Probiotic influences on motor skills

Abstract

Probiotics are bacteria whose favorable physiological properties have mostly been demonstrated in regard to anxiety and stress. More recent experiments indicate potential use of single- and multi-strain probiotics on motor-related diseases. Initial studies in patients with Parkinson’s disease and Prader-Willi syndrome are concordant with this hypothesis. In experiments with rodents, probiotics improved motor coordination in normal animals and models of Parkinson’s disease, multiple sclerosis, and spinal cord injury as well as grip strength in hepatic encephalopathy. Further studies should delineate the bacterial profile of each condition and their experimental models.

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Current Neuropharmacology, XXXX, XX, XX-XX 1
REVIEW ARTICLE
1570-159X/XX $65.00+.00 © XXXX Bentham Science Publishers
Probiotic Influences on Motor Skills: A Review
Robert Lalonde1,* and Catherine Strazielle1,2
1Laboratory of Stress, Immunity, Pathogens (EA7300), Medical School, University of Lorraine, 54500, Vandœuvre-les-
Nancy, France; 2CHRU Nancy, Vandœuvre-les-Nancy, France
Abstract: The effects of probiotics have mostly been shown to be favorable on measures of anxiety
and stress. More recent experiments indicate single- and multi-strain probiotics in treating motor-
related diseases. Initial studies in patients with Parkinson’s disease and Prader-Willi syndrome are
concordant with this hypothesis. In addition, probiotics improved motor coordination in normal ani-
mals and models of Parkinson’s disease, multiple sclerosis, and spinal cord injury as well as grip
strength in hepatic encephalopathy. Further studies should delineate the most optimal bacterial profile
under each condition.
A R T I C L E H I S T O R Y
Received: March 21, 2022
Revised: June 23, 2022
Accepted: July 13, 2022
DOI:
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Keywords: Lactobacilli, Bifidobacteria, Parkinson’s disease, multiple sclerosis, hepatic encephalopathy, motor coordination.
1. INTRODUCTION
Probiotics are defined as bacteria with favorable physio-
logical properties and are designated as psychobiotics when
they produce behavioral outcomes [1-3], the most important
of which include Lactobacillus (L.) Bifidobacterium (B.),
Streptococcus (S.), Escherichia (E.), Enterococcus (E.), and
Clostridium butyricum [4]. Most researchers in this field
have focused attention on anxiety, stress, and depression via
neurologic, endocrine, humoral, and immune systems [5-8].
The brain is affected in the absence of microbiota in germ-
free animals. Effects on the brain were likewise noted after
antibiotic administration. When bacterial strains, especially
those deemed to be beneficial, were given to animals, neuro-
biological effects occurred, some of which also occurred in
normal human subjects. Such studies were then extended to
treat specific diseases.
The effects of gut microbiota were first evaluated in gas-
trointestinal diseases, cancer, obesity, and infections and
then for neuropsychiatric symptoms [1-8]. In particular, the
treatment of liver disease and its neurological complications
with antibiotics led to an understanding of the role of micro-
biota in other neurological conditions. Since the gut is inner-
vated by the vagus nerve, several experimenters have aimed
at deciphering whether microbiotic actions are transmitted
via this pathway. At the present time, effects on animal and
human behavior have mostly been analyzed for cognition
*Address correspondence to this author at the Laboratory of Stress, Immuni-
ty, Pathogens (EA7300), Medical School, University of Lorraine, 54500,
Vandœuvre-les-Nancy, France; Tel: +33 (3) 83 15 42 56; Fax : +33 (3) 72
74 62 37; E-mail: lalondr54@gmail.com
and emotion, to a lesser extent, sensorimotor functions. In
the present review, we regard probiotic actions on sen-
sorimotor functions under various neurologic conditions.
Although most results are preliminary, this synthesis should
be of use to guide future research.
2. NORMAL SUBJECTS
2.1. Normal or Preterm Human Subjects
Probiotics undergo changes across the lifespan [9], so there
is interest in investigating their effects in children up to old
age. In a preliminary investigation of this kind, Bifidobacte-
rium, Lactobacillus, and Coprococcus strains were more
abundant in 18-month-old infants above the median in the
fine motor skill subscore of the Bayley-III battery of neuro-
development [10]. It remains to be determined whether the
administration of such strains increases motor skills in older
children and adults.
In a double-blind, placebo-controlled, randomized trial,
B. infantis BB-02 96579 + B. lactis BB-12 15954 + S. ther-
mophilus TH-4 15957 had no effect on the Gross Motor
Function Classification System score, the Bayley-III Motor
Composite Scale, or the Movement Assessment Battery for
Children in preterm children at 2-5 years of age [11]. In a
review of five papers, including the preceding one, Upadh-
yay [12] concluded that probiotics had no effect on motor
behaviors in preterm children.
