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Amyotrophic Lateral Sclerosis (ALS) Linked to Intestinal Microbiota Dysbiosis & Systemic Microbial Infection in Human Patients: A Cross-Sectional Clinical Study

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  • Steenblock Research Institute
  • Indonesian Medical Council

Abstract and Figures

Amyotrophic Lateral Sclerosis (ALS) or Lou Gehrig's disease is a neurodegenerative and neuromuscular disorder characterized by a progressive death of motor neurons & motor paralysis that culminates in death, usually within 3-5 years of diagnosis from respiratory failure due to paralysis. Currently approved ALS therapies are not curative and fail to increase healthy lifespan. The worldwide prevalence of ALS is expected to increase by 69% over the next 25 years, yet its etiology remains scientifically unverified, complicating the discovery and development of effective therapies. Through this cross-sectional clinical study employing microbiological and cellular analyses of fecal and blood samples isolated from human patients with and without ALS, we achieved to confirm recently emerging pre-clinical and clinical evidence linking ALS with intestinal dysbiosis & systemic microbial infection, and thus provide rationale for future scientific investigations of intestinal dysbiosis as a potential therapeutic target for improving and extending the healthy lifespan of human patients diagnosed with ALS.
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Steenblock et al. Int J Neurodegener Dis 2018, 1:003
Volume 1 | Issue 1
Open Access
International Journal of
Neurodegenerative Disorders
Page 1 of 4
Citaon: Steenblock DA, Ikrar T, Antonio ASS, Wardaningsih E, Azizi MJ (2018) Amyotrophic Lateral
Sclerosis (ALS) Linked to Intesnal Microbiota Dysbiosis & Systemic Microbial Infecon in Human
Paents: A Cross-Seconal Clinical Study. Int J Neurodegener Dis 1:003.
Accepted: September 10, 2018; Published: September 12, 2018
Copyright: © 2018 Steenblock DA, et al. This is an open-access arcle distributed under the terms
of the Creave Commons Aribuon License, which permits unrestricted use, distribuon, and
reproducon in any medium, provided the original author and source are credited.
Steenblock et al. Int J Neurodegener Dis 2018, 1:003
Amyotrophic Lateral Sclerosis (ALS) Linked to Intesnal Microbi-
ota Dysbiosis & Systemic Microbial Infecon in Human Paents:
A Cross-Seconal Clinical Study
David A Steenblock1#, Taruna Ikrar2,3,4*#, Andrew S San Antonio2,4, El Wardaningsih4 and Masoud J
Azizi2,4
1Steenblock Research Instute, USA
2Internaonal School of Biomedical Sciences, Pacic Health Sciences University, USA
3Cellcure Center, The Indonesia Army and Presidenal Central Hospital, Indonesia
4Neurodegenerave Disease Research Program, Pacic Health Sciences University, USA
#These authors (T.I. & D.A.S.) contributed equally to this work.
*Corresponding author: Prof. Dr. Taruna Ikrar, MD, M. Pharm, PhD, Cellcure Center, The Indonesia Army and Presidenal
Central Hospital, (RSPAD Gatot Subroto), Jln. Abdul Rahman Saleh No. 24, Jakarta 10410, Indonesia; Internaonal School
of Biomedical Sciences and Neurodegenerave Disease Research (NDR) Program, Pacic Health Sciences University
(PHSU), 5401 Business Park South, Suite 107, Bakerseld, California, 93309, USA; Tel: +62-21-3441008; +62-21-3840702,
+1 661-200-7210 , Ext 5005, Fax: +62-21-350619, +1-661-200-7216
by progressive degeneraon of both upper and lower
motor neurons, and manifests as progressive physical
paralysis that culminates in death (most oen due to
respiratory failure) within an average of 3-5 years from
disease onset [1-3]. ALS is the most common adult-onset
motor neuron disease (MND), with a worldwide annu-
al incidence of about 2 per 100,000 [4]. The worldwide
prevalence of this fatal disease is expected to increase
by up to 69% over the next 25 years [5]. ALS aects in-
dividuals of all races and ethnicies (both male and fe-
male); however, whites, males, non-Hispanics, individu-
als aged > 50 years, and those with a family history of
ALS are more likely to develop this disease [6-8]. There
is currently no cure for ALS, and its eology remains elu-
sive. The only 2 drugs approved by the FDA to treat this
disease are riluzole (a glutamate inhibitor) and edara-
vone (an an-oxidant), both of which fail to halt the pro-
gression of this disease and fail to consistently prolong
healthy lifespan (healthspan) of ALS paents beyond
several months. Thus, there is an urgent need for the
ethical scienc discovery, development, and delivery of
therapeucs that consistently extends the healthy lifes-
Abstract
Amyotrophic Lateral Sclerosis (ALS) or Lou Gehrig’s dis-
ease is a neurodegenerative and neuromuscular disorder
characterized by a progressive death of motor neurons &
motor paralysis that culminates in death, usually within 3-5
years of diagnosis from respiratory failure due to paralysis.
