Case Report

Journal of International Medical Research

48(6) 1–6
Rapid improvement in ! The Author(s) 2020
Article reuse guidelines:
Alzheimer’s disease sagepub.com/journals-permissions
DOI: 10.1177/0300060520925930
symptoms following fecal journals.sagepub.com/home/imr

microbiota transplantation:
a case report

Sabine Hazan

Abstract
Alzheimer’s disease (AD), the most common form of dementia, is a leading cause of death and a
major cause of morbidity in older people. The disease is characterized by progressive memory
loss, cognitive impairment, and the cerebral accumulation of amyloid-b peptide. Given the health
and economic impacts of AD, treatments that target the underlying etiology of AD or modify the
course of the disease are of significant interest. The gut microbiome has been increasingly impli-
cated in the pathogenesis of several neurological diseases, including multiple sclerosis and
Parkinson’s disease. Furthermore, emerging evidence has demonstrated that there are alterations
in gut microbiome composition in patients with AD, suggesting involvement of the microbiome–
gut–brain axis. We present symptom improvement in a patient with AD following fecal micro-
biota transplantation for a Clostridioides difficile infection.

Keywords
Alzheimer’s disease, fecal microbiota transplantation, gastrointestinal microbiome, microbiota,
neuroinflammation, Clostridioides difficile
Date received: 4 December 2019; accepted: 17 April 2020

Introduction
Alzheimer’s disease (AD) is a devastating
Ventura Clinical Trials, Malibu, CA, USA
neurodegenerative disease characterized by
Corresponding author:
a deterioration in memory and other cogni- Sabine Hazan, Ventura Clinical Trials, 1835 Knoll Drive,
tive domains and the cerebral accumulation CA 93003, USA.
of amyloid-b peptide. Advancing age is the Email: sabinehazan@aim.com

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2 Journal of International Medical Research

most significant risk factor for the disease, of the hypervirulent NAP1/B1/027 strain.
with incidence doubling every 5 years after In these difficult-to-treat cases as well as
the age of 65.1 Approximately 46.8 million in subsequent randomized, controlled
people worldwide currently have AD or a trials, FMT has consistently achieved cure
related dementia.2 However, this number is rates >90%.11 Serendipitous improvements
expected to increase exponentially in the following FMT have since been reported in
coming years, largely as a result of the a number of extra-intestinal conditions,
ageing population.2 The associated eco- including ASD,3 MS,12,13 and myoclonus
nomic burden of AD is substantial; in dystonia.14 To our knowledge, ours is the
2015, the total estimated worldwide cost first report of a patient who experienced
of dementia was US$818 billion, which is rapid improvement in their AD symptoms
projected to rise to US$2.0 trillion by 2030 following FMT for recurrent CDI.
because of the increased prevalence of AD.2
However, despite decades of research, the
Case report
etiology of AD remains unknown and
there are currently no preventative or An 82-year-old man presented for opinion
disease-modifying treatments. and management of recurrent CDI follow-
A growing body of experimental and ing hospitalization for methicillin-resistant
clinical data implicates the gut microbiome Staphylococcus aureus pneumonia. The
in the pathogenesis of several neurological patient had previously failed several courses
conditions, including autism spectrum dis- of antibiotics for CDI, including vancomy-
order (ASD),3 Parkinson’s disease (PD),4 cin, vancomycin with metronidazole, fidax-
and multiple sclerosis (MS).5,6 More recent- omicin, and bezlotoxumab, with relapse
ly, alterations in gut microbiome composi- confirmed via symptom recurrence and pos-
tion have been observed in patients with itive stool test.
AD,7 suggesting a potential role for the At the time of presentation, the patient
microbiome in AD pathogenesis. This was under the care of his primary care phy-
hypothesis has been supported by animal sician and his neurologist for the treatment
models;8,9 for example, germ-free amyloid- of AD, following a gradual 5-year decline in
b precursor protein transgenic mice have memory and cognition. The patient was
markedly less cerebral amyloid-b pathology taking memantine (28 mg once daily) and
compared with control mice with intestinal donepezil (23 mg once daily). The patient’s
bacteria.8 Certain bacteria within the gut dementia symptoms included confusion,
microbiota are also capable of secreting memory loss, depression, and flattened
large amounts of amyloids and lipopolysac- affect. On his most recent Mini-Mental
charides,10 a hallmark feature of AD. State Examination (MMSE) administered
Fecal microbiota transplantation (FMT) by the neurologist, the patient scored 20,
is the infusion of fecal material from a indicating mild cognitive impairment. This
healthy donor into the gastrointestinal result reflected the gastroenterologist’s find-
tract of an individual with disease. This ings and was within the expected range for
procedure represents the most powerful patients with AD. The patient’s wife
means of modulating the gut microbiome. reported that he no longer appeared to
The therapy has risen to prominence in the enjoy socializing, and required considerable
last decade following several outbreaks of assistance with basic tasks such as food
severe Clostridioides difficile infection preparation, bathing, and taking his medi-
(CDI) in North America and Europe, cation. Neuropsychiatric testing revealed
which were caused in part by the emergence significant impairments in the areas of
Hazan 3

