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The Cecal AppendixOne More Immune Component With a Function Disturbed By Post-Industrial Culture.

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THE ANATOMICAL RECORD 294:567–579 (2011)
The Cecal Appendix: One More Immune
Component With a Function Disturbed
By Post-Industrial Culture
1
MICHEL LAURIN,1 MARY LOU EVERETT,2 AND WILLIAM PARKER2*
UMR 7207, CNRS/MNHN/UPMC, Centre de Recherches sur la Paléobiodiversité et les
Paléoenvironnements, Muséum National d’Histoire Naturelle, Paris, France
2
Department of Surgery, Duke University Medical Center, Durham, North Carolina
ABSTRACT
This review assesses the current state of knowledge regarding the
cecal appendix, its apparent function, and its evolution. The association
of the cecal appendix with substantial amounts of immune tissue has
long been taken as an indicator that the appendix may have some
immune function. Recently, an improved understanding of the interactions between the normal gut flora and the immune system has led to the
identification of the appendix as an apparent safe-house for normal gut
bacteria. Further, a variety of observations related to the evolution and
morphology of the appendix, including the identification of the structure
as a ‘‘recurrent trait’’ in some clades, the presence of appendix-like structures in monotremes and some non-mammalian species, and consistent
features of the cecal appendix such as its narrow diameter, provide direct
support for an important function of the appendix. This bacterial safehouse, which is likely important in the event of diarrheal illness, is presumably of minimal importance to humans living with abundant nutritional resources, modern medicine and modern hygiene practices that
include clean drinking water. Consistent with this idea, epidemiologic
studies demonstrate that diarrheal illness is indeed a major source of
selection pressure in developing countries but not in developed countries,
whereas appendicitis shows the opposite trend, being associated with
modern hygiene and medicine. The cecal appendix may thus be viewed as
a part of the immune system that, like those immune compartments that
cause allergy, is vital to life in a ‘‘natural’’ environment, but which is
poorly suited to post-industrialized societies. Anat Rec, 294:567–579,
C 2011 Wiley-Liss, Inc.
2011. V
Key words: cecum; appendix; evolution
THE CECAL APPENDAGE AND
MICROBIAL ECOLOGY IN THE GUT
The cecal appendix in a variety of primates, rodents,
and diprotodont marsupials is a relatively narrow,
closed-end, tube-like extension from the terminal end of
the cecum, characterized by a sharp and distinct change
in the diameter of the bowel at the junction between the
cecum and appendix. In addition, small ‘‘appendix-like
structures,’’ which resemble the cecal appendix in shape
but which are present in the absence of a cecum, appear
at the junction between the small bowel and large bowel
in all extant monotremes as well as in some birds and
some actinopterygians (Smith et al., 2009). It is the purC 2011 WILEY-LISS, INC.
V
pose of this review to summarize recent changes in the
understanding of the function and evolution of the
appendix.
*Correspondence to: William Parker, Ph.D., Department of
Surgery, Duke University Medical Center, Box 2605, Durham,
NC 27710. Fax: 919-681-7263. E-mail: bparker@duke.edu
Received 7 April 2010; Accepted 6 January 2011
DOI 10.1002/ar.21357
Published online 2 March 2011 in Wiley Online Library
(wileyonlinelibrary.com).
568
LAURIN ET AL.
Since its identification in humans more than 400 years
ago and until the 21st century, the function of the appendix was not known, with substantial evidence from
the field of medicine pointing toward the idea that no
function existed. On the other hand, a wide range of biological evidence from histological and phylogenetic studies has persistently kept the idea alive that some as yet
unknown function must exist. However, only recently
was an apparent function of the human appendix identified for which its tube-like structure is apparently well
adapted, when Bollinger and colleagues (Bollinger et al.,
2007) deduced that the cecal appendix is well adapted to
facilitate maintenance of biofilms containing the mutualistic intestinal flora.
