Gut Microbiota as a Potential Treatment Target in Patient with … · Keywords Chronicheartfailure .Microbiota .TMAO(trimethylamine-n-oxide) .Diet .Prebiotic .Probiotic .Antibiotic

MEDICINE

Gut Microbiota as a Potential Treatment Targetin Patient with Chronic Heart Failure

Joshua Henrina1 & Irvan Cahyadi1 & Hoo Felicia Hadi Gunawan1& Leonardo Paskah Suciadi1

Accepted: 28 July 2020# Springer Nature Switzerland AG 2020

AbstractChronic heart failure (CHF) is a pandemic with a highmortality rate and a high economic burden. The complexity of heart failureclinical syndromes requires approaches through different therapeutic targets. Intestinal dysbiosis is a condition in the humanintestinal tract characterized by an imbalance of bacteria, causing various adverse effects. It has been linked with more than 20diseases and clinical syndromes, including chronic heart failure. The composition of intestinal microbiota is influenced bystructural and functional changes of the intestine, which happens in patients with CHF, through a complex network of cytokines,metabolic products, and numerous regulatory molecules. This condition provides exciting new fields for searching for a noveltreatment for chronic heart failure. Several interventions, including diet, probiotic, prebiotic, antibiotic, even fecal microbialtransplant, have previously been studied. This article discusses the reciprocal relationship between the heart and the gut micro-biota through various changes in the gut microbiota composition, intestinal dysfunction, and altered bacterial metabolites and thepotential therapies for modulating gut microbiota composition as a target of therapy for CHF.

Keywords Chronic heart failure . Microbiota . TMAO (trimethylamine-n-oxide) . Diet . Prebiotic . Probiotic . Antibiotic . FMT(fecal microbial transplantation)

Background

Chronic heart failure (CHF) is characterized by a fall in cardiacoutput caused by structural/functional etiologies, resulting indecreased systemic perfusion and exhibiting typical signs andsymptoms [1]. Chronic heart failure is a pandemic disease, af-fecting more than 26 million people worldwide [2]. Accordingto population-based studies, CHF involves 1–2% of the popu-lation. Consequently, there is a steep increase in healthcarespending. It is estimated that the total health expenditure spenton this disease is 31 billion dollars, 10%more than expendituresof other cardiovascular diseases in the United States [3].

Despite recent advances in CHF treatments, the mortalityrate is still high compared to other chronic diseases and its 5-year mortality rate similar to many cancers [4]. This is due tothe complexity of heart failure clinical syndromes. Thus, therehas been a dire need of new therapeutic targets for this multi-faceted disease. Currently, there has been an interest in thehuman gastrointestinal system and its microbiome as a targetof therapy, particularly a condition called gut dysbiosis.

Intestinal dysbiosis is a state of an imbalance of beneficialand deleterious bacteria in the human gut microbiota, with thenet effect of the latter one [5–7]. It has been linked to morethan 20 diseases and clinical syndromes, such as colorectalcancer, inflammatory bowel disease (IBD), and irritable bowelsyndrome (IBS), metabolic diseases, Alzheimer’s disease, andrecently, it is associated with heart failure [8, 9].

Therefore, it is an exciting new field regarding novel treat-ment explorations for CHF. In this review article, we discussthe altered gut microbiome and intestinal dysfunction withtheir downstream effects in heart failure subjects.Furthermore, we outline respective potential therapiestargeting microbial composition in CHF patients.

This article is part of the Topical Collection onMedicine

* Joshua [email protected]

1 Siloam Heart Institute, Siloam Hospitals Kebon Jeruk, Jl. PerjuanganNo.8, RT.14/RW.10, Kb. Jeruk, Kec. Kb. Jeruk, Kota Jakarta Barat,Daerah Khusus Ibukota Jakarta 11530, Indonesia

https://doi.org/10.1007/s42399-020-00436-4

/ Published online: 4 August 2020

SN Comprehensive Clinical Medicine (2020) 2:1614–1627

Main Text

Altered Gut Microbiome, Intestinal Dysfunction, andthe Role of Bacterial Metabolites in Heart FailurePatients

Gut Dysbiosis and Heart Failure

The total microbes in the human body, which primarily residein the gastrointestinal system, collectively consist of 1014 cells,ten times more than the sum of human cells, and comprisedover 2000 species [11–14]. The microbial genes are even larg-er, consist of 3.3 million genes, and are 150 more genes thanthe human genome [10]. These microorganisms coexist withits host in the gastrointestinal tract, identified as gut microbi-ota, and it is physiologically important in energy harvesting ofundigested foods, vitamin synthesis, and maintaining healthyhost immune system [12, 15].

The composition of gut microbiota is influenced by severalfactors, categorized as internal and external factors. Internalfactors, such as acute changes in fluid balance, chronic intes-tinal congestion, intestinal ischemia, hypoxia, acid and basedisorders, digestive tract dysmotility, nutritional deficiencies,and intake of certain fat types, can disrupt the balance ofintestinal flora. On the other hand, external factors that causeintestinal flora imbalance are antimicrobials, exposure to otherpatients, and the use of other drugs [16]. Both of these factorsare present in CHF patients.

In a healthy human gut, more than 90% constituent ofbacterial species are anaerobic Bacteroidetes and Firmicutes[11]. However, CHF patients experienced a decrease in bac-terial diversity and change in bacterial composition.Previously, the microbiome of heart failure patients has beenthoroughly analyzed with high-throughput sequencing tech-nology via 16S ribosomal ribonucleic acids and metagenomicsequencing. These techniques can characterize bacteria at spe-cies and strain level, respectively [13].

A pioneer 16S rRNA sequencing study by Luedde et al.involving 20 subjects with ischemic or dilated cardiomyopathyshowed that these patients experienced a significant decrease inCoriobacteriaceae, Erysipelotrichiaceae, and RuminoRuminococcaceae on the family level and a significant de-crease in Blautia, Collinsella, uncl. Erysipelotrichaceae, anduncl. Ruminococcaceae on the genus level [17].

