If this actually says something useful I don't know where it is.
From this post comes the following line:
Brain Change Claims from David Perlmutter M.D. October 2015
BrainChange
Claim #3: Gluten and grains can cause Alzheimer’s and other forms of
dementia. Eliminate all grains and gluten-containing foods from your
diet.
Scientific evidence for this claim: Crickets….aka None
The latest here for your doctor to tell you in understandable sentences what it means.
“Let Food Be Thy Medicine”: Gluten and Potential Rolein Neurodegeneration
degeneration
Aaron Lerner * and Carina Benzvi
Citation: Lerner, A.; Benzvi, C. “Let
Food Be Thy Medicine” : Gluten and
Potential Role in Neurodegeneration.
Cells 2021, 10, 756. https://doi.org/
10.3390/cells10040756
Academic Editors: Carla Perego,
Paola Rusmini and Mariarita Galbiati
Received: 4 March 2021
Accepted: 25 March 2021
Published: 30 March 2021
Publisher’s Note: MDPI stays neutral
with regard to jurisdictional claims in
published maps and institutional affiliations.
Copyright: © 2021 by the authors.
Licensee MDPI, Basel, Switzerland.
This article is an open access article
distributed under the terms and
conditions of the Creative Commons
Attribution (CC BY) license (https://
creativecommons.org/licenses/by/
4.0/).
Chaim Sheba Medical Center, The Zabludowicz Research Center for Autoimmune Diseases,
Tel Hashomer 5262000, Israel; carina.ben.zvi@gmail.com
* Correspondence: aaronlerner1948@gmail.com; Tel.: +972-525-919484
Aaron Lerner * and Carina Benzvi
Citation: Lerner, A.; Benzvi, C. “Let
Food Be Thy Medicine” : Gluten and
Potential Role in Neurodegeneration.
Cells 2021, 10, 756. https://doi.org/
10.3390/cells10040756
Academic Editors: Carla Perego,
Paola Rusmini and Mariarita Galbiati
Received: 4 March 2021
Accepted: 25 March 2021
Published: 30 March 2021
Publisher’s Note: MDPI stays neutral
with regard to jurisdictional claims in
published maps and institutional affiliations.
Copyright: © 2021 by the authors.
Licensee MDPI, Basel, Switzerland.
This article is an open access article
distributed under the terms and
conditions of the Creative Commons
Attribution (CC BY) license (https://
creativecommons.org/licenses/by/
4.0/).
Chaim Sheba Medical Center, The Zabludowicz Research Center for Autoimmune Diseases,
Tel Hashomer 5262000, Israel; carina.ben.zvi@gmail.com
* Correspondence: aaronlerner1948@gmail.com; Tel.: +972-525-919484
Abstract:
Wheat is a most favored staple food worldwide and its major protein is gluten. It is involved
in several gluten dependent diseases and lately was suggested to play a role in non-celiac autoimmune
diseases. Its involvement in neurodegenerative conditions was recently suggested but no cause-andeffect relationship were established. The present narrative review expands on various aspects of the
gluten-gut-brain axes events, mechanisms and pathways that connect wheat and gluten consumption
to neurodegenerative disease. Gluten induced dysbiosis, increased intestinal permeabillity, enteric
and systemic side effects, cross-reactive antibodies, and the sequence of homologies between brain
antigens and gluten are highlighted. This combination may suggest molecular mimicry, alluding
to some autoimmune aspects between gluten and neurodegenerative disease. The proverb of
Hippocrates coined in 400 BC, “let food be thy medicine,” is critically discussed in the frame of gluten
and potential neurodegeneration evolvement.
Keywords: gluten; nutrients; intestine; brain; neurodegeneration; gut-brain axis; cross-reactivity;
sequence homology; BLAST
For decades, the brain dominated the arena. However, the increased knowledge on gut
performances, mucosal and luminal eco-events, and immune surveyance and regulation
have flipped the dogma [1]. It appears that one can’t without the other. Facing the environment, the primary immune function of the intestine is to induce tolerance and to negate
the non-self for a long-term homeostasis.
