Curriculum Vitae

• NAMA : Prof. Dr. dr. Karel Pandelaki, Sp.PD, KEMD, FINASIM

• TEMPAT/TGL. LAHIR : Sea (Minahasa), 6 Agustus 1952
• JABATAN FUNGSIONAL : Guru Besar Ilmu Penyakit Dalam Fakultas Kedokteran
Universitas Sam Ratulangi Manado
• JABATAN STRUKTURAL :
• - Kordinator Pendidikan Spesialis-2 Bagian Ilmu Penyakit Dalam FK Unsrat Manado

• PENDIDIKAN FORMAL :
• - Dokter umum FK Unsrat Manado, 1981
• - Spesialis Penyakit Dalam FK Unair Surabaya, 1991
• - Doktor (S3) Universitas Airlangga Surabaya, 2000
• - Konsultan Endokrin, Metabolik dan Diabetes, PB PAPDI Jakarta, 2005

• ORGANISASI PROFESI :
• - Ketua PERSADIA Wilayah Sulawesi Utara
• - Ketua PERKENI Cabang Manado
• - Anggota IDI Cabang Manado
• - Pengurus/Anggota PAPDI Cabang Manado
 MICROBIOME AND
CARDIOMETABOLIC DISEASE

Karel Pandelaki

Divisi Metabolik dan Endokrin Bagian Penyakit Dalam FK

Unsrat/RSUP Prof. R. D. Kandou Manado
 Cardiometabolic Disease
• Obesity
• Type 2 Diabetes Mellitus
• Cardiovascular Disease
• Heart Failure*
• Hypertension*
• Chronic Kidney Disease*
Human Microbiota
Clinical Manifestation of Microbiota Dysregulation
(Concept of Microbiota as Endocrine Organ)

Blaser MJ, 2017

 Intestinal Microbiota
• Microbiota: the collective microorganisms
• Microbiome: the collective gene content of those
microorganisms
• “Eubiosis” : regulated (normal) microbiota
• “Dysbiosis”: dysregulated (abnormal) microbiota,
common to many diseases including diabetes,
colon cancer, IBD, ect.
Relationship Between Gut Microbiota and
Host Metabolism

Mithieux G 2018
 Gut Microbial Community
• The majority of the gut microbial community is
composed of only 5 phylae (Bacteroidetes,
Firmicutes, Actinobacteria, Proteobacteria, and
Cerrucomicrobia)
• ≥ 90% contribute of Firmicutes and Bacteriodes
• SCFA (acetate, propionate and butyrate) are
produced by bacterial fermentation of complex fiber
(polysaccharide)
• Acetat and propionate produced by Bacteroides
• Butyrate produced by Firmicutes
 Bad vs Good Microbiome
Bad Microbiome:
1. Increase Firmicutes to Bacterioides ratio (shift from 0.5 to 1.6), means
more Clostridiales and Ruminococci
2. Decrease in Bacteriodetes which stimulate anti-inflammatory T-cells (Tregs)
and generates SCFA needed for mucosal integrity
3. More Proteobacteria (pathobionts) and less of Bacteriodes in the elderly
of poor health
4. Colonies of Staphylococcus instead of Bifidobacteria in unhealthy CS infants
5. Higher Clostridiales (Firmicutes) in patients with CVD
6. Higher Actinobacteria in patients with periodontal disease (PD)

Good Microbiome:
A “Good” or “eubiotic microbiome” appears to correlate with a higher
proportion of Bacteriodetes that thrive on and convert complex fibers to SCFA
(acetate, propionate, butyrate)
 Saccharolytic Pathways in Nutrient-Gut
Microbiota Interaction
• Fermentation of fiber (polysaccharide) by intestinal
bacteria release SCFA (acetate, propionate and
butyrate)
• Acetate is present in the healthy gut in the highest
concentrations and is readily absorbed for
cholesterol production
• Propionate is exported to the liver via hepatic portal
circulation for use in gluconeogenesis
• Butyrate, unlike acetate and propionate, undergoes
limited reabsorption, instead undergoing colonocyte
oxidation
 Proteolytic Pathways in Nutrient-Gut
Microbiota Interaction
• Phosphatidyl-choline, Choline, and L-carnitine as
a constituent of red meat will metabolized by
intestinal bacteria to release Trimethylamine
(TMA)
• In the liver, TMA will converted by flavin mono-
oxygenase (FMO) to form an atherogenic
Trimethylamine-N-Oxide (TMAO)
• TMAO are a risk factor for CVD
The Major Pathways By Which Microbiota Can Alter Human
Cardiometabolic