The appendix apparently plays an important role in
the microbial ecology within the gut (Bollinger et al.,
2007). It is now well established that a wide range of
animals exist in a co-dependent manner with a large
complement of micro-organisms in their gut and on their
skin (Backhed et al., 2005; Pennisi, 2008; Hattori and
Taylor, 2009). These microorganisms depend on the host
for food and a habitat, and the animal depends on these
commensal microbes to repel infectious organisms, to
drive the normal development of the immune system,
and to aid in digestion. Thus is seems reasonable that,
like other complex organisms such as angiosperms
(Campbell and Greaves, 1990; Weller and Thomashow,
1994; Gupta et al., 2000; Fraysse et al., 2003) and corals
(Reshef et al., 2006; Ritchie, 2006; Rosenberg et al.,
2007), mammals expend substantial energy in the maintenance of the commensal bacterial flora (Bollinger
et al., 2003; Sonnenburg et al., 2004).
A wide range of experimental evidence points toward
the idea that secretory IgA and mucin, two of the most
abundantly produced macromolecules in the body, both
support the growth of biofilms (adherent colonies of bacteria growing in an extracellular matrix) on the gut epithelium (Bollinger et al., 2003; Orndorff et al., 2004;
Palestrant et al., 2004; Sonnenburg et al., 2004; Bollinger et al., 2005). This production of biofilms is apparently beneficial to both the host and the microbes, and
it provides a protected habitat for the microbes, while
simultaneously providing a barrier to infection for the
host.
The deduction that the cecal appendix is well adapted
to maintain biofilms containing the mutualistic intestinal flora (Bollinger et al., 2007) was based on a number
of observations: First, as described above, the immune
system maintains microbial biofilms in the mammalian
gut as a key component of the mutualistic relationship
between mammals and microbes (Bollinger et al., 2003;
Orndorff et al., 2004; Palestrant et al., 2004; Sonnenburg et al., 2004; Bollinger et al., 2005). Second, biofilms
are widely known to be ‘‘safe’’ zones for bacteria, where
they are protected from assault by a variety of factors
including other microbial species, and where they form a
corporative community (Costerton et al., 1987; LappinScott and Costerton, 1989; Costerton, 1995; Costerton
et al., 1995; Kolenbrander, 2000; Xu et al., 2000; Gilbert
and McBain, 2001; Lewis, 2001; Davies, 2003; Dykes
et al., 2003). Third, immune tissue (gut-associated
lymphoid tissue; GALT) is known to be concentrated in
the appendix of several species, and thus the appendix
is considered to be an ‘‘immune organ’’ (Berry, 1900).
The presence of this immune tissue, along with the fact
Fig. 1. The apparent function of the appendix. The cycle of recovery from diarrheal illness as supported by the vermiform appendix is
illustrated. In this scheme, beneficial bacteria (green) are rapidly eliminated in a diarrheal response along with pathogenic bacteria (red),
leaving a digestive tract with far less bacteria than would normally be
present (indicated by the white areas). Following this purge, bacteria
shed from the cecal appendix inoculate the colon, initiating re-growth
of the colonic flora. The location in the digestive tract, narrow lumen,
and extensive biofilms of the cecal appendix all serve to protect bacteria within the appendix from contamination with pathogenic bacteria.
