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COMPETITION FOR VITAMIN B
1
(THIAMIN) STRUCTURES
NUMEROUS ECOLOGICAL INTERACTIONS
Clifford E. Kraft
Department of Natural Resources, Cornell University
Ithaca, New York 14853 USA
e-mail: cek7@cornell.edu
Esther R. Angert
Department of Microbiology, Cornell University
Ithaca, New York 14853 USA
e-mail: era23@cornell.edu
keywords
thiamin, ecological competition, biochemistry, animal mortality,
ocean productivity, pathogenicity
abstract
Thiamin (vitamin B
1
) is a cofactor required for essential biochemical reactions in all living organ-
isms, yet free thiamin is scarce in the environment. The diversity of biochemical pathways involved
in the acquisition, degradation, and synthesis of thiamin indicates that organisms have evolved numer-
ous ecological strategies for meeting this nutritional requirement. In this review we synthesize informa-
tion from multiple disciplines to show how the complex biochemistry of thiamin influences ecological
outcomes of interactions between organisms in environments ranging from the open ocean and the Aus-
tralian outback to the gastrointestinal tract of animals. We highlight population and ecosystem re-
sponses to the availability or absence of thiamin. These include widespread mortality of fishes,birds,and
mammals, as well as the thiamin-dependent regulation of ocean productivity. Overall, we portray thiamin
biochemistry as the foundation for molecularly mediated ecological interactions that influence survival and
abundance of a vast array of organisms.
Introduction
ALTHOUGH vitamin B
1
(thiamin) was
identified more than a century ago for
its importance in maintaining human and
domestic animal health, little attention has
been paid to this vitamin’s potential role in
structuring ecological interactions in natural
environments. The diversity of approaches
used by organisms to produce, degrade, and
salvage components of thiamin points to
The Quarterly Review of Biology, June 2017, Vol. 92, No. 2
Copyright © 2017 by The University of Chicago Press. All rights reserved.
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Volume 92, No. 2June 2017THE QUARTERLY REVIEW OF BIOLOGY
151
strong selection to obtain this vitamin, often
at the expense of competitors or hosts. Clues
to the ecological importance of thiamin in
nature are disparate and have defied ready
interpretation for decades, yet we present
them here in an attempt to foster a better
understanding of an expansive biological
topic that is ripe for new insights.
The ecological importance of thiamin has
become evident from two different perspec-
tives that point in a common direction: first,
studies of domesticated and wild animals that
die from thiamin deficiency (Edwin and Jack-
man 1970; Brown et al. 2005a; Balk et al.
2016) and, second, studies of bacteria and
plants that use diverse strategies to pro-
duce and acquire thiamin (Bettendorff 2007;
Gerdes et al. 2012; Fitzpatrick and Thore
2014; Sañudo-Wilhelmy et al. 2014). Tenta-
tive linkages between these perspectives have
been proposed for years, but they have not
been tied together in a broad ecological
context. We begin this review by describing
unique features of thiamin biochemistry that
are fundamental to its ecological importance.
We then review large-scale animal die-offs
that initially brought thiamin to the attention
of researchers in the 1940s. Throughout this
review, we highlight ongoing developments
in analytical chemistry and genomics that
continue to illuminate the central influence
of thiamin in molecularly mediated interac-
tions among diverse organisms.
The Biochemistry of Thiamin
in an Ecological Context
Thiamin is a cofactor required for key met-
abolic pathways in all living things ( Jurgen-
son et al. 2009). Thiamin diphosphate (TDP,
also known as thiamin pyrophosphate or
TPP) is the active form of this vitamin re-
quired for crucial reactions in both anabolic
and catabolic intermediary metabolism, in-
cluding the pentose phosphate pathway and
the citric acid cycle (Figure 1). Although the
enzymes that bind TDP share little primary
sequence similarity except for a few residues
that accommodate thiamin and its activa-
tion, multiple lines of evidence suggest that
the thiamin cofactor was present at the ear-
liest stages of the evolution of life (Frank
et al. 2007; Monteverde et al. 2017). Thia-
min’s long history as an essential organic
cofactor underlies the potential for strong
selection to evolve numerous ecological out-
comes associated with its acquisition and use.
Free thiamin is scarce in the environment
and is only available at extremely low (pi-
comolar) concentrations in seawater and
freshwater (Table 1). Changes in ambient pH
have a substantial effect on thiamin, which
degrades at pH >7 (Maier and Metzler 1957;
Windheuser and Higuchi 1962). Under acidic
conditions where thiamin is stable, thiamin
is a cation with one or two positive charges.
This leads thiamin to be adsorbed on clay
mineral surfaces by ion exchange with cat-
ions under acidic conditions (pH 4–7) that
are common in soil (Schmidhalter et al.
1994). We have observed the pH-dependent
release of thiamin from a cation exchange
matrix in our efforts to concentrate thia-
min from ambient water samples using solid
phase extraction (in collaboration with K.
Edwards, unpublished data), which lends sup-
port to two prior studies that examined
thiamin availability in natural environments.
First, Moore and McLarty (1975) showed
that thiamin can be eluted from soil by filter-
ing a slurry of soil and distilled water. More
recently, Monteverde et al. (2015) showed
that thiamin concentrations in marine sedi-
ment porewater were greater than water col-
umn concentrations at the same location.