2.2. Normal Animals
L. plantarum + L. longum increased latencies before fall-
ing from the rotorod in 1-month-old mice, either previously
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2 Current Neuropharmacology, XXXX, Vol. XX, No. XX Lalonde and Strazielle
exposed to treadmill exercise or not [13]. The probiotic
mixture increased cerebellar concentrations of gamma-
aminobutyric acid (GABA), the cerebellum being particular-
ly relevant in performing this type of task [14]. Likewise, L.
fermentum JDFM216 increased latencies before falling from
the rotorod and decreased foot slips from a stationary beam
in 12-month-old mice [15]. These results lend credence to
the hypothesis that probiotics facilitate motor coordination
and thus may be of use in sporting events [16]. L. plantarum
SPA3 + L. rhamnosus B-8238 counteracted the decrease in
latencies before falling from the rotorod in antibiotic-induced
dysbiosis in mice [17], indicating that individuals with
suboptimal gut bacteria are more likely to improve with pro-
biotics.
3. PARKINSON’S DISEASE
3.1. Patients with Parkinson’s Disease
Most probiotic studies on motor control have been con-
ducted in the context of Parkinson’s disease. Based on gas-
trointestinal anomalies and alterations in the gut microbiota
of such patients [18-22], studies have appeared on probiotic-
induced improvements in patients’ constipation and neural
functions, possibly via anti-inflammatory and antioxidant
actions [23-30]. For example, L. salivarius LS01 and L. aci-
dophilus LA02 DSM 21717 reduced proinflammatory cyto-
kines as well as increased anti-inflammatory cytokines [31].
In an open-label, single-arm, baseline-controlled trial of
patients with Parkinson’s disease, L. plantarum PS128 im-
proved the total score of the Unified Parkinson’s Disease
Rating Scale (UPDRS) and its akinesia subscore as well as a
single index, mobility, and activities of daily living in the 39-
item Parkinson’s Disease Questionnaire (PDQ-39) [32].
Likewise, L. acidophilus + L. fermentum + L. reuteri + B.
bifidum improved the total score of the UPDRS in a double-
blind trial [33].
3.2. Animal Models of Parkinson’s Disease
L. acidophilus + L. plantarum + L. paracasei + L. del-
brueckii subsp. bulgaricus + L. brevis + B. longum + B. breve
+ B. infantis + S. thermophilus, designated as SLAB51, was
given before a unilateral 6-hydroxydopamine (6-OHDA)
injection in the mouse striatum and improved the use of the
contralateral forepaw in the cylinder test and postural asym-
metry in the elevated body swing test [34]. The supplement
also counteracted 6-OHDA-induced decreases in tyrosine
hydroxylase and dopamine transporter immunoreactivity in
the substantia nigra, indicating preservation of dopaminergic
neurons. Likewise, L. salivarius subsp. salicinius AP-32
increased locomotor speed and stride length while decreasing
stance time in gait analyses of rats unilaterally injected with
6-OHDA along the nigro-striatal tract [35]. The probiotic
also increased the number of tyrosine hydroxylase-positive
neurons in the substantia nigra and the striatum. In a similar
manner, L. plantarum PS128 improved step adjustment in
gait analyses of rats unilaterally injected with 6-OHDA
along the nigro-striatal tract and increased tyrosine hydrox-
ylase-positive neurons in the substantia nigra [36]. In addi-
tion, 6-OHDA unilaterally injected in the substantia nigra
followed by intraperitoneally administered apomorphine
augmented contralateral rotations compared with controls
and L. acidophilus + L. reuteri + L. fermentum + B. bifidum
prevented these and increased the number of substantia nigra
neurons destroyed by the neurotoxin [37]. L. fermentum U-
21 alone counteracted the paraquat-induced increase in la-
tencies before descending from a vertical pole and the de-
crease in the number of tyrosine hydroxylase-positive neu-
rons in the substantia nigra [38].
In addition to 6-OHDA, probiotics appear effective in
counteracting anomalies caused by the peripheral injection of
another dopamine neurotoxin, methyl-phenyl-tetrahydro-
pyridine (MPTP). Indeed, L. plantarum CRL 2130 + S.
thermophilus CRL 807 and CRL 808 decreased latencies
before descending from the vertical pole and latencies before
traversing the horizontal stationary beam and increased tyro-
sine hydrolase-positive cell counts in the substantia nigra of
MPTP-injected mice [39]. The same effects were found with
Clostridium butyricum [40]. Moreover, a mixture of L. lactis
MG1363 + glucagon-like peptide-1 (GLP-1) reduced laten-
cies before descending from the vertical pole and increased
open-field activity in mice injected with MPTP as well as
counteracting declines in the number of tyrosine hydrox-
ylase-positive neurons in the substantia nigra [41, 42].