Neurodegenerative diseases are characterized by the progressive loss of structure or
function of neurons, finally resulting in their death. The most frequent ones are Parkinson’s (PD) and Alzheimer’s diseases (AD). They are genetically mediated but, the role of
environmental factors is constantly unraveled. More specifically, the place of the nutrients,
dysbiome and its metabolome, luminal enzymatic modification of naïve proteins, increased
permeability and the resulting leaky gut is gaining knowledge [2,3]. In parallel, brain–
gluten cross-reactive antibodies and peptides’ sequences identity between gliadin peptides
and cerebral antigens are constantly reported. Hence, strengthening the autoimmune
processes of molecular mimicry in neurodegenerative conditions [4]. In this regard, the
present narrative review describes the potential detrimental effects of gluten ingestion on
neurodegenerative disease evolvement.
The first part of this review addresses the relationship between gluten and neurodegenerative diseases, while the second part screen the cross-reactivity and the sequence homology between gluten peptides and human central nervous systems’ antigens. The literature
search covered the period 2000–2020 and included studies that describe gluten/gliadin association with neurodegenerative disorders. Research studies, reviews, and case–control series were included, while case reports were excluded. The literature search was performed
Cells 2021, 10, 756. https://doi.org/10.3390/cells10040756 https://www.mdpi.com/journal/cellsCells 2021, 10, 756 2 of 18
using the PubMed, MEDLINE, Embase, Scopus, and Cochrane Database of Systematic Reviews databases to identify the most relevant information. The following search keywords
were used “gluten” or “gliadin” AND “Neurodegenerative” or “neuroinflammatory” or
“neuropsychiatric” AND “Alzheimer disease” or “Parkinson’s disease” or Amyotrophic
Lateral Sclerosis, and Multiple Sclerosis, were searched. Additional studies were identified by examining the reference list of the retrieved articles. The search was limited to
articles published in English. Relevant articles were selected for full-text review on the
basis of screened titles and abstracts. Since primary and personal data were not included,
human rights approval was not necessary. Sequence homologies between related human
brain antigens and Gluten/Gliadin peptides were explored. The UniProt Knowledgebase
(www.uniprot.org/, accessed on 15 December 2020) was used to extract α/β-Gliadin MM1,
(UniProt: P18573). The NIH/US National Library of Medicine’s Basic Local Alignment
Search Tool (BLAST) sequence matching program, (blast.ncbi.nlm.nih.gov/Blast.cgi, accessed on 24 December 2020) was used to identify sequence homology between Gliadin
epitopes and central nervous system (CNS) antigenic sequences. The Immune Epitope
Database (www.iedb.org, accessed on 21 March 2021) was searched to extract all human
antigens epitopes that are implicated in central neuronal diseases. This included Alzheimer
disease, Parkinson’s Disease, Amyotrophic Lateral Sclerosis, and Multiple Sclerosis. The
aggregated epitopes were “Linear Epitopes” of “B cells” OR “HLA I” OR “HLA II” AND
were rated as “Positive Assays”. In addition, neuronal epitopes that were found in the
literature search to have cross reactivity or sequence homology with Gliadin, were included
in this epitopes list [5–11]. Following this, a pairwise local alignment tool was used, EMBOSS Matcher (www.ebi.ac.uk/Tools/psa/emboss_matcher/, accessed on 4 October 2019).
This tool implements an algorithm that is based on the Bill Pearson’s Lalign application,
version 2.0u4 (February 1996). Using a Python script, the EMBOSS Matcher was executed
on each of the neuronal epitopes against the Gliadin sequence and the following cutoff
parameters were used to express the results: peptide length ≥ amino acids, similarity
≥50% and identity ≥50%.
2. Gluten and Tissue Transglutaminase Potential Involvement in Neurodegeneration
The world market of wheat surpasses all other crops combined and gluten is its
major protein, comprising 80% of the wheat’s proteins. It is the most favored staple
food worldwide and a major food additive in the processed food industries [12]. Gluten
essentiality, its protein’s quality and consumption necessity for human health is debatable.
However, there is no doubt regarding its inductive role in gluten dependent disease like
celiac disease (CD), dermatitis herpetiformis, gluten ataxia, gluten allergy, and potentially
in non-celiac wheat sensitivity [13,14].
The two most frequent conditions are non-celiac wheat sensitivity and CD with
incidences of 1–6% and 1–1.5%, respectively. Dermatitis herpetiformis, gluten allergy and
gluten ataxia are much less frequent with an prevalence of 1:10,000, 0.2–0.5%, and very
rare, respectively [15].