that the immune system supports mutualistic biofilms in
the gut (point #1, above), points toward the appendix as
a potential site of maintenance for the biofilms. Fourth,
biofilms were found to be most concentrated on the epithelium of the appendix, with less coverage of the epithelium by biofilms in the more distal parts of the large
bowel (Bollinger et al., 2007). Fifth, biofilms in a variety
of settings are known to be in a continual state of shedding and regeneration, and it was expected that the relatively rapid turnover of the gut epithelium in general,
regardless of location in the gut, would dictate a rapid
turnover of any biofilms that happen to be adherent in
the gut. Thus, it is expected that any epithelial surface,
including that of the appendix, will regularly shed or
release fragments of any adherent biofilms, thus serving
as an inoculum for any downstream niches that might
potentially be available. Sixth, the location of the appendix at the terminal end of the cecum is well suited to
avoid infection by a pathogen invading the host by passive flow with the fecal stream. Finally, the long, narrow
lumen of the appendix is well shaped to retard infection
by pathogens invading the large bowel via the oral
route. These factors, when combined, paint a picture of
the appendix as well adapted to facilitate re-inoculation
of the intestinal flora in the event that the bowel should
be infected by a pathogen (Bollinger et al., 2007). The
cycle of infection, purging of the gut by diarrhea, and reinoculation of the gut by commensal organisms from the
appendix is shown in Fig. 1. Given the tremendous disease burden imposed by untreated drinking water in
FUNCTION AND EVOLUTION OF THE CECAL APPENDIX
human populations without access to modern water
treatment and sanitation facilities (see discussion
below), it seems highly likely that this proposed function
of the appendix might be advantageous for survival, at
least in humans.
A HISTORY OF THE FUNCTION
OF THE APPENDIX
Leanardo da Vinci’s failure to publish his now wellknown drawings of the human appendix made in the
1490’s had little to do with the length of time required
to find the apparent function of the appendix. Although
Berengario da Carpi published the first description of
the human appendix in 1521, Antony van Leeuwenhoek
did not identify bacteria until more than 150 years later,
in 1676 (Van Leeuwenhoek, 1684). After the discovery of
bacteria, almost another 200 years elapsed before a rudimentary understanding of mutualistic relationships was
proposed (Schwendener, 1868; De Bary, 1879; Honnegger, 2000), and it was not until the late 1800’s that Louis
Pasteur and other microbiologists pioneered the idea
that the bacteria in the gut were vital to the life of the
host (Schottelius, 1902; Gordon and Pesti, 1971). Further, it was not until the early 1900’s that an increased
understanding of the immune system and the observation that the appendix is associated with substantial
amounts of immune tissue (GALT) led to the conclusion
by Berry that the appendix had some specific yet unidentified immune function (Berry, 1900). Studies
throughout the 1900’s based on phylogeny and immunology (e.g., Keith, 1912; Neiburger et al., 1976; Gorgollon,
1978; Scott, 1980; Spencer et al., 1985; Zahid, 2004) continued to support the conclusion that the cecal appendix
possesses some specific yet unknown function for which
it is adapted. However, well-known but misleading
observations made in the field of medicine, discussed
below, in conjunction with a failure to identify the function of the appendix, left most people comfortable with
the idea that the appendix had no function at all.
Because of the intense focus on pathogenic microbiology during the 1900’s, the immune system was considered to be strictly anti-microbial in nature. This view
was extended even to the relationship between the
immune system and the mutualistic microbes of the gut
(Williams and Gibbons, 1972). Thus, given that the
immune system was considered anti-bacterial, it stood to
reason that the appendix, already identified as an
immune ‘‘organ,’’ was also anti-bacterial in some way. In
addition, Pasteur’s opinion about the mutualistic nature
of the normal gut flora was not shared by everyone in
the early 1900’s, with some holding that the microbes
within the mammalian gut were antagonists to our well
being (Nencki, 1886; Metchnikoff, 1903; Gordon and
Pesti, 1971).
It was not until the mid 1900’s that Pasteur’s opinion
about the beneficial nature of the normal gut flora
became firmly established (Donaldson, 1964). A vast
body of work during the late 1900’s provided a complex
and evolving understanding of the function of the GALT,
but why the GALT should be associated with the appendix remained a mystery. An important barrier to understanding the appendix was overcome in 2003 when it
was realized that the immune system supports growth
of beneficial (mutualistic) bacteria in the mammalian
569
gut (Bollinger et al., 2003; Sonnenburg et al., 2004).
This important shift in thinking made possible the
deduction that the human appendix is a well-adapted
‘‘safe-house’’ for the maintenance of the mutualistic gut
bacteria (Bollinger et al., 2007). Indeed, as long as the
immune system is thought of as entirely anti-microbial,
it is very difficult to visualize a useful function of the appendix, or why the GALT would be associated with the
long, narrow structure.