In yet another Parkinsonian model, L. rhamnosis GG + L.
rhamnosus + L. plantarum LP28 + L. lactis subsp. lactis + B.
bifidum + B. longum reduced latencies before traversing the
stationary beam and increased latencies before falling from
the rotorod as well as improving gait patterns in MitoPark
PD mice, characterized by inactivation of the Tfam (tran-
scription factor A) mitochondrial gene in dopamine neurons
[43]. The mixture also added protective actions on substantia
nigra dopamine neurons as determined by the number of
tyrosine hydroxylase-positive cells.
4. MULTIPLE SCLEROSIS
4.1. Patients with Multiple Sclerosis
Motor dysfunctions, sometimes leading to paresis, figure
as important features in the symptomatology of multiple scle-
rosis [44]. Although there is doubt as to whether gut dysbiosis
marks the cause or consequence of the disease, it has been
considered a contributing factor [45-49]. Meta-analyses re-
vealed the beneficial effects of probiotic supplementation on
general health and depression in patients with multiple scle-
rosis [50-52]. In a double-blind trial, L. reuteri + L. casei +
L. plantarum + L. fermentum + B. infantis + B. lactis im-
proved the global score of the Expanded Disability Status
Scale (EDSS) and the General Health Questionnaire-28
(GHQ-28) in patients with multiple sclerosis, the former
featuring the ability to walk [53]. Further experiments must
delineate whether this or other mixtures specifically improve
motor scores.
4.2. Animal Models of Multiple Sclerosis
Antibiotics increased latencies before falling from the
rotorod and improved axon damage in mice exposed to intra-
cranial infection with Theiler’s murine encephalomyelitis
virus (TMEV), a model of multiple sclerosis [54], lending
credence to the hypothesis that gut microbiota influences
demyelinating diseases. In further support of this hypothesis,
L. acidophilus DSM 24735 + L. paracasei DSM 24734 +L.
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Probiotic Influences on Motor Skills Current Neuropharmacology, XXXX, Vol. XX, No. XX 3
plantarum DSM 24730 + L. + L. bulgaricus DSM 24734 +
B. infantis DSM 24737 + B. longum DSM 24736 + B. breve
DSM 24732 + S. thermophiles DSM 24732, designated Vi-
vomixx, increased latencies before falling from the rotorod
and exhibited anti-inflammatory actions in TMEV-treated
mice [55]. Both the Vivomixx mixture and a 3-strain mixture
of L. acidophilus LA 201 + L. salivarius LA 304 + B. lactis
LA 304, designated Lactibiane iki, were examined in another
murine model of multiple sclerosis: pertussis toxin-induced
experimental autoimmune encephalomyelitis [56]. As in the
previous study, both probiotic mixtures increased latencies
before falling from the rotorod. On the contrary, neither L.
plantarum nor Bifidobacterium B94 had any effect on
swimming speed in rats exposed to ethidium bromide-induced
demyelination [57]. In a third model of demyelination, the
murine cuprizone-induced model, L. casei T2 augmented
spontaneous alternation rates in a Y-maze [58], a measure of
mental flexibility [59], so it remains to be determined whether
these results can be generalized to motor coordination. More
experiments are needed to determine whether motor signs
should be included in the conclusions of a general review [60]
and a meta-analysis [61] indicating probiotic-induced im-
provements on overall signs, body weight gain, and survival
in experimental autoimmune encephalomyelitis.
5. SPINAL CORD INJURY
5.1. Patients with Spinal Cord Injury
Gut microbiota may be an important factor in mediating
neural repair following spinal cord trauma [62]. In particular,
spinal cord trauma may cause gut dysbiosis [63], so treating
this condition becomes all the more relevant to the patholog-
ical process. Even with minimal actions on sensorimotor
functions, psychobiotics may be of use in mitigating anxiety
and depression [5-7].
5.2. Animal Models of Spinal Cord Injury
A mixture of broad-spectrum antibiotics worsened spinal
cord pathology and slowed down recovery of locomotion in
mice exposed to spinal cord trauma [64]. Like control mice,
antibiotic-treated mice eventually exhibited consistent plantar
stepping but without forelimb/hindlimb coordination and were
more prone to paw anomalies and trunk instability. Converse-
ly, L. casei + L. plantarum + L. acidophilus + L. delbrueckii
subsp. bulgaricus + B. longum + B. breve + B. infantis + S.
salivarius subsp. thermophilus, designated VSL#3, promoted
spinal cord recovery relative to the vehicle-treated group by
increasing the frequency of plantar stepping and fore-
limb/hindlimb coordination along with improving paw posi-
tion and trunk stability. The product also reduced lesion vol-
ume as well as axon and myelin pathology at the injury site.