Another 16S rRNA sequencing study by Kummen et al.that involved 84 subjects (40 discoveries; 44 validation)with stable systolic HF showed that the microbial richnessof the HF group is reduced significantly compared to con-trols, even after adjusting for demographics and comorbid-ities [18]. Furthermore, there were several depletions oftaxa from Lachnospiraceae family, which are butyrate-producing bacteria. Butyrate has anti-inflammatory proper-ties and stimulatory T cell regulation. Unsurprisingly, there

was an increased T cell activation that negatively correlateswith Lachnospiraceae. Therefore, gut dysbiosis hypothe-sized to be involved in chronic immune activation in HF[18].

Kamo et al. also showed similar fecal 16s rRNA sequenc-ing results. In comparison to healthy controls, Eubacteriumrectale and Dorea longicatena were less abundant in HF sub-jects. Additionally, in older HF subject (> 60 years old), pro-portions of Bacteroidetes were diminished, whereasProteobacteria flourished. Also, the Lactobacillus genus wasenriched in contrast to Faecalibacterium genus, which wasdepleted [19].

Cui et al. have characterized intestinal dysbiosis in CHFpatients, also with 16s rRNA sequencing. There was a de-crease in Faecalibacterium praustnitzii and an increase inRuminococcus gnavus numbers [20]. Through functionalanalysis, they also showed that butyrate-forming enzymegenes, namely, butyrate-acetoacetate CoA transferase, experi-enced a significant decline [20].

In addition, there was a growth of pathogenic bacteria suchas Campylobacter, Shigella , Salmonella , Yersiniaenterocolitica, and some of Candida species in CHF patients[16].

Intestinal Dysfunction and Its Repercussions in Heart FailurePatients

Several processes contribute to intestinal dysfunction in HFpatients. In the setting of gut dysbiosis, there are reducednumbers of butyrogenic bacteria, such as Faecalibacteriumpraustnitzii [7, 21, 22]. Butyrate is the primary energy sourcefor intestinal epithelium, so it is vital to maintain the intestinalbarrier’s integrity. This bacteria also exerts an anti-inflammatory effect through IL-10 production [7]. On the oth-er hand, increased growth of bacteria, such as R. gnavus, in-cites inflammatory responses by cytokine generation (IFN-Y,IL-17, and IL-22) [20]. Furthermore, the above mentionedpathogenic microorganisms generate inflammatory reactions,which aggravate intestinal dysfunction [16].

The congestion in CHF patients, characterized by increasedright atrial pressure, causes intestinal microcirculation insuffi-ciency, which ultimately increases intestinal permeability[16]. A study that evaluated the gut’s morphology and func-tion between CHF and control subjects showed that smallintestine and colon permeability are increased by 35% and210%, respectively. Furthermore, this condition is accompa-nied by thickening of the terminal ileum and the entire colon.In comparison to control subjects, higher concentrations ofbacteria within the mucus of in CHF were noted [23].

There is also a reduction in CHF patients’ intestinal perfu-sion, which is caused by blood flow redistribution, vasocon-striction, and congestion. Physiologically, the intestinal villihave a countercurrent microcirculation system between

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arterioles and venules. Thus, the lowest oxygen concentrationis at the end of the villus due to shunts. However, if hemody-namic instability occurs, these terminal parts of villi are proneto hypoxia and ischemia [24, 25]. Decrease in intestinal mu-cosal pH, which indicates intestinal ischemia, is found in CHFpatients after exercise with mild intensity [26].

Consequently, intestinal dysfunction causes translocationof the major component of the outer membrane of gram-negative bacteria, identified as lipopolysaccharides (LPS)/en-dotoxins. Also, LPS is one of the most potent triggers of pro-inflammatory cytokines [25]. A study showed that the im-mune system sensitivity of CHF patients to LPS, assessedby TNF-α secretion, is an independent predictor of mortality[27]. Furthermore, LPS levels are found to be higher in CHFpatients with systemic congestion, compared to non-congested ones [28]. These patients also experienced a moresevere decline in intestinal absorptive function, characterizedby a decrease in active and passive carrier-mediated transports[26].

In addition, intestinal dysfunction exacerbates intestinaldysbiosis of CHF patients. To prevent excessive immune re-actions to normal microflora while remaining responsive topathogenic bacteria, intact intestinal epithelial cells are crucialfor the maintenance of homeostasis in the digestive tract im-mune system [29].

Shift in Bacterial Metabolites Profile and Their Impacton Chronic Heart Failure

Owing to its capacity to produce and regulate several metab-olites that can reach distal organs and system via circulation,the intestinal microbiota has been designated as the largestendocrine organ [14]. Furthermore, gut microbiota can pro-duce hundreds of products, more than any endocrine organs[14]. Therefore, the impact of human intestinal microbiota andits metabolites on health could not be understated. There arefour bacterial metabolites of significant importance due totheir effect on chronic heart failure subjects: trimethylamine-N-oxide (TMAO) and short-chain fatty acids (SCFA) bile acidand indoxyl sulfate and p-cresyl sulfate.

TMAO Based on the metagenomic analysis of CHF patients,there is an increase in LPS and TMAO forming genes, cholineTMA lyase [20]. Several studies have demonstrated negativeassociations between TMAO and the heart. In heart failurewith systolic dysfunction subjects, increased levels ofTMAO, choline, and betaine were associated with higherlevels of plasma NT-proBNP and more severe left ventriculardiastolic dysfunction. Moreover, of the three phospholipidmolecules, only TMAO levels predict adverse events, inde-pendent of age, estimated glomerular filtration rate (eGFR),mitral inflow E/A ratio, and NTproBNP levels [30].