Concentrations of free thiamin within hu-
mans and other animals are low due to tight
sequestration of the vitamin and the effi-
cient recycling of available thiamin. Typical
values found in whole human blood are
70–180 nmol/L TDP (the biologically rele-
vant, active form) and 75–195 nmol/L for
total thiamin (thiamin + thiamin monophos-
phate + thiamin diphosphate; Lu and Frank
2008). Measurements of thiamin concentra-
tions from human tissues or tissues of or-
ganisms not consumed by humans are less
common in the literature (for exceptions, see
Rindi and Ferrari 1977; Tillitt et al. 2005).
The scarcity of thiamin measurements from
environmental samples and organism tissues
largely reflects that analytical methods to mea-
sure thiamin are expensive and not amen-
152 Volume 92THE QUARTERLY REVIEW OF BIOLOGY
able to high-throughput analyses (Brown et al.
1998; Okbamichael and Sañudo-Wilhelmy
2005; Edwards et al. 2017).
Many bacteria, fungi, and plants can syn-
thesize thiamin (Fitzpatrick and Thore 2014).
The synthesis of thiamin requires indepen-
dent production of thiazole and pyrimidine
precursors that are coupled to form thia-
min phosphate as the last step of thiamin
synthesis ( Jurgenson et al. 2009; Figure 2).
This dependence on key intermediates has
allowed bacteria and plants lacking a full
complement of thiamin synthesis enzymes
to develop diverse approaches to obtain
TDP, particularly when precursors can be
scavenged from the environment (Gerdes
et al. 2012; Sañudo-Wilhelmy et al. 2014).
These variable approaches indicate that
Figure 1. Metabolic Pathways Requiring Thiamin
Thiamin diphosphate (TDP) is a cofactor in several enzymes—including pyruvate dehydrogenase, a-keto-
glutarate dehydrogenase, transketolase, and branched chain a-ketoacid dehydrogenase—that are associated with
glycolysis, the pentose phosphate pathway, and the citric acid cycle. These pathways allow for the production of nic-
otinamide adenine dinucleotide phosphate (NADPH), adenosine triphosphate (ATP), and ribose-5-phosphate
permitting downstream generation of amino acids, nucleic acids, and fatty acids. Thin black arrows highlight enzy-
matic reactions that require thiamin as a primary cofactor. See the online edition for a color version of this figure.
THIAMIN INFLUENCE ON ECOLOGICAL INTERACTIONSJune 2017 153
thiamin synthesis has been shaped by dif-
ferent selection forces from environmental
conditions and interactions with other organ-
isms (Helliwell et al. 2013). This contrasts
with the relatively invariant approaches used
by eukaryotic phytoplankton to produce other
B vitamins, such as B
12
, for which the syn-
thetic pathways seldom differ among taxa
(Bertrand and Allen 2012). Helliwell et al.
(2013) conclude that dynamic interactions
between organisms have shaped divergent ap-
proaches for thiamin synthesis often found
in closely related taxa. Animals obtain thia-
min through consumption of food, with the
known exception of ruminants that absorb
thiamin released from ruminal microbes as
they are lysed during postruminal digestion
(Breves et al. 1980, 1981).
The various approaches used by bacteria,
plants, and fungi to synthesize thiamin are
complex, and this molecule has unique and
unexpected properties (Settembre et al.
2003). For example, the biosynthesis of
HMP (4-amino-2-methyl-5-hydroxymethylpy-
rimidine)—the pyrimidine component of thi-
amin—was described as “without precedent
in the biosynthetic or organic chemistry lit-
erature”by Lawhorn et al. (2004:2538). Like-
wise, Fitzpatrick and Thore (2014) reviewed
the biochemistry of thiamin synthesis in eu-
karyotes and highlighted a unique behavior
of thiamin synthesis enzymes in fungi and
plants, in which they self-destruct and can-
nibalize cellular cofactors required for other
essential biochemical reactions.
The availability and persistence of thiamin
is strongly influenced by physical and chem-
ical factors that degrade thiamin, such as
ultraviolet radiation, temperature, alkaline
conditions, and inorganic bases such as sul-
fites (Maier and Metzler 1957; Gold et al.
1966; Button 1968; Gold 1968; Boissier and
Tillement 1969; Carlucci et al. 1969). Vari-
ous degradation products of thiamin occur
in environmental matrices ( Jenkins et al.
2007), and the formation of HMP as a deg-
radation product of thiamin has been re-
ported under varying pH and temperature
conditions in laboratory experiments (Wind-
heuser and Higuchi 1962; Boissier and Til-
lement 1969). Although the degradation
products of thiamin in environmental ma-
trices are not thoroughly characterized, it
is conceivable that HMP could be formed
through similar conditions in environmen-
tal waters and soils. Thiamin is also subject
TABLE 1
Thiamin concentrations reported from environmental samples
Thiamin (pM) Location Reference
Freshwater
119-703 Lake Sagami, Japan Ohwada and Taga (1972)
222-1293 Lake Tsukui, Japan Ohwada et al. (1972)
15-59 Lake Tahoe, U.S. Carlucci and Bowes (1972)
12-316 Lake Biwa (main basin), Japan Kurata and Kadota (1981)
29-797 Lake Biwa (south basin), Japan Kurata and Kadota (1981)
12-190 Peconic River, New York, U.S. Gobler et al. (2007)
Marine
0-593 Surface waters, Southeast Alaska sea Natarajan (1968)
330-770 Marine sediment porewater, coastal California, U.S. Monteverde et al. (2015)
30-280 Marine water column profile, coastal California, U.S. Sañudo-Wilhelmy et al. (2012)
Soil
8900–29,800 nM Soil water extract Moore and McLarty (1975)
Additional results from marine waters (with similar concentrations) are presented in Monteverde et al. (2015) and Suffridge
et al. (2017).