Its potential role in extraintestinal manifestation of CD and remote organs’ pathologies
is well reported [16,17]. In addition, its place in the enteric eco-events in the trajectory
of the gut-brain axis was recently described [18]. After ingestion, gluten is digested by
luminal proteases to various gliadin peptides which are the offending molecules in the
gluten-related diseases [19]
Most recently, gluten’s potential role in neurodegeneration was suggested by Mohan et al. [20]. The authors comprehensibly described and suggested that dysregulated
microbiome, anti-tissue transglutaminase (tTG) 6 in celiac ataxia, various gut derived
biomolecular condensates or extracellular microbial vesicles might play parts in neurodegenerative evolvement. Furthermore, the authors alluded to various therapeutical
strategies to prevent or treat those brain conditions. Not only gluten withdrawal, but probiotics, and some nutraceuticals, such as phyto and synthetic cannabinoids, were suggested
to mitigate dietary gluten-induced neurodegeneration [20]. The clinical basis for gluten as-Cells 2021, 10, 756 3 of 18
sociated CNS diseases comes from the numerous neurological, psychiatric and behavioral
manifestations, extensively describes in gluten induced conditions in Table 1 [16,21–30].
in several gluten dependent diseases and lately was suggested to play a role in non-celiac autoimmune
diseases. Its involvement in neurodegenerative conditions was recently suggested but no cause-andeffect relationship were established. The present narrative review expands on various aspects of the
gluten-gut-brain axes events, mechanisms and pathways that connect wheat and gluten consumption
to neurodegenerative disease. Gluten induced dysbiosis, increased intestinal permeabillity, enteric
and systemic side effects, cross-reactive antibodies, and the sequence of homologies between brain
antigens and gluten are highlighted. This combination may suggest molecular mimicry, alluding
to some autoimmune aspects between gluten and neurodegenerative disease. The proverb of
Hippocrates coined in 400 BC, “let food be thy medicine,” is critically discussed in the frame of gluten
and potential neurodegeneration evolvement.
Keywords: gluten; nutrients; intestine; brain; neurodegeneration; gut-brain axis; cross-reactivity;
sequence homology; BLAST
1. Introduction
The gut–brain axes connote a very complex and a challenging topic that tries to decipher the cross-talks between the two extrema, hence functionally dependent compartments.For decades, the brain dominated the arena. However, the increased knowledge on gut
performances, mucosal and luminal eco-events, and immune surveyance and regulation
have flipped the dogma [1]. It appears that one can’t without the other. Facing the environment, the primary immune function of the intestine is to induce tolerance and to negate
the non-self for a long-term homeostasis.
Neurodegenerative diseases are characterized by the progressive loss of structure or
function of neurons, finally resulting in their death. The most frequent ones are Parkinson’s (PD) and Alzheimer’s diseases (AD). They are genetically mediated but, the role of
environmental factors is constantly unraveled. More specifically, the place of the nutrients,
dysbiome and its metabolome, luminal enzymatic modification of naïve proteins, increased
permeability and the resulting leaky gut is gaining knowledge [2,3]. In parallel, brain–
gluten cross-reactive antibodies and peptides’ sequences identity between gliadin peptides
and cerebral antigens are constantly reported. Hence, strengthening the autoimmune
processes of molecular mimicry in neurodegenerative conditions [4]. In this regard, the
present narrative review describes the potential detrimental effects of gluten ingestion on
neurodegenerative disease evolvement.