A different study by the same group also revealed thatpatients with higher TMAO levels were associated with anincreased risk of mortality of 3.4 times greater. After adjustingfor traditional risk factors and BNP levels, high TMAO levelsstill predict mortality risk in 5 years with a hazard ratio [HR]of 2.2; 95% CI: 1.42 to 3.43; p < 0.001 [31].

TMAO is also a proatherogenic molecule. Based on theplasma metabolomic analysis of patients with atherosclerosis,increased levels of TMAO were noted and correlate directlywith their pathology [32]. The reverse cholesterol transport isalso inhibited by TMAO, which consequently caused macro-phage foam cell formation, and ultimately concludes withcholesterol accumulation in atheromatous plaques [33]. A pro-spective observational study of CHF patients from Norwayshowed that TMAO levels were the highest in NYHA classesIII-IV and in ischemic etiology. It was also found thatprognostically higher TMAO levels were associated with re-duced transplant-free survival [34].

The synthesis of TMAO is derived from choline andcarnitine-rich products, such as red meat and poultry. Thesesubstances then converted into trimethylamine (TMA) enzy-matically by intestinal bacterial TMA-lyase. The formedTMA will then undergo oxidation by the flavin monooxygenase-3 enzyme (FMO-3) in the liver to becometrimethylamine-N-Oxide (TMAO), which then will be excret-ed through kidneys [35].

Of note, despite high choline levels and carnitine in eggsand meat, fish consumption increased TMAO levels 42–62times higher than those two foods [36]. However, this findingdoes not necessarily become a reason to limit fish consump-tion because it has been clinically proven to confer acardioprotective effect [37]. High TMAO content is neededfor fish physiology because it can reduce protein denaturationsdue to stressors such as organic ion content (in organisms thatuse urea as osmolytes for buoyancy) or high hydrostatic pres-sure (deep-sea organism) [35, 38].

This contradictory finding led to the conclusion thatTMAO is not the cause of the aforementioned pathology,but it only serves as a biomarker that reflects the state ofintestinal microbiota. Accordingly, higher Firmicutes ratiocompared to Bacteroides was found in subjects who had highTMAO levels [36]. Koeth et al. also reported these identicalfindings that subjects with high TMAO levels have a lowproportion of Bacteroides genus [32].

Short-Chain Fatty Acids Short-chain fatty acids (butyrate, ac-etate, and propionate) are the products of non-digestible starchfermentation by colonic bacteria and produce mainly via thesaccharolytic pathway and with some contribution by the pro-teolytic pathway [39–41]. SCFAs play a crucial role in energysubstrates of the intestinal epithelial cell by stimulating thecolonic blood flow, and uptake of fluid and electrolyte [42].Several studies showed that the role of SCFAs presumably

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important in CHF through maintaining protective gut barrier,immune, and blood pressure modulation, which we outlinedbelow.

Production of butyrate by gut microbiota is essential tomaintain gut barrier integrity, primarily in the colon, by de-pleting oxygen through intracellular metabolism, which stabi-lizes hypoxia-inducible factor-1 (HIF-1) [43]. SCFAs alsopossess anti-inflammatory properties. The activation of Gprotein-coupled receptor 43 (Gpr43) on T reg cell by SCFAsinduces T reg cell proliferation, whereas Th17 cells are down-regulated, skewing the balance to anti-inflammation state [44].

In a rat model of myocardial infarction (MI) with depletedgut microbiota through antibiotic treatment, there was a dose-dependent increase in mortality. However, fecal reconstitutionand SCFAs supplementation increase rat’s survival. Furtherelucidation found that gut microbiota’s metabolites, primarilySCFAs, modulate host physiology and injury response in MIthrough increasing CX3CR1+ monocytes to the peri-infarctzone [45].

Moreover, acetate producing bacteria proved to have a pro-tective effect on the mouse model of hypertension, in whichthere is a decrease in blood pressure, a decrease in renal andcardiac fibrosis, and cardiovascular improvement [46].Furthermore, transcriptome analysis found that the EGR-1, aprimary regulator of cardiac hypertrophy, cardiorenal fibrosis,and inflammation, is also downregulated [46].

SCFAs also modulate blood pressure through interactionwith olfactory receptors (Olfr), Gpr that provideschemosensing in other tissues. When bound to Olfr78, whichexpressed in the kidney, specifically in the renaljuxtaglomerular apparatus, SCFAs modulate renin secretion.Also, Olfr78 and Gpr41 were present in smooth muscle cellsof the small resistance vessels. Interaction of propionate withthis receptors culminates in vasodilation ex vivo, leading toacute hypotensive response [47].

Bile AcidApart from bile acids’ (BAs) physiological role of fatemulsification of dietary fat and cholesterol elimination, bileacids are now recognized as signaling molecules that interactwith receptors (plasma and nuclear), promoting vital down-stream effects [48].

Primary BAs secreted by the liver are metabolized by gutmicrobiota to secondary BAs by deconjugation, dehydroge-nation, and dehydroxylation in the distal small intestine andcolon [49]. A previous study showed that CHF patients expe-rienced a reduction in primary BA levels, while specific sec-ondary BAs, namely lithocholic acid (LC), glycine conjugatedLC (GLC), taurine conjugated LC (TLC), and glycine conju-gated ursodeoxycholic acid (GUDCA) were increased [50].This finding is correlated with reduced heart failure patients’survival.

A study found a dose-dependent negative chronotropic ef-fect of cholic acid, a primary bile acid, on myocardial cells

[51]. This effect can also be found for secondary bile acids,albeit at lower concentrations than in primary bile acids. Astudy by Binah et al. have shown that secondary bile acidsat 10−3 mol/L, in the form of deoxycholic acid (DCA), causeda reduction of both density and affinity of beta-adrenoreceptors [52].