154 Volume 92THE QUARTERLY REVIEW OF BIOLOGY
Figure 2. Thiamin Synthesis From Thiazole and Pyrimidine Precursors
Thiamin synthesis by bacteria, plants, and fungi requires independent production or acquisition of a thiazole
precursor hydroxyethylthiazole (HET) phosphate and a pyrimidine precursor 4-amino-2-methyl-5-hydroxy-
methylpyrimidine (HMP) pyrophosphate that combine to form thiamin monophosphate, which is phosphory-
lated to become the active form of the molecule that serves as the cofactor thiamin pyrophosphate (TDP). See
the online edition for a color version of this figure.
THIAMIN INFLUENCE ON ECOLOGICAL INTERACTIONSJune 2017 155
to biological degradation, as was first recog-
nized in bacteria producing two distinct thi-
amin-degrading enzymes (thiaminase I and
II) that replace the thiazole moiety of intact
thiamin with different nucleophiles (Kimura
1965; Murata 1965; Figure 3).
We suggest that the physical and bio-
logical degradation of thiamin has several
important consequences for ecological inter-
actions. First, it exacerbates the scarcity of
thiamin in natural environments. Second,
the degradation of thiamin can increase the
availability of its two primary constituents or
their analogues; some bacteria, plants, and
fungi have enzymes that can salvage these
compounds for use in synthesizing thiamin,
providing a selectable advantage over those
organisms that have to synthesize thiamin
from more fundamental components. Third,
some degradation products of thiamin are
toxic analogues that inhibit enzymatic reac-
tions for which thiamin is a required cofac-
tor ( James 1980; Sudarsan et al. 2005).
Because vitamin B
1
is required in small
quantities, the import or salvage of compo-
nents required for thiamin synthesis is a
suitable option for thiamin auxotrophs that
circumvent implementation of a complete
thiamin synthesis pathway (Croft et al. 2006;
Zallot et al. 2014). Vitamin auxotrophy is
defined as a condition in which organisms
requireanexternalsourceoftheseessen-
tial molecules, but some organisms previ-
ously characterized as thiamin auxotrophs
are now known to have incomplete synthe-
sis pathways that allow them to make thia-
min from precursors such as HMP.
According to the Black Queen Hypothesis
presented by Morris et al. (2012), the evo-
lutionary loss of costly genes required to
produce thiamin would be expected to occur
in circumstances in which an organism could
obtain this vitamin or its precursors through
other mechanisms. The complexity of phy-
toplankton and bacterial genomes is be-
ginning to reveal what now appear to be a
dazzling array of ecological strategies used by
these organisms to obtain essential organic
compounds, such as thiamin (Worden et al.
2015). The most thoroughly documented
examples of auxotrophy for a thiamin pre-
cursor have been shown in microbes that re-
quire HMP, the end product of one of the
two independent branches of the thiamin
biosynthetic pathway (Figure 2); these HMP
auxotrophs include the malaria-causing pro-
tist Plasmodium falciparum and the human
pathogen Listeria monocytogenes (Wrenger
et al. 2006; Schauer et al. 2009). A similar
reliance upon acquisition of HMP from the
environment has been documented in the
abundant SAR11 clade of marine chemo-
heterotrophic bacteria that cannot use ex-
ogenous thiamin and instead are HMP
auxotrophs (Carini et al. 2014). These au-
thors observed diel changes in HMP concen-
trations in open ocean waters and confirmed
that several marine bacteria exude HMP in
batch culture, indicating that HMP auxo-
trophs have a ready supply of HMP in ma-
rine waters (Carini et al. 2014). Another
example of a thiamin salvage pathway tar-
geting HMP was provided in a study showing
that enzymes in the TenA protein family are
used by soil bacteria (Bacillus halodurans)to
hydrolyze base-degraded thiamin taken up
from the environment, thereby releasing
HMP that is subsequently used in thiamin
synthesis ( Jenkins et al. 2007). TenA en-
zymes are commonly found in prokaryotes,
plants, and fungi, and were originally de-
scribed as the thiamin-degrading enzyme,
thiaminase II (Murata 1965). However, fol-
lowing the description of their role in thia-
Figure 3. Thiamin is Degraded by Thiaminase I an d Thiaminase II Into Pyrimidine and Thiazole
Components
156 Volume 92THE QUARTERLY REVIEW OF BIOLOGY
min salvage by Jenkins et al. (2007), similar
examples have been reported from other
organisms (Zallot et al. 2014).
Several early laboratory culture studies also
indicated that in the absence of thiamin, phy-
toplankton can use either the thiazole or
pyrimidine moieties from the environment
to satisfy a thiamin requirement (Droop
1958; Provasoli and Carlucci 1974). Other
studies of bacteria suggested that thiamin
degradation products are used in thiamin
synthesis (Douthit and Airth 1966; Wang
et al. 1968). More recently, studies using ge-
nomic techniques have revealed prolificand
unrecognized alternatives to the prevailing
understanding of thiamin synthesis pathways
(Bettendorff 2007; Gerdes et al. 2012; Fitz-
patrick and Thore 2014; Sañudo-Wilhelmy
et al. 2014). Overall, the complicated chem-
istry and variety of ecological strategies used
by microorganisms to obtain thiamin precur-
sors reflects the presence of conditions that
foster competition for thiamin, thiamin pre-
cursors, and thiamin degradation products.