THE EFFECT OF APPENDICITIS ON
THINKING ABOUT THE FUNCTION
OF THE APPENDIX
Clinical experience with the appendix demonstrates
that the human appendix is, in fact, a detriment to life
in many cases. More than one in every 20 people in a
typical industrialized country will be afflicted with an
inflamed appendix during the course of their lifetime,
with an expected mortality rate of about 50% in the absence of medical intervention. This observation might be
viewed as evidence of a significant Darwinian fitness
value of a ‘‘safe-house’’ to protect beneficial bacteria.
However, almost a century ago, Arthur Keith (Keith,
1912) proposed a much more likely explanation that
would not be proven for another 60 years:
‘‘When we come to realize how slowly evolutionary
processes have affected man’s body in past times,
we can hardly expect our internal digestive system
to adapt itself to the rapid pace demanded by the
ever-accumulating resources of civilization.’’
It is now known that Keith was correct, and that in
fact appendicitis is a disease associated with industrialized cultures but not developing cultures (Barker and
Morris, 1988; Barker et al., 1988a,b; Bickler and
DeMaio, 2008). For example, the typical incidence of
childhood appendicitis in the United States appears to
be about 35-fold greater than the incidence in segments
of the African population that are unaffected by modern
health care and sanitation practices (Bickler and
DeMaio, 2008). Importantly, the incidence of appendicitis
increases with the adoption of Western lifestyles in
both African countries (Bickler and DeMaio, 2008) and
in Europe (Barker and Morris, 1988; Barker et al.,
1988a,b).
In the 1980’s, two British epidemiologists, David
Barker and David Strachan, found an explanation for
the fact that the appendix can become inflamed in a lifethreatening manner in industrialized countries (Barker
and Morris, 1988; Barker et al., 1988a,b; Strachan,
1989). They not only found a key to understanding the
cause of appendicitis, but of a variety of other diseases
related to over-reactivity of the immune system, including allergies and many autoimmune diseases. Providing
the first evidence for what became known as the
‘‘hygiene hypothesis,’’ Barker and Strachan independently found that immune system over-reactivity was a
consequence of the hygienic environment associated
with cultural changes following the industrial revolution
(Barker and Morris, 1988; Barker et al., 1988a,b; Strachan, 1989).
The conclusions of the hygiene hypothesis were
opposed by the observation that certain components of
570
LAURIN ET AL.
an ‘‘unhygienic environment’’ as defined by post-industrial standards, such as dust-mite derived allergens and
certain viral infections, can increase rather than lower
the propensity for allergy or autoimmune disease
(McGeady, 2004; Kivity et al., 2009). Indeed, ideas other
than the hygiene hypothesis have been proposed which
might, in part, account for over-reactive immune systems in developed countries (McGeady, 2004; Bickler
and DeMaio, 2008). However, work during recent years
has distinguished immunosuppressive environmental
factors such as chronic colonization with helminths from
immunostimulatory environmental factors such as acute
viral infections and exposure to high levels of potential
allergens (Bjorksten, 2009; Kivity et al., 2009). At the
same time, strong support for the hygiene hypothesis
came from a variety of directions (Yazdanbakhsh et al.,
2001; Gale, 2002; Capron et al., 2004; Falcone et al.,
2004; McGeady, 2004; Wilson and Maizels, 2004; Fumagalli et al., 2009), and the hypothesis has gained widespread support (Rook, 2009). The role of decreasing
biome diversity in hygiene-associate hyperimmune
responsiveness has become particularly well established,
with most of the research focused on symbiotic worms,
or helminths. Not only has helminth colonization in
patients suffering from some immune-associated disorders been found to alleviate or halt the progression of
those disorders (Summers et al., 2003; Correale et al.,
2008; Reddy and Fried, 2009), but at least some of the
underlying reasons why helminth colonization down-regulates the immune system have become evident. First,
the helminth load in a typical mammal produces dozens
if not hundreds of soluble molecules which down-regulate the immune system (Hewitson et al., 2009). Not
only does helminth colonization actively down regulate
the immune system as a means of evading destruction
by the immune system (Hewitson et al., 2009), but
increased activity of the immune system as a result of
the colonization provides feedback inhibition that leads
to a decreased sensitivity of the system (Lohr et al.,
2009; Mizrahi and Ilan, 2009; Workman et al., 2009).