Contrastingly, in a double-blind, randomized controlledtrial study to examine the effect of ursodeoxycholic acid(UDCA), a secondary bile acid, on the endothelial functionand inflammatory biomarkers in CHF patients, there was lim-ited but significant improvement in peripheral blood flow ofheart failure patients, it is independent of inflammation,shown by unchanged TNF and IL-6 plasma levels [53].

Therefore, more studies are needed to fill the gaps of un-derstanding between BAs and gut microbiota and their impacton cardiovascular disease, specifically on CHF patients.

Indoxyl Sulfate and P-Cresyl Sulfate Chronic kidney disease isa common comorbid in CHF patients. Due to impair excretionsystem, consequently, several substances that exhibited nega-tive impact on cardiac physiology are retained. Indoxyl sulfate(IS) and p-cresyl sulfate (PS), collectively identified as uremictoxins, are microbial byproducts of ammonia degradation bygut microbiota.

In an experimental rat model, IS mediates adverse cardiacremodeling through mitogen-activated protein kinase(MAPK) p38, p42, and p44 and NFKB pathways activation[54]. Moreover, IS can induce hypertrophy through IS inhibi-tion of AMP-activated protein kinase (AMPK)/uncouplingprotein 2 (UCP) pathway, which is vital by suppressing mito-chondrial reactive oxygen species [55]. In addition, IS inducescardiomyocyte hypertrophy by activating the extracellularsignal-regulated protein kinase 1/2 pathways [56].

Thus, regarding the adverse effects of these uremic toxins,more studies are needed to confirm whether the manipulationof gut microbiota can effectively decrease these toxic sub-stances (Fig. 1).

Potential Therapies for Targeting Gut Microbiota inHeart Failure Patients

We have mentioned above, the reciprocal relationship be-tween CHF patients and their gut microbiota. The shift inmicrobial composition, consequently increasing hazardousbacterial metabolites while decreasing beneficial metabo-lites, ultimately impacts cardiac physiology. Furthermore,increased numbers of pathogenic bacteria aggravate sys-temic inflammation by reaching the circulation via the dys-functional intestinal system. Therefore, targeting the gutmicrobial composition is of paramount importance. We de-scribed several approaches outlined below (Fig. 2 andTable 1).

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Dietary Modification

Several dietary modifications have a positive impact on CHFpatients. The most commonly mentioned diets are the DietaryApproach to Stop Hypertension (DASH) and theMediterranean diet. The DASH diet is an eating plan endorsedby AHA/ACC guidelines consisting of a diet rich in fruits,vegetables, whole grains, and low-fat dairy foods, includingmeat, fish, poultry, nuts, and beans, while sugar-sweetenedfoods and beverages, red meat, and added fats are limited

[79]. In several observational studies, the DASH diet hasshown to reduce the incidence of HF [80–82].

In the Woman’s Health Initiative (WHI) study, researchersfound that higher scores of the DASH diet were associatedwith fair lower mortality in women with HF after adjustmentwith multiple variables [83]. A positive finding was also re-ported by Rifai et al. in a small randomized controlled trial ofthe DASH diet and general HF dietary recommendationsconsisting of 24 subjects each [57]. There was a significantimprovement of endothelial function at 1 month measured by

Fig. 1 Altered gut microbiome, intestinal dysfunction, and the role ofbacterial metabolites in heart failure patients. This flowchart depicts thealternations of gut microbiota composition, intestinal dysfunction, and the

role of bacterial metabolites in heart failure patients. These three factorsare, directly or indirectly, reciprocal with heart failure status

Fig. 2 Strategies for gut microbiota composition modulation

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Table1

Summaryof

studiesof

strategies

forgutm

icrobiotacompositio

nmodulation

Treatment

Author(year)

Researchsubjects

Interventio

nResearchDesign

Results

Reference

Diet

Rifaietal.(2015)

48wom

anwith

heartfailure

DASH

dietvs

placebo

Small,random

ized

controlledstudy

Better6-min

walking

test

(6-M

WT)andquality

oflifescores

after3months

[57]

Estruch

etal.

(2018)

(PREDIM

ED

TRIA

L)

7447

subjectswith

high

cardiovascular

risk

Mediterraneandiet+

extra-virginoliveoilvs

Mediterraneandiet+

mixed

nutsvs

control

diet

Observatio

nalcohort

study

Cardiovasculareventswere

foundto

belowerin

the

Mediterraneandietgroup

with

oliveoilo

rnuts

[58]

Probiotics

Linetal.(2013)

Spontaneouslyhypertensive

rats

10%

PSPY

+100%

high

GABAcontent,

captopril1

5.6mg/kg,

vsplaceboof

distilled

water

Experim

entalanimal

model

PSPY

stim

ulates

anti-apoptotic

pathways

andenhances

cardiacsur-

vival

[59]

Lametal.(2012)

Ratswith

myocardial

infarctio

nLa

ctobacillus

plantarum

299v

vsvancom

ycin

Experim

entalanimal

model

Infactsize

reductionand

improved

leftventricular

functio

n

[60]

Gan

etal.(2014)

Ratswith

heartfailuredueto

chronicocclusionof

the

coronary

arteries

Lactobacillus

rham

nosus

GR-1

vsplacebo

Experim

entalanimal

model

Improved

LVfunctio

nand

hypertrophyattenuation

[61]

Ettinger

etal.

(2017)

Neonatalrat’sventricular

cardiomyocytes

Lactobacilliv

sStreptococcus

salivariusK12

In-vitrocellculture

Improved

cardiacfunction

[62]

Wangetal.(2015)

Ratsfedwith

ahigh-fatdiet

Normaldietandhigh-fat

dietvs

high-fatdiet+

multi-strain

probiotic

groups

Experim

entalanimal

model

Cardiom

yoctye

apoptosis

attenuation

[63]

Danilo

etal.(2017)

Micewith

myocardial

infarctio

nby

ischem

ia/reperfusion

inju-

ry

Bifidobacteriumanimalis

subsp.lactis420

(B420)

vsLa

ctobacillus

salivarius33

vssaline

Experim

entalanimal

model

Myocardialinfarction

mitigatio

nviaTregcell

augm

entatio

nand

antiinflammatory

cytokines

[64]

Contstanzaetal.