The presence of numerous thiamin-sen-
sitive riboswitches in a variety of marine phy-
toplankton incapable of thiamin synthesis
indicates the presence of strong selection
pressures to efficiently acquire thiamin and
thiamin precursors in ocean environments
where thiamin is scarce (McRose et al. 2014).
Riboswitches are short sequences within
mRNA that regulate translation according
to substrate availability. One of the first dis-
covered and the most numerous class of ri-
boswitches is the thiamin pyrophosphate (TPP)
riboswitch that regulates thiamin produc-
tion by shutting down the production of thi-
amin synthesis enzymes in the presence of
TPP (Mironov et al. 2002; Winkler et al.
2002; Breaker 2011). The discovery that ri-
boswitches control numerous thiamin-respon-
sive genes in marine phytoplankton indicates
that the presence of thiamin regulates many
aspects of primary production in marine eco-
systems (McRose et al. 2014; Sañudo-Wilhelmy
et al. 2014). Moulin et al. (2013) similarly
reported finding numerous thiamin ribo-
switches in bacteria and plants controlling
the synthesis of genes with varied functions.
In the freshwater green alga (Chlamydomonas
reinhardtii), riboswitches independently con-
trol synthesis of the pyrimidine and thiazole
moieties of thiamin, indicating that synthe-
sis is regulated by the varying availability
of these components in the external envi-
ronment (Moulin et al. 2013). A review of
bacteria-diatom interactions indicates that
bacteria can sense compounds produced by
diatoms, leading to acquisition of diatom-
specific products and also opening up the
possibility that bacteria can exploit diatoms
by causing cell stress or lysis (Amin et al.
2012). Paerl et al. (2015) found that some
thiamin auxotrophic marine phytoplankton
have unusually high cell quotas of this vi-
tamin, which would make them particularly
desirable prey for zooplankton. Sañudo-Wil-
helmy et al. (2012) showed that the vertical
distributions of B vitamins at different ocean
locations were site-specific and independent
of each other, suggesting that biological pro-
cesses (i.e., synthesis, uptake, excretion) were
as important as physical processes in deter-
mining B vitamin concentrations in ocean
waters.
Although it is tempting to draw analogies
between processes found in aquatic primary
producers and vascular plants in terrestrial
environments, the available literature pro-
vides few clear insights about thiamin-medi-
ated ecological interactions in land plants.
Still, the absence of thiamin synthesis en-
zymes and the presence of salvage enzymes
for the pyrimidine and thiazole moieties of
thiamin in the model plants Arabidopsis and
maize (Gerdes et al. 2012) indicates that land
plants may acquire thiamin through complex
strategies similar to those found in marine
primary producers. In addition, the incon-
sistent enhancement of horticultural plant
growth by thiamin observed in extensive
studies in the 1930s and 1940s (Rasmussen
1999) suggests that complex biochemical in-
teractions, not discernible at that time, were
responsible for these variable results.
Toxicity and Pathogenecity
Associated With Thiamin
An additional interesting and complicating
part of the story of the ecological impor-
tance of thiamin is its potential for facilitat-
ing toxic or pathogenic conditions, which
THIAMIN INFLUENCE ON ECOLOGICAL INTERACTIONSJune 2017 157
stems directly from the chemical structure
of this vitamin. For example, the produc-
tion and external release of toxic thiamin
antagonists could be used by organisms to
overwhelm competitors that are thiamin
auxotrophs. Several synthetic thiamin ana-
logues or fragments have been developed
that are toxic to microorganisms under lab-
oratory conditions. For example, early lab-
oratory experiments with pyrithiamine, a
synthetic analogue of thiamin with substi-
tution of the thiazole ring with a similarly
functionalized pyridine ring, demonstrated
its toxicity to fungi and bacteria through
binding thiamin pyrophosphate riboswitches
(Robbins 1941; Woolley and White 1943a,b;
Sudarsan et al. 2005). Amprolium, base-sub-
stituted thiamin with a methylated pyridine
derivative, blocks the transporter responsi-
ble for the uptake of thiamin and hence is
toxic to certain coccidia protozoa, includ-
ing Eimeria species ( James 1980). In natural
environments thiamin analogues may be pre-
sent that have similar toxic effects on compet-
itors and host organisms. The only known
naturally produced toxic thiamin analogue
is 20-methoxy-thiamin-pyrophosphate, which
is produced by bacteria that convert a py-
rimidine analogue called bacimethrin (Ni-
shimura and Tanaka 1963; Reddick et al.
2001). Bacimethrin is produced by a synthetic
pathway in the pathogenic bacterium Clos-
tridium botulinum (Cooper et al. 2014), al-
though its ecological context has not been
explored. The thiamin precursor HMP has
also been characterized as toxic to rats
(Haughton and King 1958), which is consis-
tent with the observation by Garavito et al.
(2015) that in some contexts pyrimidine anti-
metabolites can disrupt biochemical path-
ways. Together, the reported toxicity of
bacimethrin and HMP support the possibil-
ity that organisms produce extracellular thi-
amin degradation products (e.g., pyrimidine
analogues) as a strategy to interfere with thi-
amin utilization by competitors.