Currently approved ALS therapies are not curative and fail
to increase healthy lifespan. The worldwide prevalence of
ALS is expected to increase by 69% over the next 25 years,
yet its etiology remains scientically unveried, complicat-
ing the discovery and development of effective therapies.
Through this cross-sectional clinical study employing micro-
biological and cellular analyses of fecal and blood samples
isolated from human patients with and without ALS, we
achieved to conrm recently emerging pre-clinical and clini-
cal evidence linking ALS with intestinal dysbiosis & system-
ic microbial infection, and thus provide rationale for future
scientic investigations of intestinal dysbiosis as a potential
therapeutic target for improving and extending the healthy
lifespan of human patients diagnosed with ALS.
RESEARCH ARTICLE
Check for
updates
Introducon
Amyotrophic Lateral Sclerosis (ALS) or Lou Gehrig’s
disease is a neurodegenerave disorder characterized
Steenblock et al. Int J Neurodegener Dis 2018, 1:003 Page 2 of 4
82 human paents included in this study, 54 (26 male
& 28 female) were diagnosed with ALS per the revised
El Escorial criteria, and 28 (14 male & 14 female) did
not have ALS or ALS-related symptoms and served as
a control group in this study. At the me of biological
(blood and feces) sample collecon & analyses, the
mean age of human paents with ALS (ALS Paents)
was 63.5 ± 12.3 years, and those without ALS (Non-ALS
Paents) was 59.4 ± 13.4 years.
Fecal & blood sample analyses
Concentraon of fecal secretory-IgA was determined
by an enzyme-linked immunosorbent assay (ELISA). Se-
rum white blood cell dierenal was determined by au-
tomated cell counng. Screening for a panel of 5 intes-
nal pathogenic bacteria was conducted per culture-based
microbiological methodology. LabCorp, Doctor’s Data,
and Great Palms Laboratory completed all afore men-
oned fecal & blood samples analyses per contemporary
best pracces in clinical laboratory science.
pan (healthspan) of ALS paents beyond what is current-
ly possible. The eology of ALS has not been fully elu-
cidated in the peer-reviewed scienc literature; how-
ever, evidence is emerging to indicate that disturbances
in the intesnal microbiota are involved in the cause &
progression of ALS and other neurodegenerave diseas-
es [9]. Here, we provide clinical evidence linking intes-
nal dysbiosis & systemic microbial infecon with ALS
and discuss raonale for further scienc invesgaon
of this link and it’s potenal as a therapeuc target.
Materials and Methods
Human subjects
Data from the blood and fecal analyses of 82 human
paents were used in this retrospecve cross-seconal
study. The Steenblock Research Instute (SRI) & its Eth-
ics Commiee approved of this retrospecve cross-sec-
onal clinical study. All human paents were > 18 years
of age & were able to provide informed consent. Of the
0
100
200
300
400
ALS
Control
Concentraon (mg/dl)
F I G U RE 1 : FE C A L S E C R ET O R Y
I M M U NO G L O B UL I N A
A L S VS . N O N- A L S H U M A N P A T I EN T S
( C O N T R O L )
Figure 1: Mean concentration of fecal secretory-IgA is consistently & signicantly higher in ALS relative to Non-ALS Patients
(323.96 ± 30.73 mg/dL vs. 106.71 ± 5.56 mg/dL; P < 0.001).