(2014)

20patientsNYHAIIandIII

CHFandEF<50%

1000

mgSacharromyces

boulardiid

aily

vsplacebo

Randomized,

double-blind,

placebo-controlled

pilottrial

Reductio

nof

inflam

matory

biom

arkersand

improvem

ento

nthe

ventriclefunctio

n

[65]

Prebiotics

Beserra

etal.

(2015)

Effecto

fprebioticsand

synbioticsin

lipid

and

glucoseprofile

-Meta-analysis

Prebioticscanreduce

LDL,

andtriglycerides,andtotal

cholesteroland

increase

HDL

[66]

Kellowetal.

(2014)

Prebiotic

supplementatio

nin

adults

-Sy

stem

aticreview

Reduced

postprandial

glucose

[67]

Dew

ulfetal.

(2013)

30obesewom

enInulin-typefructans

vsmaltodextrin(placebo)

Doubleblind,

placebo-controlled

interventionstudy

IncreasedBifidobacterium

andFaecalib

acterium

prausnitziiin

thefeces

[68]

Delzenneetal.

(2005)

Normalanddiabeticrats

Normaldiet+10%

inulins

type

fructans

vsnorm

aldiet

Animalexperiment

IncreasedGLP-1,decreased

ghrelin

,and

average

energy

intake

inrats

[69]

1619SN Compr. Clin. Med. (2020) 2:1614–1627

Tab

le1

(contin

ued)

Treatment

Author(year)

Researchsubjects

Interventio

nResearchDesign

Results

Reference

Fernandesetal.

(2017)

Effectofinulin

-typefructans,

galacto-oligosaccaharides

andsynbioticson

inflam

-matorymarkerin

adults

with

obesity

-Sy

stem

aticreview

Reduced

pro-inflam

matory

cytokines(TNF-alpha,

IL-6)

[70]

Barengolts

etal.

(2016)

Roleof

microbiota,

prebiotics,probiotics,and

synbioticsin

obesity

,prediabetes,anddiabetes

mellitus

type

2

-Sy

stem

aticreview

Reduced

fastingand

postprandialglucose,and

improved

insulin

sensitivity

[71]

Antibiotic

Conraadsetal.

(2017)

10CHFpatientswith

class

III-IV

NYHA

Polymyxin

B/Tobramycin

Non-placebo

controlled,pilot

trial

Reduced

cytokine

productio

nandim

proved

peripheral

endothelialfunction

[72]

100patientswith

STEMI

Antibiotic

injection

Experim

entalanimal

model

Reduced

inflam

mationand

cardiacdamage

[73]

Fecal Microbia-

lTranspl-

antatio

n(FMT)

Costello

etal.

(2019)

73subjectswith

active

ulcerativ

ecolitis

Donor

FMTor

autologous

FMTvia

colonoscopy

Randomized

clinical

trial

Higherlik

elihoodof

remission

at8weeks

after

1weekof

treatm

entin

donorFM

Tgroup

comparedto

autologous

FMT.

[74]

Suskindetal.

(2015)

9pediatricpatientswith

Crohn’sdisease

FMTby

nasogastrictube

Prospective,

open-labelstudy

Faster

remission

inFM

Ttreatedpatients

[75]

Kassam

etal.

(2013)

Patientswith

Clostridium

difficileinfection(CDI)

Meta-analysis

89.7%

patientswith

CDI

experiencedclinical

resolutio

nafterFM

T.

[76]

Moayyedietal.

(2015)

70subjectswith

anactive

ulcerativ

ecolitis

FMTby

sigm

oidoscopy

vsplacebo

Randomized

ControlledTrial

24%

patientswho

received

FMTand5%

who

received

placebowerein

remission

at7weeks

[77]

Andersonetal.

(2012)

Inflam

matoryboweldisease

patients(IBD)

System

aticReview

Improved

symptom

sand

increasedIBDremission

[78]

DASH

dietaryapproach

tostop

hypertension,P

SPYpurplesw

eetpotatoyogurt,G

ABAγ-aminobutyricacid,LVleftventricular,NYH

ANew

YorkHeartAssociatio

n,CHFcongestiv

eheartfailure,LDLlow

density

lipoprotein,H

DLhigh

density

lipoprotein,G

LP1glucagon-likepeptide-1,TN

F-alpha

tumor

necrosisfactor-alpha,IL-6interleukin-6

1620 SN Compr. Clin. Med. (2020) 2:1614–1627

higher arterial elasticity in the DASH group. After 3 months,the DASH diet group has significantly better exercise capacityreflected by a 6-min walking test (6 MWT) and better qualityof life scores. Also, there was an improvement in endothelialfunction at 3 months, albeit insignificant. Furthermore, in apilot trial that examined this diet and its impact on 13 hyper-tensive female patients with HFpEF, it was found that after3 weeks of the DASH diet, there were significant weight re-duction and improvement on cardiac function, better bloodpressures (systolic and diastolic; clinic and 24-h ambulatory),and improvement on multiple biomarkers such as increased inplasma acylcarnitines and reduced plasma BNP and urineisoprostanes [84–86].

Unlike the DASH diet pattern that emphasizes high proteinand low-fat dairy intake, the Mediterranean diet focuses onmonounsaturated fats, particularly olive oil [83]. ThePREDIMED trial is the largest randomized controlled trial todate that examines the impact of the Mediterranean diet onmajor cardiovascular events (MACE) in a high cardiovascularrisk population [87]. This study has proven that diet rich inolive oil and nuts is better compared to reduce fat diet only.Nevertheless, no association was found between diet and heartfailure incidence based on pre-specified secondary outcomeanalysis of the PREDIMED trial [88]. Another study found nobenefits of adherence to the Mediterranean diet for heart fail-ure mortality in the long term, although reduction of hospital-ization rates was noted [58].