In a review of repair mechanisms used by
organisms to eliminate damaged metabo-
lites, Linster et al. (2013) noted that half of
the known metabolite repair systems act on
highly reactive coenzymes such as thiamin.
Another study by this research group identi-
fied a Nudix enzyme that renders harmless
what they refer to as “damaged”forms of
thiamin (Goyer et al. 2013). These authors
did not consider the origin of these damaged
thiamin analogues, although the produc-
tion of bacimethrin by a bacterial pathogen
suggests that repair or disposal of thiamin
analogues could be useful in an ecological
context in which thiamin analogues are pro-
duced by organisms to enhance their path-
ogenicity. Overall, the widespread presence
of metabolite repair mechanisms supports
the idea that toxic byproducts of thiamin
and thiamin precursors exert strong natural
selection on organisms.
Microbial depletion of externally avail-
able thiamin could also foster pathogenicity
by competing with hosts for thiamin. This
could be similar to interactions described
by Schaible and Kaufmann (2004) who ob-
served that pathogenic bacteria often re-
quire iron as a growth factor and compete
with host organisms for this element. Thia-
min is involved in the regulation and acti-
vation of immune cells and proteins within
the immune system (Manzetti et al. 2014);
therefore, the tandem strategy of blocking
thiamin-dependent pathways with thiamin
analogues and thiamin depletion could en-
able bacteria to compromise host immune
defenses. This might explain the presence
of the extracellular thiamin-degrading en-
zyme known as thiaminase I in the operon
that produces bacimethrin, suggesting that
these bacteria have a coordinated strategy
of removing thiamin from their external en-
vironment in host organisms while produc-
ing an extracellular toxic thiamin analogue
(Cooper et al. 2014).
Further evidence indicating that thiamin
removal is associated with pathogenicity is
provided by three bacterial groups capa-
ble of producing thiaminase I, all of which
include closely related pathogenic and non-
pathogenic strains (Table 2). This is consis-
tent with the observation by Dethlefsen et al.
(2007) that all bacterial pathogens of hu-
mans have congeners that are part of the nor-
mal microbiota. For example, people living
in Southeast Asia develop a disease known
158 Volume 92THE QUARTERLY REVIEW OF BIOLOGY
as melioidosis following infection with the
thiaminase I-producing bacterium Burkholde-
ria pseudomallei, whereas the closely related
B. thailandensis does not cause human dis-
ease but has been considered a pathogen
of insects (Fisher et al. 2012; Pilátová and
Dionne 2012). Propst et al. (2010) showed
that a DpurM mutant of B. pseudomallei ren-
dered incapable of thiamin biosynthesis was
avirulent in a mouse model. This is consis-
tent with the hypothesis that B. pseudomallei
thrives in a thiamin-depleted environment
within its host, simultaneously degrading the
host immune system while outcompeting
bacteria that require thiamin.
A similar pairing of pathogenic and non-
pathogenic congeners occurs in the only
group of eukaryotes (phylum Percolozoa)
known to contain a gene for thiaminase I,
the unicellular protozoans Naegleria fowleri
(pathogenic) and N. gruberi (nonpathogenic;
Kreinbring et al. 2014). Clostridium sporogenes
is another thiaminase I-producing bacterium
commonly found in sheep and human gas-
trointestinal tracts that has been generally
considered benign, although strains of its
close relative C. botulinum (also a thiaminase I
producer) are pathogenic to many organ-
isms (Hatheway 1990). Paenibacillus,another
bacterial genus with a thiaminase I consid-
ered responsible for Laurentian Great Lakes
fish mortality (Honeyfield et al. 2002), also
includes many insect pathogens (Gardener
2004), and we have completed experiments
with several thiaminase I-containing Paeni-
bacillus strains demonstrating that these bac-
teria are pathogenic to Drosophila (unpub-
lished data).
The potential role of thiamin depletion
in fostering pathogenicity receives additional
support from the observation that most harm-
ful algal bloom (HAB) organisms are vita-
min B
1
and B
12
auxotrophs (Tang et al. 2010).
In a review of the biogeochemistry of B vi-
tamins in marine waters, Sañudo-Wilhelmy
et al. (2014) provided evidence that B vita-
min availability determines phytoplankton
species composition and biomass production
in some areas of the ocean. These authors
also observed that the removal and release
of essential B vitamins favors algae that uti-
lize B vitamins released during algal bloom
conditions (Sañudo-Wilhelmy et al. 2014).
Harmful algal blooms may therefore be pro-
duced by organisms capable of using the
thiamin released when their toxins kill other
organisms.
Animal Mortality From
Thiamin Deficiency
The importance of thiamin limitation in
nature has been particularly evident in stud-
ies from the past 25 years that have shown a
substantial influence of thiamin deficiency
on mortality in populations of wild animals.
For several decades the literature associat-
ing thiamin deficiency with animal mortal-
ity focused on domesticated animals such
as chickens, sheep, cattle, and other rumi-
nant mammals (Shintani 1956; Edwin and
Jackman 1970; Thomas et al. 1987; Ramos
et al. 2003) rather than free-living organ-
isms in natural environments. This changed
in the 1990s when thiamin deficiency was
shown to be responsible for the large-scale
mortality of fish populations in both the
Laurentian Great Lakes and the Baltic Sea
(Brown et al. 2005a); it is these observations
that prompted our interest in this topic.
