+ NO.
O2.-
OxidaseSS NhomakorabeaH
R-S-
S
ONOO.
Cu2+
S
S
H
S
Plasmamembrane
Q10
Intracellular
NADH
Krebs cycle
Adapted from James Morré 2019 J Inorg Biochem 100 2140-2149
ATP
Genetic and environmental factors contribute to aberrant protein conformation
• Patients usually present with multiple intestinal symptoms including:
Nausea Poor appetite Gastric reflux
Abdominal pain Abnormal bowel motility Bloating
Fatigue, gastro-intestinal symptoms
III
Severe disease
Abnormal faecal test, high H2S, exposure to heavy metals that has caused aberrant protein conformation (APD)
H2S
E. coli
H2S
Cell
ATP
Mitochondria
Bacteria
MM M (metals)
SCH3 M
SCH3
SCH3 M
SCH3
PRPC
PRPDX
Heavy metals interfere directly with energy production
Extracellular
PROTEA biopharma Press Conference
Ritz Hotel London, Thursday 28th of May 2009
Unravelling the Origin of Myalgic Encephalomyelitis: Gastrointestinal Dysfunction, Production of Neurotoxins and Environmental Exposure
• ...but exogeneous exposure can be extremely toxic In excess, H2S acts as a mitochondrial poison. It can directly inhibit enzymes involved in the cellular production of energy. H2S also interferes with oxygen transport by blocking hemoglobin in the red blood cells.
and neurocognitive symptoms Disease severity can range from moderate to extremely severe: patients bedridden for years, totally caregiver dependent • Prevalence estimates: 0,3 to 0,6%; one million patients in the USA, two million patients in Europe This may just be the tip of the iceberg
TH1 cells
Protection against intracellular pathogens (viruses, bacteria)
Dysbiosis causes a decrease of CD8+ cells and TH1 immunity
IL-12
IFN-g
Naïve
IL-4
T cells
PRPC
PRPDX
Genetic
Mutation s
Environmental Acquired
Heavy Metals
PRP DX
Abnormal conformation can be transmitted from one cell to another
PRC PRPDX
Cell
Metals
Symptoms Headache Arm pain Shoulder pain Myalgia Palpitations Sleep disturbance
r and p-values r=.17, p<0.01 r=.20, p<0.003 r=.15, p<0.04 r=.20, p<0.003 r=.16, p<0.02 r=.20, p<0.004
Prof. Kenny De Meirleir, M.D, Ph.D Chris Roelant, Ph.D Marc Frémont, Ph.D
Myalgic encephalomyelitis: A highly prevalent debilitating disease
• Persistent, debilitating fatigue associated with numerous physical
Enterococcus, Streptococcus, Prevotella are strong H2S producers
Cumulative effects of H2S and heavy metals
Gut
Mold
Strept Fungi
E N T E R O
Gut barrier
Other gaseous mediators : NO. CO.
Henry Butt, University of Melbourne
Bacterial overgrowth correlates with symptoms severity
• Streptococcus spp. counts correlate with symptom expression :
Henry Butt, University of Melbourne
Alterations of intestinal microflora (anaerobes)
• Among anaerobic bacteria, Prevotella is the most consistently overgrown bacteria :
Henry Butt, University of Melbourne
Hydrogen sulfide produced by bacteria works as a potent toxin for the body
• Hydrogen sulfide (H2S) has important physiological functions... H2S is produced by the cells and is an important gaseous signal molecule, involved in regulation of blood pressure, neurotransmission, muscle relaxation and regulation of inflammation
Organisms Bacteroides spp. Prevotella spp. Bifidobacterium spp. Lactobacillus spp.
Control 3.2 x 1011 1.0 X 108 6.0 x 108 2.7 x 107
ME patients 1.6 x 1011 9.0 x 109 5.5 x 109 1.8 x 108
Symptoms Post Exertional fatigue Photophobia Mind going blank Cervical gland lymphodynia Palpitations Dizziness/Faintness
r and p-values r=.15, p<0.03 r=.14, p<0.04 r=.17, p<0.01 r=.14 p<0.04 r=.15, p<0.03 r=.14, p<0.05
No fatigue, possible gastrointestinal symptoms. Low VO2, slow recovery. May be asymptomatic
Restore the gut: probiotics
II Moderate disease
Abnormal faecal test, high H2S, exposure to heavy metals
• High socio-economic cost Cost to the society estimated as approximately $16 billion in the USA, €20 billion in Europe
Intestinal disorders in ME patients
Increasing immune dysregulations (depressed T and NK cells, Th17 activation, opportunistic infections…)
Immune alterations resulting from intestinal dysfunction
• Inflammation of the gastrointestinal tract