Providencia
regeri: 16.67%
Pseudomonas
aeruginosa:
83.33%
Pseudomonas
chlororaphis
group: 16.67%
Salmonella spp:
66.67%
Staphylococcus
aureus:16.67%
0
50
100
Prevalence (%)
FIGURE 2: PREVALENCE OF INTENSTINAL PATHOGENIC
BACTERIA IN 54 HUMAN PATIENTS WITH ALS
Figure 2: Fecal carriage of one or more bacterial species was detected in 100% of the 54 Human ALS Patients in this study.
Steenblock et al. Int J Neurodegener Dis 2018, 1:003 Page 3 of 4
alence of pseudomonas aeruginosa and salmonella spp
is found to be 83.3% and 66.7%, respecvely (Figure 2),
thereby indicang an increased suscepbility in the ALS
Paents’ intesne to harbor pathogenic bacterial spe-
cies relave to that of healthy non-clinical populaons.
This study’s nding of intesnal dysbiosis as a feature in
ALS is in agreement with smaller cross-seconal clinical
studies conducted in 2016 [14] and 2017 [15], both of
which evaluated the intesnal microbiome of ALS Pa-
ents through dierent methodologies to confer status
of intesnal dysbiosis.
This study’s analysis of serum white blood cell con-
centraon indicates that human ALS Paents have a
signicantly elevated neutrophil-to-lymphocyte rao
(Figure 3), which is an indicaon of systemic inamma-
on in response to systemic microbial infecon [16,17].
Intesnal dysbiosis has been shown to cause intesnal
barrier dysfuncon or intesnal epithelial hyperper-
meability in a mouse model of ALS [18,19], thereby
providing an anatomical pathway for the migraon of
pathogenic intesnal microbes and/or their metabol-
ic byproducts into the systemic circulaon via the gut
circulatory system to elicit systemic microbial infecon.
Given the co-occurrence of intesnal dysbiosis and sys-
temic microbial infecon in 100% of the ALS Paents
enrolled in this study, it is plausible that a similar physio-
logical phenomenon is occurring in human ALS Paents.
This study’s nding of systemic microbial infecon as a
feature of ALS Paents is consistent with that of a pre-
vious smaller study reporng the presence of serum
pathogenic microbial byproducts & systemic inamma-
on in human ALS Paents [20].
In a recent pre-clinical study ulizing a mouse mod-
el of ALS, it was demonstrated that intesnal dysbio-
sis precedes the development and progression of ALS
Data expression & analysis
Dierences between groups (ALS Paents vs. Non-
ALS Paents) were determined by ANOVA with Stu-
dent’s t-test. Data are expressed as mean ± standard
error of the mean (SEM). A P < 0.05 was considered as
stascal signicance.
Results
Figure 1, Figure 2 and Figure 3.
Discussion
Intesnal dysbiosis is widely dened as an abnormal
elevaon in the concentraon of pathogenic microbial
species that reside within the intesnal lumen and has
recently been associated with the eology and progres-
sion of many neurodegenerave diseases [9]. Secretory
immunoglobulin A (SIgA), an endogenous anmicrobial
factor measurable in feces, is naturally found in the ex-
ternal secreons bathing mucosal surfaces of the intes-
ne at a concentraon that is posively proporonal to
the concentraon of pathogenic microbial species that
reside within the intesnal lumen [10]. This cross-sec-
onal clinical study found that the mean concentraon
of fecal secretory immunoglobulin A (SIgA) is signicant-
ly higher (> 300%) in ALS Paents relave to Non-ALS
Paents (Figure 1), thereby indicang that ALS Paents
harbor a signicantly higher concentraon of patho-
genic microbial species in their intesnal lumen and are
thus in a state of intesnal dysbiosis. Furthermore, fecal
carriage prevalence of one or more pathogenic bacterial
species was conrmed in 100% of ALS Paents enrolled
in this study (Figure 2). Among healthy human popula-
ons, fecal carriage prevalence of the pathogenic bac-
teria pseudomonas aeruginosa and salmonella spp is
8.2% and 2-3%, respecvely [11-13]. However, in this
study’s populaon of ALS Paents, fecal carriage prev-
0
2.5
5
7.5
10
12.5
15
Lymphocytes
Monocytes
Eosinophils
Basophils
Concentraon (1x10^9 Cells Per uL)
FIGURE 3: SERUM WHITE BLOOD CELL DIFFERENTIAL
ALS VS. NON-ALS PATIENTS (CONTROL)
CONTROL
ALS
Figure 3: Mean serum concentration of Neutrophils (10.09 × 109 Cells vs. 2.78 × 109 Cells, P = 0.036), Lymphocytes (4.63 ×
109 Cells vs. 2.19 × 109 Cells, P = 0.015), and Eosinophils (1.95 × 109 Cells vs. 0.14 × 109 Cells, P = 0.023) are signicantly
higher in ALS relative to Non-ALS Human Patients.