Animal mortality from thiamin deficiency
was first recognized during the 1940s in mink
and foxes raised for fur production (Green
and Evans 1940; Stout et al. 1963), after which
a similar mortality syndrome was found in
free-ranging cattle, sheep, and goats (Edwin
and Jackman 1970; Thomas et al. 1987; Ra-
TABLE 2
Confirmed thiaminase I producers and closely
related human pathogens containing gene sequences
that are nearly identical to thiaminase I
Confirmed
thiaminase I
producers
Nearly identical
sequence similarity in
closely related pathogens
Burkholderia thailandensis Burkholderia pseudomallei
Clostridium sporogenes Clostridium botulinum
Naegleria gruberi Naegleria fowleri
Paenibacillus apiarius
P. thiaminolyticus
P. dendritiformis
THIAMIN INFLUENCE ON ECOLOGICAL INTERACTIONSJune 2017 159
mos et al. 2003). Large die-offs from what
can be symptomatically interpreted as thiamin
deficiency were also reported from Austra-
lian sheep, cattle, goats, and horses as early
as 1911 (Henry and Massey 1911), prior to
the recognition that vitamin B
1
—or any vi-
tamin—was essential to life processes. In fact,
animal mortality from thiamin deficiency
was the source of insight for understanding
the importance of vitamin B
1
as described in
a presentation at the 1929 Nobel Prize award
ceremony honoring Christiaan Eijkman, who
recognized the similarity between beriberi
(human thiamin deficiency) and a similar
syndrome in chickens.
The extensive literature reporting sheep
mortality from thiamin deficiency has fo-
cused on the consumption of specific plants
as a causal factor for the resulting polioen-
cephalomalacia, primarily focusing upon the
presence of thiaminases in these plants and
in sheep fecal material (Evans et al. 1975;
Linklater et al. 1977; Edwin and Jackman
1981; Candau and Massengo 1982; Thomas
1986; Ramos et al. 2005). Some sheep mor-
tality events have been massive, such as a re-
port by Pritchard et al. (1978) describing
the death of 2220 sheep in the Gwydir basin
of Australia after grazing upon water ferns
(Marsilea sp.) that contained thiaminase I
(McCleary and Chick 1977). The veterinary
literature is replete with examples of sheep
mortality from thiamin deficiency, yet this
literature has largely focused on the efficacy
of thiamin injections to alleviate this prob-
lem (e.g., Bourke et al. 2003; Ramos et al.
2005), not the ecological significance of such
events.
Thiamin deficiencies in wild populations
of predatory fish were first recognized in the
1990s as responsible for a widespread mor-
tality syndrome observed for decades in valu-
able Baltic Sea and Laurentian Great Lakes
fisheries (Fisher et al. 1995). However, the
cause of this thiamin deficiency remains un-
known. The mortality syndrome was recog-
nized in the 1960s and 1970s by managers
of Laurentian Great Lakes fisheries who ob-
served extensive hatchery mortality of newly
hatched Pacific salmon raised from eggs col-
lected from wild fish. This was referred to as
“early mortality syndrome”(McDonald et al.
1998) at the same time that a similar embry-
onic mortality syndrome was observed in Bal-
tic Sea hatcheries rearing Atlantic salmon
(Salmo salar) and sea-run brown trout (Salmo
trutta; Hansson et al. 2001). In both the Bal-
tic Sea and Laurentian Great Lakes, salmo-
nine fish mortality was regularly observed
in recently hatched offspring of wild fish
captured in spawning tributaries (McDonald
et al. 1998). Twenty years passed before the
similarity between these syndromes was rec-
ognized and confirmed as resulting from thi-
amin deficiency (Fisher et al. 1995).
More recent studies have demonstrated
that the thiamin deficiency observed in pred-
atory salmonine fishes is caused by the pres-
ence of high levels of thiaminase I in their
prey (Brown et al. 2005b; Honeyfield et al.
2005a). Yet the source of and conditions re-
sponsible for large amounts of thiaminase I
in certain fishes remain uncertain. High
levels of thiaminase I activity have been rou-
tinely observed in clupeid fishes—includ-
ing alewife (Alosa pseudoharengus), gizzard
shad (Dorosoma cepedianum), and Baltic her-
ring (Clupea harengus; Wistbacka et al. 2002;
Tillitt et al. 2005)—but mortality from thia-
min deficiency has not been reported from
these clupeids. Instead, mortality has been
observed in early life stages (i.e., shortly af-
ter hatching) of predators feeding on these
forage fish. For example, sac-fry mortality
in Atlantic salmon (Norrgren et al. 1993;
Bengtsson et al. 1999) and sea-run brown
trout (Landergren et al. 1999) in the Baltic
Sea has been linked to consumption of clu-
peid prey containing thiaminase I. A similar
type of mortality in sac fry of North Ameri-
can lake trout has been documented (Hon-
eyfield et al. 2005b). Fish hatchery managers
have developed a practice similar to that
used by veterinarians to address sheep mor-
tality: by adding thiamin to hatchery water
systems, they increase thiamin levels in sal-
monine eggs that otherwise exhibit thiamin
deficiency and thereby eliminate sac-fry mor-
tality (Koski et al. 1999; Wooster et al. 2000;
Brown et al. 2005a).