Further, fossil evidence of helminth colonization in early
Cretaceous dinosaurs (Poinar and Boucot, 2006) and
even in Devonian jawless vertebrates (Lukševics et al.,
2009) suggests that persistent colonization with helminths has resulted in selective pressures that must
have influenced evolution of the immune system for at
least 400 million years. Thus, based on a variety of
observations made by medical science and confirmed by
other areas of investigation, it is not the immune system
that is at fault for the incidence of appendicitis or of a
variety of immune-associated diseases, but rather an
incompatibility between human biology and post-industrial culture.
It has been argued that the appendix may not have
been lost during the course of natural selection because
any decrease in the size of the appendix would make the
structure even more dangerous than it is at present
(Neese and Williams, 1996). This argument is refuted by
several observations. First, the fact that appendicitis is
caused by recent changes in human culture associated
with industrialization (Barker and Morris, 1988; Barker
et al., 1988a,b; Bickler and DeMaio, 2008) indicates that
selection pressure due to appendicitis was probably not
substantial prior to about 1860. Since the increased risk
of appendicitis which occurred in the mid to late 1800’s
was quickly followed by surgical procedures effectively
preventing mortality from appendicitis (Drinkwater,
1924), it is doubtful that appendicitis will ever exert
pressure for elimination of the appendix. Second, dozens
of individuals have been identified patients who were
born with the congenital absence of an appendix (Pester,
1965). Thus, loss of the appendix is a biological possibility in humans. Third, cladistic analyses suggest that the
appendix has been lost several times during evolutionary history, accounting for the absence of an appendix in
some rodents and possibly some primates (Smith et al.,
2009). Such losses may result from a reduction in the
selection pressure to maintain an appendix, perhaps due
to changes in such factors as diet and social behavior
that decrease the impact of intestinal pathogens on the
health of the population. Although the exact nature of
such changes remains unknown, the taxonomic distribution of the appendix (Fig. 2) clearly shows that the appendix has been lost more than once during the course
of evolution. Finally, a number of taxa, including the
wombat, the Cape dune mole-rat, the meadow vole, and
the scaly-tailed flying squirrel, have an appendix that is
much smaller in terms of absolute size than that found
in humans (Smith et al., 2009). Indeed, it is difficult to
imagine an appendix as large as the human appendix in
a rodent that is <1% the size of a human. Thus, a very
small appendix is not necessarily a dangerous appendix.
THE EFFECT OF APPENDECTOMY ON
THINKING ABOUT THE FUNCTION
OF THE APPENDIX
Perhaps, the most obvious and clearest evidence that
the appendix has no significant function in humans
inhabiting developed countries is the fact that >5% of
the population in these countries do not have their appendix due to appendectomy, and there are no apparent
negative long-term side effects from that surgical procedure. In fact, until recently, the only clear clinical association with appendectomy was a slight decrease in the
incidence of ulcerative colitis (Koutroubakis and Vlachonikolis, 2000). Of great interest is a recent, prospective
study demonstrating that appendectomy significantly
improves the symptoms of 90% of patients with ulcerative proctitis, a type of ulcerative colitis, and leads to a
complete remission of all symptoms in 40% of those
patients (Bolin et al., 2009). Although it has long been
known that ulcerative colitis, like appendicitis, is associated with modern hygiene, and that there is some connection between appendectomy and colitis (Koutroubakis
and Vlachonikolis, 2000), the finding that the appendix
apparently plays a direct role in ulcerative colitis is new.