These data should encourage further analyses in the patterns
of dysbiosis seen after spinal cord injury so that optimal pro-
biotics are proposed.
6. PRADER-WILLI SYNDROME
6.1. Patients with Prader-Willi Syndrome
Prader-Willi syndrome is a disorder caused by the dele-
tion of paternally expressed genes at the Chr. 15q11.2-q13
locus, resulting in hypotonia, developmental delay, hyper-
phagia, obesity, and such neuropsychiatric signs as psychosis
and compulsive behaviors [65]. Gut microbiotas have been
linked to Prader-Willi syndrome [66], so a randomized, dou-
ble-blind, placebo-controlled trial of L. reuteri LR-99 was
conducted [67]. The probiotic improved the total score and
fine motor skill subscore of the ASQ-3 test as well as the
social communication subscore of the Gilliam Autism Rating
Scale (GARS-3) while reducing body mass index.
6.2. Animal Models of Prader-Willi Syndrome
To our knowledge, a probiotic has yet to be examined in
rodent models of Prader-Willi syndrome [68, 69].
7. HEPATIC ENCEPHALOPATHY
7.1. Patients with Hepatic Encephalopathy
Motor performance is impaired even in minimal hepatic
encephalopathy [70]. Neurocognitive scores in patients with
hepatic encephalopathy were correlated with the presence of
bacterial DNA [71] in line with the hypothesis that favorable
bacteria are of use in treating this condition. Indeed, probiot-
ics are useful in treating biochemical anomalies of hepatic
encephalopathy [72-75]. However, their use on human motor
control has been left unexamined.
7.2. Animal Models of Hepatic Encephalopathy
The E. coli Nissle 1917 bacterium was genetically modi-
fied to consume and convert excessive ammonia to arginine
and further modified to synthesize butyrate in rats with ligat-
ed bile ducts [76]. When the engineered product synthesized
arginine + butyrate, forelimb and hind-limb grip strength
improved, but not latencies before falling from the rotorod.
The combination of the antibiotic rifaximin, along with the
Vivomixx probiotic mentioned above, was given in rats with
ligated bile ducts, a model of type C hepatic encephalopathy
[77]. On magnetic resonance spectroscopy scans, duct liga-
tion increased glutamine levels in the hippocampus and cer-
ebellum, effects counteracted by rifaximin + Vivomixx,
whereas the antibiotic alone was without effect. Duct ligation
also decreased creatine levels in the cerebellum, an effect
also counteracted by rifaximin + Vivomixx administration,
while yet again, the antibiotic alone was without effect. De-
spite these favorable biochemical actions, there was no effect
on bile duct ligation-induced hypoactivity in the open field.
Further experimentation is required to determine whether
probiotics specifically improve the sensorimotor impairment
underlying hepatic encephalopathy.
CONCLUSION
Positive results have been obtained on the UPDRS in
patients with Parkinson’s disease given two Lactobacillus
mixtures, data supported by those on three animal models
measuring gait and motor coordination in vertical poles, sta-
tionary beams, and rotorod tests. One positive finding has
been reported with L. reuteri on fine motor skills of the
GARS-3 in Prader-Willi syndrome. But only experiments in
mice or rats exist in regard to multiple sclerosis, spinal cord
injury, and hepatic encephalopathy. In two models of multi-
ple sclerosis, Lactobacillus combined with Bifidobacterium
improved rotorod performance. Another mixture containing
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4 Current Neuropharmacology, XXXX, Vol. XX, No. XX Lalonde and Strazielle
Lactobacillus and Bifidobacterium facilitated gait patterns in
spinal cord injury. In hepatic encephalopathy, an improve-
ment in grip strength was noted with E. coli. There is interest
in extending such protocols with other motor-related diseas-
es, such as spinocerebellar atrophy and amyotrophic lateral
sclerosis.
LIST OF ABBREVIATIONS
GLP-1 = Glucagon-like Peptide-1
MPTP = Methyl-phenyl-tetrahydro-pyridine
PDQ-39 = Parkinson’s Disease Questionnaire
TMEV = Theiler’s Murine Encephalomyelitis Virus
6-OHDA = 6-Hydroxydopamine
UPDRS = Unified Parkinson’s Disease Rating Scale
CONSENT FOR PUBLICATION
Not applicable.
FUNDING
Supported by EA7300.
CONFLICT OF INTEREST
The authors declare no conflict of interest, financial or
otherwise.
ACKNOWLEDGEMENTS
Declared none.
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