Niewdrop M, 2014
The Major Pathways By Which Microbiota Can Alter Human
Cardiometabolic

Niewdrop M, 2014
Impact of Western Diet to Obesity

Kasselman LJ et al. 2018

Saturated Fatty Acid & Cholesterol Diet

Fowler D, 2017
 High Fat Diet and T2DM

Hur KY, Lee MS, 2015

 Dietary Fiber (Polysaccharides)

Hur KY, Lee MS, 2015

 Gut Microbiota – Host Interaction

Hansen TH et al, 2015

Gut Microbiota and Possible Molecular Pathways Linked to
Cardiovascular and Cardiometabolic Diseases

Tang, WHW, et al. 2017

Gut Microbiome and Cardiovascular Disease

Tang WHW, 2017

 The Gut Microbiota: an Emerging Risk Factor for
Cardiovascular Disease

European Journal of Immunology, Volume: 48, Issue: 4, Pages: 564-575, First published: 12 December 2017, DOI: (10.1002/eji.201646879)
 Link Between Microbiota and CMD
(Summary)
Microbiota Metabolite
• Atherosclerosis ↑Lactobacillus ↑TMAO
↓Roseburiam
• Hypertension ↑Firmicutes/Bacteroides ↑SCFA
ratio
• Heart Failure ↑Escherichia coli, ↑TMAO
Klebsiella pneumonia,
Streptococcus viridans
• Obesity, T2DM ↑Firmicutes, ↓Bacteroides ↑BAs, SCFA,
LPS, and TMAO
• CKD ↑Firmicutes, proteobacteria ↑Indoxyl sulfate,
p-creosol sulfate,
ammonia and
urea, and TMAO
 Prebiotic and Probiotic
• Prebiotics are non-digestible but fermentable polysaccharides, such as
inulin, fructo-oligosaccharides, galacto-oligosaccharides, or lactulose
which promote SCFA production and the growth of beneficial bacteria,
especially Bifidobacterium and Lactobacillus
• Studies in healthy humans and rodents have demonstrated that
prebiotic consumption reduces hunger and enhances satiety
• Probiotics are defined as live microorganisms that confer a beneficial
health effect on the host when administered in proper amounts
• Some probiotic strains, especially those of the genera Lactobacillus
and Bifidobacterium, have been shown to ameliorate obesity and
metabolic disorders
 Fact on Diets and Microbiome
• Important correlations:
- Western diets are linked to Obesity, Type 2 diabetes, and CVD
- Vegans and types on a Mediterranean diet have less CVD
- Western diets have less complex fermentable fiber than Mediterranean diets

• Trimethylamine (TMA) and TMAO (TMA oxide):

- Dietary carnitine and phosphotidyl choline from red meat and lecithin (eggs) is
converted to TMA by the gut microbiome
- Blood levels of TMA are strongly linked to vascular plague formation and CVD
- Vegans and herbivores have lower TMA and TMAO levels than omnivores

• TMA, CVD and the microbiome:

- Less carnitine and more complex fiber results in more Bacteriodetes
- Probiotics (Lactobacilli) are associated with weight loss but not lowering of TMA
- Short ester forms (acetyl-l-carnitine) are being tested as a competitive dietary
substitute to lower TMAO
 Conclusions
• Intestinal microbiota may play an important role in the patho-
genesis of Type 2 diabetes mellitus by influencing body weight,
proinflammatory activity, and insulin resistance.
• Dietary nutrients characterized by TMA-group (phosphatidyl
choline, choline and carnitine) are metabolized into the atherogenic
compound TMAO by intestinal bacteria
• The TMA/TMAO pathway likely represents only one of many
microbe-dependent pathways that will ultimately be linked to
cardiovascular disease pathogenesis and proven to be an important
diagnostic and therapeutic target for cardiovascular diseases
• SCFA help maintain gut barrier function by reducing luminal pH and
inhibiting some pathogenic microorganisms
• Prebiotics and Probiotics may be beneficial for this condition
TERIMA KASIH