However, none of these studies examine the impact of dietintervention directly on the gut microbiota of CHF patients,and new studies with the perspectives on gut microbiota com-position are needed.

Probiotic

The International Scientific Association for Probiotics andPrebiotics (ISAPP) expert panel consensus in 2013 endorsedthe definition of probiotic as stated by Food and AgricultureOrganization of the United Nations and the WHO (FAO/WHO) in 2000, which is “live microorganisms which whenadministered in adequate amounts confer a health benefit onthe host.” [89] Based on animal research studies and random-ized control trial studies, there are several potential probioticsfor heart failure patients.

A study by Lin et al. in 2013 explored the effects ofprobiotic-fermented purple sweet potato yogurt (PSPY) withhigh γ-aminobutyric acid (GABA) content on cardiac apopto-sis in spontaneously hypertensive rat (SHR) hearts [59]. Theyfound that PSPY supplementation enhances cardiac survivaland activates anti-apoptotic pathways in hypertensive hearts.The numbers of apoptotic cells were detected using DAPI andTUNEL staining. In the SHR-PSPY groups, a decrease in thenumber of TUNEL-positive cardiac myocytes was observed.

The first probiotic that has shown cardioprotective effect isLactobacillus plantarum 299v. Lam et al. found that in themyocardial infarction rat model, Goodbelly administration(trade name for Lactobacillus plantarum) reduced the infarctsize associated with myocardial ischemia by 29% and in-creased left ventricular mechanical function by 23% througha reduction of blood leptin levels [60].

Replicating the latter study, Gan et al. found that in ratswith heart failure due to chronic coronary artery occlusion,Lactobacillus rhamnosus GR-1 supplementation is associatedwith better left ventricular function and attenuated hypertro-phy. This effect is not by a mechanism of reperfusion, which isabsent in these rats but by reduced post-infarction hypertrophyand remodeling. Furthermore, the benefit persisted althoughthe treatment is withdrawn [61].

Initially, it was thought that Lactobacillus rhamnosus GR-1attenuates phenylephrine-induced cardiac hypertrophy byinhibiting alfa 1-adrenergic receptor agonist through it’s majorsecreted protein-1 (MSP-1), also known as p75. However,using a mutant strain showed that MSP-1 is not needed forthis inhibition. Thus, further studies about factors produced bythese bacteria and their ability to prevent cardiac remodelingare warranted [62].

A high-fat diet is known to cause cardiomyocyte dysfunc-tion and apoptosis. Compared to rats fed with a high-fat dietonly, rats fed with a high-fat diet and multi-strain lactic acidbacteria supplements showed normal myocardial architectureand interstitial spaces. Furthermore, the Western blot analysisshowed that apoptotic pathways (Fas receptor andmitochondrial-dependent) were suppressed and insulin-likegrowth factor I receptor (IGF1R)-dependent survival signal-ing components were upregulated in these rats. These findingssuggest that through phosphatidylinositol-3 kinase/AKTsurvival-signaling pathway activation, this multi-strain lacticacid bacteria attenuates cardiomyocyte apoptosis [63].

A mice model of myocardial infarction by ischemia/reperfusion-induced cardiac injury showed that pretreatmentwith Bifidobacterium animalis subsp. Lactis 420 (B420) com-pared to saline (control) or Lactobacillus salivarius 33 (Ls-33)mitigates adverse impact of MI, which dependent on CD25+FoxP3+ regulatory T (Treg) cells augmentation and shift in cy-tokines production towards anti-inflammatory cytokines [64].

Regarding the promising results of targeting of human mi-crobiota for the treatment of cardiovascular diseases, in 2014Constanza et al. conducted a randomized, double-blind,placebo-controlled pilot trial of 20 CHF patients withNYHA functional class II-III and EF < 50%, to take1000 mg Saccharomyces Boulardii daily or placebo for3 months. At the end of the study, compared to the placebo,in the treatment arm, there is a reduction of inflammatorybiomarkers (creatinine, HsCRP, and uric acid) and improve-ment of the left ventricle function assessed by ejection fractionand left atrial diameter [65].

1621SN Compr. Clin. Med. (2020) 2:1614–1627

Although promising, questioning probiotic’s safety mustbe exercised. Based on one systematic review and meta-analysis of seven RCTs of probiotics for functional constipa-tion, only one reported minor adverse event, i.e., loose stools[90]. Others have reported, in high-risk patients (one of whichis heart failure), bacteremia and sepsis can occur [91, 92].

Prebiotic

According to the International Scientific Association forProbiotics and Prebiotics (ISAPP), prebiotics is “a substratethat is selectively utilized by host microorganisms, conferringa health benefit” [89]. To date, there is no data regarding theeffects of prebiotic on human microbiota in heart failure pa-tient’s but prebiotic has been proven useful in many states ofdiseases [40, 66–68]. One of the most commonly researchedprebiotic is inulin.

Inulin is prebiotic from a large family of other prulin types,such as oligofructose and fructooligosaccharides [93]. Inulinis a broad term comprised of all linear fructans with betafructose-fructosyl glycosidic bonds []. This glycosidic bondis unique to its structural and physiological properties. Thefructose monomer bonds’ beta configuration gives theinulin-type fructans a unique property, which is resistant toenzymatic hydrolysis by enzymes in saliva and small intestineso that it can be fermented in the large intestine [93].

The benefits of inulin on human health have been welldocumented. Inulin supplementation is beneficial for patientswith obesity, overweight, diabetes, metabolic syndrome, anddyslipidemia because of its anti-inflammatory effects [40,66–71, 94]. These diseases have one thing in common, beinglow-grade inflammatory diseases [95]. Chronic heart failure isalso a low-grade inflammatory disease due to the excessiveproduction of pro-inflammatory cytokines.