Additional studies have documented thi-
amin deficiency as a cause of mortality in
160 Volume 92THE QUARTERLY REVIEW OF BIOLOGY
nondomesticated animals consuming fish
prey with high thiaminase I levels, such as
wild alligators (Honeyfield et al. 2008) and
captive marine mammals. Thiamin deficiency
in marine mammals was first reported for a
captive gray seal (Halichoerus grypus) fed smelt
(Osmerus mordax; Myers 1955). This was fol-
lowed by reports of thiamin deficiency in
captive California sea lions (Zalophus califor-
nianus; Rigdon and Drager 1955) and bottle-
nosed dolphin (Tursiops truncatus) maintained
on fish diet (White 1970) and captive har-
bor seals fed a diet including Baltic herring
(a clupeid fish) and smelt (Wohlsein et al.
2003). More recently, mortality from thiamin
deficiency was reported in captive harbor
seals fed fish with high levels of thiaminase I
(Croft et al. 2013).
Bird mortality from thiamin deficiency has
been reported from captive herring gulls fed
an exclusive diet of alewife from Lake Mich-
igan (Friend and Trainer 1969). Bartoli et al.
(1997) also reported that young yellow-leg-
ged gulls raised from eggs in captivity died
within one week of hatching when fed an
exclusive diet of unspecified fish. Balk et al.
(2009) described thiamin deficiency as the
cause of large-scale declines of three abun-
dant European bird species living near the
Baltic Sea (herring gulls, starlings, and com-
mon eider). Although these authors did not
link this mortality to fish consumption by
their study bird populations, this and other
work by this research group (Balk et al. 2016)
has expanded recognition of the potential
large-scale ecological influence of thiamin
deficiency upon a broader range of wild an-
imal populations.
Balk et al. (2009) have provided the best
evidence that mortality of wild animal pop-
ulations from thiamin deficiency had in-
creased through time. By contrast, fisheries
mortality associated with thiamin deficiency
was recognized almost simultaneously in the
1960s and 1970s by managers of Lauren-
tian Great Lakes and Baltic Sea fisheries, but
earlier problems of this nature could have
gone unnoticed. A unique, 30-year record of
coho salmon mortality in a Michigan hatch-
ery shows a variable and vaguely increasing
trend, but this trend was not suitable for sta-
tistical analysis (Brown et al. 2005a). The
question of whether wild animal mortality
from thiamin deficiency has increased in re-
cent decades therefore likely remains unan-
swerable unless future research identifies an-
thropogenic causes that have contributed
to increased mortality.
Human Thiamin Deficiency From
Consuming Wild Organisms
Human morbidity resulting from thiamin
deficiency in the 19th century prompted
subsequent research showing that changes
in prevailing diets and food processing ex-
acerbated thiamin deficiency, which was
then largely alleviated by enriching human
food sources with added thiamin (Williams
1961). Vitamin B deficiencies were first rec-
ognized in humans relying upon diets with
little available thiamin, but studies of hu-
man microbial endosymbionts also provided
the first clues that biochemical changes in
the gastrointestinal tract might lead to thia-
min deficiency and death. These clues were
developed in a remarkable series of studies
by the Vitamin B Research Committee of
JapanthatoccurredattheendofWorld
War II when that nation’s population faced
devastating food shortages (Shimazono and
Katsura 1965). Prior to the war, Japan had
made substantial progress in addressing wide-
spread human B vitamin deficiencies associ-
ated with the prevailing diet of polished rice.
Within a decade after the war’send,thiscom-
mittee’s studies helped eliminate this human
health problem in Japan, while at the same
time providing fundamental insights for un-
derstanding thiamin deficiency as an eco-
logical and environmental concern.
The Japanese literature on beriberi and
thiamin was reviewed and summarized in
an English translation published in the mid-
1960s (Shimazono and Katsura 1965) that de-
scribed the presence of thiamin-degrading
bacteria in feces from a substantial propor-
tion (5–18%) of Japanese residents (Murata
1965). Human consumption of organisms
containing thiaminase I, such as raw seafood,
had been previously and speculatively de-
scribed as a potential causal factor of thia-
THIAMIN INFLUENCE ON ECOLOGICAL INTERACTIONSJune 2017 161
min deficiency in Asian countries (Williams
1961), but the origin of thiamin-degrading
enzymes was unknown. The ill-fated explor-
ers Robert Burke and William Wills, who
died on their return trip after traversing the
Australian continent in 1860, provide a fre-
quently cited example of human thiamin
deficiency caused by the consumption of
food containing thiaminase I. The diaries of
Burke and Wills have led historians to con-
clude that they died from thiamin deficiency
caused by consuming raw waterfern, Marsilea
drummondii, known as nardoo (Earl and Mc-
Cleary 1994). Although this plant contains
high levels of thiaminase I (McCleary and
Chick 1977), it was commonly consumed by
aboriginal hunter-gatherers, who cooked the
plant—and therefore denatured the thiamin-
degrading enzyme—before eating it. Addi-
tional examples of human thiamin deficiency
caused by the consumption of plants with
thiaminase I have been reported, such as
an experimental study in which human sub-
jects consumed bracken fern, another plant
with high thiaminase I levels (Samruatruam-
phol and Parsons 1955).
Studies of human thiamin deficiency in
West Africa have identified insects as con-
tainingthiamin-degrading enzymes thatpro-
duce dizziness, vomiting, and ataxia when
consumed in large quantities (McCandless
2010). As with other examples of thiaminase
I-induced thiamin deficiency, this syndrome
was first described as a neurological disease
referred to as “encephalitis tremens”with-
out any knowledge of its underlying etiology
or connection to thiamin deficiency (Wright
and Morley 1958). Subsequent studies in
western Nigeria concluded that this human
thiamin deficiency syndrome was caused by
consumption of larvae of the lepidopteran
Anaphe venata (Adamolekun et al. 1997), af-
ter which Nishimune et al. (2000) confirmed
that these larvae contained high levels of thi-
aminase I.