The first part of this review addresses the relationship between gluten and neurodegenerative diseases, while the second part screen the cross-reactivity and the sequence homology between gluten peptides and human central nervous systems’ antigens. The literature
search covered the period 2000–2020 and included studies that describe gluten/gliadin association with neurodegenerative disorders. Research studies, reviews, and case–control series were included, while case reports were excluded. The literature search was performed
Cells 2021, 10, 756. https://doi.org/10.3390/cells10040756 https://www.mdpi.com/journal/cellsCells 2021, 10, 756 2 of 18
using the PubMed, MEDLINE, Embase, Scopus, and Cochrane Database of Systematic Reviews databases to identify the most relevant information. The following search keywords
were used “gluten” or “gliadin” AND “Neurodegenerative” or “neuroinflammatory” or
“neuropsychiatric” AND “Alzheimer disease” or “Parkinson’s disease” or Amyotrophic
Lateral Sclerosis, and Multiple Sclerosis, were searched. Additional studies were identified by examining the reference list of the retrieved articles. The search was limited to
articles published in English. Relevant articles were selected for full-text review on the
basis of screened titles and abstracts. Since primary and personal data were not included,
human rights approval was not necessary. Sequence homologies between related human
brain antigens and Gluten/Gliadin peptides were explored. The UniProt Knowledgebase
(www.uniprot.org/, accessed on 15 December 2020) was used to extract α/β-Gliadin MM1,
(UniProt: P18573). The NIH/US National Library of Medicine’s Basic Local Alignment
Search Tool (BLAST) sequence matching program, (blast.ncbi.nlm.nih.gov/Blast.cgi, accessed on 24 December 2020) was used to identify sequence homology between Gliadin
epitopes and central nervous system (CNS) antigenic sequences. The Immune Epitope
Database (www.iedb.org, accessed on 21 March 2021) was searched to extract all human
antigens epitopes that are implicated in central neuronal diseases. This included Alzheimer
disease, Parkinson’s Disease, Amyotrophic Lateral Sclerosis, and Multiple Sclerosis. The
aggregated epitopes were “Linear Epitopes” of “B cells” OR “HLA I” OR “HLA II” AND
were rated as “Positive Assays”. In addition, neuronal epitopes that were found in the
literature search to have cross reactivity or sequence homology with Gliadin, were included
in this epitopes list [5–11]. Following this, a pairwise local alignment tool was used, EMBOSS Matcher (www.ebi.ac.uk/Tools/psa/emboss_matcher/, accessed on 4 October 2019).
This tool implements an algorithm that is based on the Bill Pearson’s Lalign application,
version 2.0u4 (February 1996). Using a Python script, the EMBOSS Matcher was executed
on each of the neuronal epitopes against the Gliadin sequence and the following cutoff
parameters were used to express the results: peptide length ≥ amino acids, similarity
≥50% and identity ≥50%.
2. Gluten and Tissue Transglutaminase Potential Involvement in Neurodegeneration
The world market of wheat surpasses all other crops combined and gluten is its
major protein, comprising 80% of the wheat’s proteins. It is the most favored staple
food worldwide and a major food additive in the processed food industries [12]. Gluten
essentiality, its protein’s quality and consumption necessity for human health is debatable.
However, there is no doubt regarding its inductive role in gluten dependent disease like
celiac disease (CD), dermatitis herpetiformis, gluten ataxia, gluten allergy, and potentially
in non-celiac wheat sensitivity [13,14].
The two most frequent conditions are non-celiac wheat sensitivity and CD with
incidences of 1–6% and 1–1.5%, respectively. Dermatitis herpetiformis, gluten allergy and
gluten ataxia are much less frequent with an prevalence of 1:10,000, 0.2–0.5%, and very
rare, respectively [15].
Its potential role in extraintestinal manifestation of CD and remote organs’ pathologies
is well reported [16,17]. In addition, its place in the enteric eco-events in the trajectory
of the gut-brain axis was recently described [18]. After ingestion, gluten is digested by
luminal proteases to various gliadin peptides which are the offending molecules in the
gluten-related diseases [19]
Most recently, gluten’s potential role in neurodegeneration was suggested by Mohan et al. [20]. The authors comprehensibly described and suggested that dysregulated
microbiome, anti-tissue transglutaminase (tTG) 6 in celiac ataxia, various gut derived
biomolecular condensates or extracellular microbial vesicles might play parts in neurodegenerative evolvement. Furthermore, the authors alluded to various therapeutical
strategies to prevent or treat those brain conditions. Not only gluten withdrawal, but probiotics, and some nutraceuticals, such as phyto and synthetic cannabinoids, were suggested
to mitigate dietary gluten-induced neurodegeneration [20]. The clinical basis for gluten as-Cells 2021, 10, 756 3 of 18
sociated CNS diseases comes from the numerous neurological, psychiatric and behavioral
manifestations, extensively describes in gluten induced conditions in Table 1 [16,21–30].
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