As described in the mechanisms mentioned earlier, thereare changes in intestinal morphology and function in CHFpatients. These situations culminate with intestinal epithelialdysfunction and increased intestinal permeability [11].Increased permeability makes it more accessible for LPS toenter the bloodstream and induces the production of inflam-matory cytokines [12]. These cytokines, namely IL 6 andTNF-α, being cardiosupressors, are associated with worsen-ing clinical symptoms, short-term, and long-term survival [13,14]. It is expected that with the immunomodulatory effect ofinulin, this pro-inflammatory cytokines can be suppressed inCHF patients.

In the colonic mucosa, inulin administration can counteractoxidative stress induced by LPS [96], which is particularlybeneficial for CHF patients, where epithelial dysfunctionand LPS translocation occur [12–14]. Inulin also has a protec-tive effect against several pathogens, such as Candidaalbicans, Listeria monocytogenes, and Salmonellatyphimurium [41]. This effect is undoubtedly advantageous

for CHF patients who experience an increase in the numberof pathogenic bacteria [8].

Antibiotic

The idea of utilizing antibiotics in preventing cardiovasculardisease is not new. Several randomized controlled trials havebeen conducted for preventing coronary heart disease; albeitwith disappointing or inconclusive results [97–99]. In the set-ting of heart failure, one pilot study has examined the role ofantibiotics in advanced chronic heart failure patients. In a non-randomized, non-placebo-controlled pilot trial involving 10patients, Conraads et al. evaluate the role of selective decon-tamination of the digestive tract (SDD) using PolymyxinB/Tobramycin, a non-absorbable antibiotic [72].

They hypothesize that antibiotic treatment will suppressmonocyte activation and cytokines production caused by en-dotoxin production of gram-negative bacilli (GNB) and im-provement of the peripheral endothelial function assessed byflow-mediated dilation. This study ends with a conclusion thatSSD can decrease endotoxin production significantly. Hence,the decrease of monocyte activation and cytokine productionand the improvement of peripheral endothelial function.

Other studies have shown that when antibiotics are injectedto eliminate intestinal bacterial translocation, it can alleviatesystemic inflammation and myocardial cell damage in micewith myocardial infarction [73]. Rifaximin has also beenfound to reduce the toxicity and translocation of bacteria,has an anti-inflammatory effect and positively regulates thecomposition of intestinal flora and promotes the growth ofbifidobacteria, Faecalibacterium prausnitzii, and lactobacil-lus aside from its bactericidal and bacteriostatic property[100].

However, the considerable cost and the need for frequentmonitoring of its efficacy and the microbiota flora hinderedthis approach for daily clinical practice. Therefore, we shouldweigh the side effects of antibiotics and their clinical effects.

Fecal Microbial Transplantation

Currently, no study has been conducted to evaluate fecal mi-crobial (FMT) transplantation as a treatment for CHF.Although several studies, especially related to the gastrointes-tinal tract diseases, mostly have yielded positive results[74–78]. Nevertheless, the main concern regarding the FMTis its safety. One study reported that FMT could cause bacter-emia and death related to multidrug-resistant E. coli that canbe traced from the donor’s feces [101]. Nevertheless, seriousadverse events are rarely encountered, and if they do, they arecaused by causes other than FMT or due to pre-existing co-morbidities [102].

1622 SN Compr. Clin. Med. (2020) 2:1614–1627

Ongoing Clinical Trials

To find pertinent clinical trials regarding prebiotic/probiotic/synbiotic that target gut microbiota to treat heart failure, wesearch clinicaltrials.gov with keywords that consist of “gutmicrobiota” and “heart failure”. Our search yields fourclinical trials, which we outlined below (Table 2).

There is an ongoing phase II randomized clinical trial con-ducted by Mayerhofer et al. designated as GutHeart(NCT02637167), highlighting the importance of the humanintestinal system andmicrobiota and its impact on heart failurepatients. This study randomized 150 heart failure patients withan ejection fraction of < 40% in 4 centers, consisting of threegroups which are rifaximin (nonabsorbable antibiotic),Saccharomyces boulardii (ATCC74012), and no treatment(control) with the primary endpoint of LVEF after 3 monthsof treatment and the secondary endpoints of intestinal micro-biota composition, microbiota metabolites, other cardiac pa-rameters, inflammatory and anti-inflammatory mediators,quality of life regarding health, functional capacity, and endo-thelial function [103]. Soon, we will able to see the results ofthis trial.

The Probiotics and Inflammatory Status in Patients WithHeart Failure (PROBHF) study (NCT03968549), estimated tobe completed around 31st August 2020, is a randomized,double-blind placebo-controlled trial of 58 patients with heartfailure, New York Heart Association (NYHA) III and IV,aiming to verify the influence of supplementation of the pro-biotic Lactobacillus acidophilus in the lowering of serumlevels of TNF-alpha in the patients with HF. Subjects willreceive probiotics and placebo for 6 months. Outcome mea-sured will be the levels of TNF alpha, interleukins 1,6 and 10,LPS, B-type natriuretic peptide (BNP) and C-reactive protein(CRP) at the beginning and end of study [104].

Another ongoing study is “Characterize the GutMicrobiotain Subjects With Heart Failure and Pre-heart Failure WithPreserved Eject ion Fraction” by Handberg et al .(NCT02728154) [105]. This study is an observational cohortstudy of 220 participants, comparing the fecal microbiota ofsubjects with normal heart function, subjects with diastolicheart dysfunction before heart failure developed, and subjectswith heart failure. The study also examines inflammatory cy-tokine and serum amyloid, inflammatory cells between groupsfrom their blood samples, and is estimated to be completed byDecember 2021.