Steenblock et al. Int J Neurodegener Dis 2018, 1:003 Page 4 of 4
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symptoms, and that reversal of intesnal dysbiosis with
a dietary probioc intervenon alleviates ALS symptoms
and progression, reverses intesnal barrier dysfuncon,
and prolongs healthy lifespan [19]. This strongly indi-
cates that intesnal dysbiosis may be a modiable cause
of ALS. Through this cross-seconal clinical study, we
achieved to conrm recently emerging pre-clinical and
clinical evidence linking ALS with intesnal dysbiosis &
systemic microbial infecon, and thus provide raonale
for future scienc invesgaon of intesnal dysbiosis as
a potenal therapeuc target for extending the healthy
lifespan of human paents diagnosed with ALS.
Author Contribuons
T.I. and D.A.S. performed data collecon & paent
examinaons. T.I. performed data analysis, prepared
the gures, & wrote the manuscript. M.J.A composed &
revised the manuscript per reviewer feedback. A.S.S.A.
& E.W. revised the manuscript.
Conflict of Interest Statement
The authors declare that the research was conduct-
ed in the absence of any commercial or nancial rela-
onships that could be construed as a potenal conict
of interest. Authors claim no conicts of interest related
to the research described in the manuscript.
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... For example, P. aeruginosa rhamnolipids, secreted surfactants, were shown to enhance the aggregation of human α-synuclein [37], and its functional amyloid, FapC, was involved in heterologous cross-seeding with amyloid-beta [25]. Combined with our data, these results may explain why P. aeruginosa abundance is overrepresented in patients with PCDs [38,39]. Additionally, P. aeruginosa can adhere to the intestinal epithelial barrier and secrete virulence factors that damage the intestinal epithelium [40]. ...
... With an estimated 8% of the population being asymptomatically colonized by P. aeruginosa, this bacterium may be one of the primary silent microbial contributors to neurodegenerative diseases [47]. data, these results may explain why P. aeruginosa abundance is overrepresented in patients with PCDs [38,39]. Additionally, P. aeruginosa can adhere to the intestinal epithelial barrier and secrete virulence factors that damage the intestinal epithelium [40]. ...
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Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that specifically affects motor neurons and leads to a progressive and ultimately fatal loss of functions, resulting in death typically within 3 to 5 years of diagnosis. The disease starts with a focal center of weakness, such as one limb, and usually spreads to other extremities, the brain, and often kills by affecting the respiratory muscles. Recent studies reveal a trend towards an increase in the ALS mortality rate, but the significance of this trend remains unclear. Recent ALS incidence studies have given new insight into ALS epidemiology. ALS seems to be distributed uniformly in different countries, with age-specific incidence rates showing a progressive increase up to the 60-79 age group [1]. The pathophysiological mechanisms underlying the development of familial ALS seem multifactorial with emerging evidence of a complex interaction between genetic and molecular pathways [2]. This review provides new insights into the two different form of ALS which primarily highlights epidemiology, clinical manifestations, pathophysiological, current state of ALS therapy and what the best directions are regarding future ALS research. Future directions to treat and manage ALS via stem cell therapy, possibly new drug discoveries, and diet are given.
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