memory and semantic language abilities, Improvements in AD symptoms occurred

nonverbal learning, and divided attention as early as 2 months post-FMT and contin-
and response inhibition. His scores in ued to the 6-month follow-up visit (the date
these areas were within the first through of the last follow-up), with no noted rever-
fifth percentiles for function. sion of symptoms. The resolution of symp-
Following a detailed discussion regard- toms occurred in a stepwise manner: first,
ing the potential risks and benefits associat- there was increased mental acuity and
ed with the procedure, the patient improved affect observed at 2 months
underwent a single 300 mL FMT infusion post-FMT, and this was followed by
(per the Borody method)15 using stool from marked improvements in memory and
the patient’s 85-year-old wife as a donor. mood by 4 and 6 months post-FMT,
The patient’s wife was intellectually acute, which were accompanied by more expres-
with normal affect and stable mood. sive affect. These findings paralleled
Following the procedure, the patient’s improvements in the patient’s MMSE
CDI symptoms resolved, and repeat stool scores, which increased to within the range
testing 2 months later was negative. of normal cognition by 2 months post-
At the follow-up visit 2 months post- FMT. Eradication of CDI was also con-
FMT, the patient’s wife reported improve- firmed at the 2-month follow-up visit, via
ments in the patient’s mental acuity and the resolution of symptoms and a negative
affect. The MMSE was re-administered by stool test.
the gastroenterologist (and subsequently by The central role of the gut microbiome in
the neurologist) and the patient scored 26, neurological dysfunction has been increas-
indicating normal cognition. Four months ingly recognized, and alterations in gut
post-FMT, the patient reported continued microbiome composition have consistently
improvement in memory, with no progres- been reported in ASD,3 PD,4 and MS.5,6
sion in symptoms. The patient now remem- Rapid and dramatic improvements have
bered his daughter’s birthday, which he had also been observed in several of these con-
not been able to recall previously, and was ditions following manipulation of the gut
able to correct the physician’s recollections microbiome, including with FMT, which
of his symptoms. Six months post-FMT, further supports a causal association. In
the patient reported a marked improvement an open-label study in 18 children with
in mood, was more interactive, and showed ASD, 2 weeks of vancomycin treatment fol-
more expressive affect. Readministration of lowed by daily FMT infusions for 7 to
the MMSE revealed that the patient’s score 8 weeks resulted in significant improve-
had further increased to 29. ments in core ASD symptoms, which per-
Because no study was conducted, no sisted at the 2-year follow-up.3
ethics approval or consent was required. Furthermore, in a case series of three
Verbal consent was obtained from the patients with MS and underlying gastroin-
patient for the publication of the report; testinal symptoms, 5 to 10 days of FMT
however, this was merely a courtesy because infusions resulted in a profound reversal
all data have been de-identified. of major neurological symptoms, and led
to longstanding disease remission.12
Similarly, a 61-year old female with second-
Discussion ary progressive MS achieved disease stabil-
To our knowledge, this is the first report of ity for over 10 years following FMT for
a case of rapid reversal of AD symptoms in recurrent CDI.13 In addition, in a patient
a patient following FMT for recurrent CDI. with myoclonus dystonia, significant
4 Journal of International Medical Research

