletion of species responsible for the production of short chain fatty acids, like butyrate, was closely associated with disease progression.
Thus, nutritional strategies geared towards bolstering populations of butyrate-producing bacteria could help to slow down disease progression and onset.
Alexis Cowan, Ph.D.
Fromentin S, Forslund SK, Chechi K, Aron-Wisnewsky J, Chakaroun R, Nielsen T, Tremaroli V, Ji B, Prifti E, Myridakis A, Chilloux J, Andrikopoulos P, Fan Y, Olanipekun MT, Alves R, Adiouch S, Bar N, Talmor-Barkan Y, Belda E, Caesar R, Coelho LP, Falony G, Fellahi S, Galan P, Galleron N, Helft G, Hoyles L, Isnard R, Le Chatelier E, Julienne H, Olsson L, Pedersen HK, Pons N, Quinquis B, Rouault C, Roume H, Salem JE, Schmidt TSB, Vieira-Silva S, Li P, Zimmermann-Kogadeeva M, Lewinter C, Søndertoft NB, Hansen TH, Gauguier D, Gøtze JP, Køber L, Kornowski R, Vestergaard H, Hansen T, Zucker JD, Hercberg S, Letunic I, Bäckhed F, Oppert JM, Nielsen J, Raes J, Bork P, Stumvoll M, Segal E, Clément K, Dumas ME, Ehrlich SD, Pedersen O. Microbiome and metabolome features of the cardiometabolic disease spectrum. Nat Med. 2022 Feb;28(2):303-314. doi: 10.1038/s41591-022-01688-4. Epub 2022 Feb 17. PMID: 35177860; PMCID: PMC8863577.
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