The apparent function of the appendix may, in fact, shed
light on these observations if taken into account in light
of the hygiene hypothesis: It is possible that the appendix associated with a hyperactive immune system helps
maintain colitis by maintaining bacteria toward which
the immune system is reacting in a hygiene-associated,
pathogenic fashion. On the other hand, the considerable
amounts of GALT housed in the appendix may be responsible for driving hygiene-associated, aberrant
immune reactions that lead to ulcerative colitis even in
regions of the gut distant from the appendix. Regardless
of the mechanism(s) by which the appendix might contribute to ulcerative colitis, it is clear that the absence of
Fig. 2. Phylogenetic tree of mammalian relationships with the most
parsimonious evolutionary occurrence of the appendix and appendixlike structures mapped onto it. Taxa usually ranked as families were
included as terminal operational taxonomic units (OTUs) as described
by Smith and colleagues (Smith et al., 2009). For the source of the topology, see (Smith et al., 2009). The time calibration was taken mostly
from a compilation of the paleontological literature that one of us (M. L.)
used in previous and ongoing studies (Germain and Laurin, 2005; Pouydebat et al., 2008) in which references to the primary literature can be
found. For some clades for which little paleontological data are available, ages were taken from a molecular study (Bininda-Emonds et al.,
2007), but ages were decreased by about 20% to compensate for the
fact that molecular ages are frequently much greater than paleontological ages of the same clades (Marjanovic and Laurin, 2007). A recent
geological timescale (Gradstein et al., 2004) was introduced using the
Stratigraphic Tools for Mesquite (Josse et al., 2006). Names of stages
(Gradstein et al., 2004) were abbreviated and short stages were omitted
because space is insufficient to show the full names or even abbreviations at appropriate size. The optimization was performed in Mesquite
2.72 (Maddison and Maddison, 2009) using ordered states (taxa with
variable expression of the appendix are considered as intermediate
between taxa with and taxa without consistent expression of a cecal
appendix); this differs slightly from the methods used by Smith et al.
(2009). The phylogenetic signal in the distribution of the cecal appendix
was assessed using a random taxon reshuffling analysis as described
by Laurin (2004, 2005) using Mesquite, and was found to be highly significant (P < 0.0001) for the overall tree. However, the phylogenetic signal was not significant within the Euarchontoglires (P ¼ 0.34) or in
Diprotodontia (P ¼ 0.20), perhaps reflecting the recurrent nature of that
character within that clade. The rise of the appendix or propensity to
evolve an appendix at the base of the Euarchontoglires and of Diprotodontia is indicated by red bars.
572
LAURIN ET AL.
an appendix causes no obvious adverse effects in developed countries.
Given the apparent function of the appendix, it is not
surprising that appendectomy in the face of modern health
care and hygiene has no ill effects. The apparent function
of the appendix points toward a utility under conditions in
which rapid recovery of the gut flora following diarrheal illness is important. Such recovery is not expected to be particularly important in developed countries where advanced
technology for handling sewage and producing drinking
water are commonplace. In addition, the effective governmental regulation of food production in developed countries
further reduces the impact of diarrheal illness on the population. These measures, combined, effectively eliminate the
possibility of widespread epidemics of waterborne and foodborne gastrointestinal infection, and thus the possibility
that the normal gut flora will be contaminated or lost from
a wide swath of the population. Finally, diarrheal illness is
of only passing concern when the population is not struggling with issues such as starvation, malnutrition, or dehydration, and when medicines and nutritional support are
readily available to prevent mortality due to infection of
the gastrointestinal tract.
Ironically, the only animal other than humans which has
an appendix and which lives in an environment sufficiently
hygienic to render the appendix useless is probably the laboratory rabbit. We suggest that the use of the laboratory
rabbit in hygienic (i.e., biome-depleted) environments to
study the function of the appendix may have contributed to
the idea that the appendix had no important function.