improvement in tremor and functional def- accumulation of b-amyloid protein plaques

icits were reported following the manipula- between neurons represents a hallmark of
tion of gut microbiota with vancomycin, AD. However, the initiating factor respon-
rifaximin, and metronidazole for chronic sible for the development and propagation
diarrhoea.14 In another study, a 71-year of these prion-like proteins is unknown.
old male with longstanding constipation Amyloids are secreted by a wide range of
and PD experienced a rapid and dramatic pathogenic and non-pathogenic bacteria,
reduction in PD symptoms, including an and play an important role in cell adhesion
absence of persistent tremors, glabellar tap and biofilm formation.10 Similarities
reflex, and cogwheel rigidity, when his con- between the tertiary structure of microbe-
stipation was treated with vancomycin, derived amyloids and b-amyloid in AD
metronidazole, and colchicine.16 may trigger antigen cross-reactivity, thus
Gut bacteria may contribute to the path- potentially initiating the formation of AD.
ogenesis of AD via a number of mecha- Interestingly, both microbe-derived amy-
nisms. Microbe-mediated bidirectional loids (such as curli) and AD-related b-amy-
communication pathways exist between loid are recognized by the same Toll-like
the gut and the central nervous system, receptor (TLR)2/TLR1 complex.21 Finally,
and many of the neurotransmitters that reg- dysbiosis itself may contribute to the devel-
ulate mood and cognition in the brain, such opment of AD. A dysbiosis-induced
as gamma-aminobutyric acid (GABA) and increase in gut permeability may potentially
dopamine, are also synthesized and catabo- lead to persistent systemic inflammation,
lized by gut bacteria. GABA dysfunction disruption of the blood–brain barrier, and
has been shown to play a role in AD,17 ultimately neurodegeneration.
and abnormally high GABA concentrations Neuroinflammation plays a central role
have recently been identified in reactive in the pathogenesis of AD,22,23 and is char-
astrocytes of post-mortem AD patients.18 acterized by elevated levels of pro-
Molecular mimicry is a well-documented inflammatory cytokines,23 nuclear factor
strategy that is commonly employed by jb signalling,24 and aggregation of activat-
pathogens to gain a competitive advantage ed microglia in damaged areas.25 The influ-
over their host. It occurs when similarities ence of the gut microbiome on
between microbial proteins and host neuroinflammation in AD remains poorly
peptides result in the cross-activation of understood, as do the exact mechanisms
autoreactive T or B cells and a loss of of action of FMT in this disease.
self-tolerance.19 Rheumatic fever after However, the potent immunomodulatory
Streptoccocus pyogenes infection is a classic effects of FMT are well recognized. FMT
example of this; antigen cross-reactivity has been demonstrated to ameliorate chron-
between streptococcal M protein and cardi- ic intestinal colitis in both humans and
ac myosin results in the targeting of myo- animal models via the downregulation of
cardial tissue.19 However, a number of pro-inflammatory cytokines, promotion of
other well-documented molecular mimicry anti-inflammatory responses, and inhibition
events exist, and a recent database study of nuclear factor jb activity.26–28 In addi-
catalogued 261 validated host–microbial tion, similarly beneficial effects have since
mimicry interactions.20 Although the focus been observed in several other conditions
to date has been on the role of molecular with an inflammatory component.13,29,30
mimicry as a cause of autoimmune diseases, Thus, FMT may have a positive effect on
this mechanism may also be exploited in the cognitive function in AD via alterations in
development of AD. The progressive the levels of circulating cytokines.
Hazan 5

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