The need for FibEr Addition in SympTomatic HeartFailure (FEAST-HF) study (NCT03409926) by Ekowitzet al. is a single-center, randomized, quadruple blinded clinicaltrial in ambulatory patients with chronic HF to evaluatewhether dietary supplementation with acacia gum reducesHF-related biomarkers NT-proBNP and ST2 and how thegut microbiome responds to dietary supplementation with aca-cia gum [106]. This study enrolls 72 participants with Ta

ble2

Summaryof

ongoingstudies

No.

Study

(clin

icaltrialregistry

number)

Principalinvestig

ator

Startdate

Estim

ated

completiondate

Design;

subjects

Interventio

nPrim

aryoutcom

e

1GutHeartStudy

(NCT02637167)

Cristiane

CMayerhofer,MD

11th

March

2016

31stDecem

ber2019

PhaseIIrandom

ized

clinicaltrial;150

participantswith

systolicHF

Saccharomyces

boulardii

2×1000

mg,Rifaxim

in1×550mg

LVEFafter3months

oftreatm

ent

2PR

OBHFStudy

(NCT03968549)

Fernando

Bacal,M

DPh

D6thNovem

ber2018

31staugust2020

Randomized,double-blind,placebo

controlledtrial;58

participantswith

HFNYHAIII-IV

Lactobacillusacidophilus

Serum

TNF-αlevels

3CharacterizetheGut

Microbiotain

Subjects

With

HeartFailu

reand

Pre-heartF

ailure

With

PreservedEjection

Fraction(N

CT02728154)

Eileen

MHandberg,Ph

DOctober

2016

Decem

ber2021

Observatio

nalcohortstudy;2

20participantsconsistin

gof

50subjectswithoutH

Fas

norm

alcontrols,120

subjectswith

history

ofHFand50

subjectswith

pre-HFp

EF

–Fecalm

icrobiotafrom

stoolsam

ple

4FE

AST

-HFStudy

(NCT03409926)

Justin

Ezekowitz,M

BBCh

13th

Septem

ber2018

30th

Septem

ber2021

Single-center,random

ized,quadruple

blindedclinicaltrial;72

participants

with

establishedheartfailure

AcaciaGum

5g/day,Acacia

Gum

10g/day

NTproBNPlevel

LVEFleftventricularejectio

nfractio

n,TN

F-alpha

tumor

necrosisfactor-alpha,N

TproBNPn-term

inalprobrainnatriuretic

peptide

1623SN Compr. Clin. Med. (2020) 2:1614–1627

established Heart Failure. Microcrystalline Cellulose given10 g per day is used as the active comparator towards inter-ventions of Acacia Gum 5 g/day and Acacia Gum 10 g/day for12 weeks. Result of the study is to be expected by 30thSeptember 2021.

Conclusion

The gut microbiota composition as a treatment target forchronic heart failure is an exciting and novel research field.In this article, we have briefly explained the alterations in thecomposition of the human microbiota, intestinal dysfunction,and shifted bacterial metabolites profiles’, and their potentialeffects on chronic heart failure patients. Several potentialagents and therapeutics have been identified, although muchmore research needed, especially randomized controlled trials,to confirm the safety and efficacy of these agents.

Acknowledgements The authors are grateful to Quinta FebryaniHandoyono, MD for her assistance on figure design

Authors Contribution JH, IC, and HFHG contributed to conception anddesign, literature research, and drafting the manuscript. JH also providesrevision of the manuscript. LPS contributed in revision of the manuscript,supervision, and final approval of the manuscript. All authors apporovedthe final manuscript

Availability of data and material Not Applicable

Compliance with ethical standards

Competing interests The authors declare that they have no competinginterests

Ethical approval and consent to participate Not Applicable

Consent for Publication Not Applicable

Abbreviations CHF, Chronic heart failure; IBD, Inflammatory boweldisease; IBS, Irritable bowel syndrome; IL-10, Interleukin 10; IFN-Y,Interferon gamma; IL-17, Interleukin 17; IL-22, Interleukin 22; LPS,Lipopolysaccharides; TNF-α, Tumor necrosis factor-α; LPS,Lipopolysaccharides; TMAO, Trimethylamine-N-oxide; SCFA, Short-chain fatty acids; NT-proBNP, N terminal pro brain natriuretic peptide;eGFR, Estimated glomerular filtration rate; NYHA, New York HeartAssociation; TMA, Trimethylamine; FMO-3, Flavin mono oxygenase-3; Gpr43, G protein-coupled receptor 43; Th1, T helper 1; Th17, T helper17; MI, Myocardial infarction; Olfr78, Olfactory receptors 78; Gpr41, Gprotein-coupled receptor 41; BAs, Bile acids; LC, Lithocholic acid; GLC,Glycine conjugated lithocholic acid; TLC, Taurine conjugated lithocholicacid; GUDCA, Glycine conjugated ursodeoxycholic acid; DCA,Deoxycholic acid; UDCA, Ursodeoxycholic acid; MAPK, Mitogen-acti-vated protein kinase; AMPK/UCP, AMP-activated protein kinase/uncoupling protein 2; DASH, Dietary approach to stop hypertension;AHA/ACC, American Heart Association/American College ofCardiology; WHI, Women Health Initiatives; 6 MWT, 6-minute walkingtest; HFpEF, Heart failure with preserved ejection fraction; MACE,Major adverse cardiovascular events; ISAPP, The International

Scientific Association for Probiotics and Prebiotics; FAO/WHO, Foodand Agriculture Organization of the United Nations/World HealthOrganizations; GABA, γ-Aminobutyric acid; SHR, Spontaneously hy-pertensive rats; PSPY, Purple sweet potato yogurt; MSP-1, Major secret-ed protein-1; IGF1R, Insulin-growth factor I receptor; Treg, Regulatory Tcells; EF, Ejection fractions; RCTs, Randomized controlled trials; FDA,Food and Drug Administration; GRAS, Generally recognized as safe;SDD, Selective decontamination of digestive tract; GNB, Gram-negativeBacillus; FMT, Fecal microbial transplantation

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