Unfortunately, outbreaks of human mor-
tality from thiamin deficiency continue to
occur in individuals consuming adequate di-
etary sources of thiamin, such as a 2014 event
on a Pacific island (Nilles et al., unpublished
manuscript). Similarities between this hu-
man mortality and mortality from thiamin
deficiency in other animal populations sup-
port the idea that unspecified ecological
interactions—perhaps between hosts and en-
dosymbionts or involving pathogenic organ-
isms—are responsible for these events.
Thiamin-Mediated Ecological
Interactions
A central tenet of ecological theory is that
organisms compete for nutrients and that
this competition affects many aspects of plant
communities, such as species diversity and
relative abundance (Tilman 1988). Empiri-
cal studies exploring competition for chem-
ical resources have traditionally focused on
the outcomes of competition for nitrogen
and phosphorus, with less attention paid to
other nutrients such as potassium and silica
(Miller et al. 2005). Despite an awareness
that more complicated molecules might be
subject to competition among organisms,
most ecological studies of nutrient limita-
tion have focused on the sequestration, deg-
radation, and transformation of relatively
simple molecules containing nitrogen (e.g.,
N
2
,NO
3
,andNH
4
). However, it is logical
to expect that the requirement for other
more complicated chemical compounds, such
as thiamin, would constitute a strong selec-
tion force and would induce organisms to
develop the capacity to use these resources
in a manner that renders them unavailable
to competitors.
In the previous sections we have provided
examples suggesting that organisms use many
different strategies to acquire thiamin and
can use thiamin degradation products in a
manner that gives them a competitive ad-
vantage over other organisms living in the
same environment. Most of these examples
were microbial or have a plausible microbial
connection. For example, one of the mys-
teries associated with the thiamin-degrading
enzyme, thiaminase I, is whether its presence
in animals is due to de novo production by
these organisms or by microbial endosym-
bionts (Richter et al. 2012). The localized dis-
tribution of this enzyme in the rhizomes of
bracken fern and gastrointestinal tract of
162 Volume 92THE QUARTERLY REVIEW OF BIOLOGY
fishes is consistent with the hypothesis that
microbial sources are responsible for the
presence of thiaminase I in these organisms
(Kraft et al. 2014). Regardless of whether
thiaminase I is produced de novo or by micro-
bial endosymbionts, biochemical transforma-
tions of thiamin almost certainly influence
interspecies interactions, biological commu-
nity composition, and broad-scale ecosystem
processes such as the production of phyto-
plankton in ocean environments.
Conclusion
Abundant evidence suggests that the ac-
quisition and degradation of thiamin plays
a central role in competitive interactions,
symbiotic associations, and pathogenic inter-
actions that have large-scale influences upon
animal mortality and marine productivity.
It has been obvious for more than a century
that organisms need to produce or consume
enough thiamin to survive. But it has not
been obvious that the unique biochemistry
of this vitamin places it as the focus of an ex-
tensive set of ecological interactions.
In considering the ecological influence
of biochemical transformations of thiamin,
it is important to consider the potential for
anthropogenic alterations of biochemical
cycles involving thiamin synthesis and deg-
radation. Specifically, thiamin has been in-
creasingly added to the human and animal
food supply since the chemical synthesis
of this vitamin was developed in the 1930s
(Williams 1961). Industrial production of
thiamin was approximately 3300 tons in the
1990s (Burdick 1998), and most of the thi-
amin sold worldwide is used for dietary
supplements. Although this practice has un-
questionably contributed to improvements
in human health, its potential environmental
consequences have never been considered.
We suggest that human activities have pro-
vided concentrated sources of thiamin at such
locations as sewage treatment plants and ani-
mal feedlots, based on the observation that
excess thiamin cannot be stored by humans
and is excreted (Tasevska et al. 2008). Phys-
ical and biological degradation would then
lead to the presence of atypically large con-
centrations of thiamin degradation products
(e.g., HMP) suitable for the proliferation
of organisms associated with harmful algal
blooms and other pathogenic conditions.
In this review we suggest that an ecological
battle is being fought in diverse ecosystems
over thiamin and its pyrimidine and thiazole
precursors. Competition for thiamin occurs
among organisms living in the same envi-
ronment, as well as among organisms living
within other organisms, leading to pathoge-
nicity. This ecological competition occurs in
open ocean waters of the Sargasso Sea, one
of the most nutrient poor ecosystems on
Earth, and this competition occurs within
the nutrient rich gastrointestinal tracts of fish
in the Laurentian Great Lakes and sheep
grazing in Australia. Casualties from this
competition have been evident for decades
in mass mortality events observed in fishes
and ruminant mammals but, until now, no
effort has been made to develop a broad eco-
logical framework for understanding these
phenomena.
acknowledgments
We thank Nelson Hairston, Katie Edwards, Roxanne
Razavi, Laura Martin, and two anonymous reviewers
for helpful comments on the manuscript. We also thank
Katie Edwards for preparing the figures. Finally, we
thank Dale Honeyfield and Tadhg Begley for spark-
ing our interest in this topic and consistently provid-
ing key insights.
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