Although diarrheal disease does not significantly affect
some human populations due to the factors mentioned
above, other human populations are less fortunate. For
example, the World Health Organization reported that
diarrheal disease was the fourth leading cause of disability-adjusted life years lost in the most populated African
countries in 2000, lagging behind only HIV-AIDS, lower
respiratory tract infections, and malaria (2001). Even
more telling is the observation that diarrheal disease
was the single greatest cause of disability-adjusted life
years lost in 2000 in the most populated countries in
South-East Asia (2001). Thus, acute diarrhea associated
with contaminated drinking water or food was still a
major factor in the survival of human populations in the
very recent past, and was potentially one of the primary
disease-related selection pressures on all human populations in the distant past. With this in mind, it seems
very likely that any biological mechanism associated
with the recovery from diarrheal illness would be highly
advantageous to survival in a culture devoid of the medicine and technology associated with industrialization.
The above argument provides an explanation for the
observation that the loss of an appendix does no harm in
human populations living in industrialized countries,
and supports the conclusion that the appendix serves no
apparent function in these populations. However, the
same argument strongly suggests that the appendix may
have been important for all human populations in the
past, and indeed may still be important for many human
populations today.
THE EVOLUTION OF THE APPENDIX
Charles Darwin noted the apparent lack of a function
of the appendix in humans, and concluded that it must
be an evolutionary remnant from a primate ancestor
that ate leaves (Darwin, 1871). This idea was supported
by the now-refuted (Fisher, 2000; Smith et al., 2009)
view that in primates, the appendix is present only in
hominids. The argument has been made that even
though the rabbit also has an appendix, it is substantively different because it is large enough in size (about
three times larger than the primate appendix, making it
proportionately vastly larger in rabbits than in primates) to aid in digestion, and thus the primate appendix
should still be considered unique.
The erroneous ideas regarding the unique and vestigial nature of the appendix in hominids are still found in
many textbooks, and may continue to remain widely
held until the function and broad phylogenetic distribution (see below) of the appendix are widely appreciated.
If indeed the appendix had no function, the most likely
explanation might be that the structure is a vestige of
evolution. Further, the high prevalence of appendicitis
and the apparent absence of negative side-effects following appendectomy, described above, have been taken as
direct evidence that the appendix is, in fact, a vestigial
structure that is detrimental to life (Müller, 2002).
It was not until recently that Smith et al. (2009)
described in detail the various morphotypes and the
phylogenetic distribution of the cecal appendix and appendix-like structures. The idea that the appendix is a
harmful vestige of evolution was not supported by the
comparative anatomical approach in a phylogenetic context (Smith et al., 2009). This approach revealed that
species with an appendix belong to two clades (Fig. 2): A
variety of Diprotodontia (diprodent marsupials) such as
the wombat, the ringtailed possum, and the cuscus have
an appendix. Second, a wide variety of Euarchontoglires,
the clade including rodents, lagomorphs (rabbits and
hares), and primates, also have appendices. Euarchontoglires with an appendix include a wide range of primates
from both main clades (haplorhines and strepsirhines),
rabbits, and a wide range of rodents from eight taxa traditionally considered families. Further, some species outside of Diprotodontia and Euarchontoglires, including all
extant monotremes, have an appendix-like structure,
although they do not have a true appendix. These observations clearly refute the idea that the primate appendix
is unique, especially since the human appendix falls
somewhere in the middle range when comparing the
size and shape of human appendix with the appendices
from other species. The appendix of the mole-rat, for
example, is about 10 times smaller than the human appendix, whereas the appendix of the rabbit is about
three times larger (Smith et al., 2009). Thus, although
the term ‘‘vermiform’’ traditionally refers specifically to
the primate appendix, it is unclear whether the primate
appendix is particularly distinguished by anything but
its name (Smith et al., 2009). More importantly, it is this
evolutionary analysis, demonstrating the broad phylogenetic distribution of the appendix, which indicates most
directly that the function of the cecal appendix at least
compensates for the cost of building and maintaining
the structure.
An analysis of the phylogenetic distribution and morphological features of the appendix strongly suggest that
the appendix can be described as a ‘‘recurrent phenotype’’ among Euarchontoglires and perhaps among
Diprotodontia. Recurrent phenotypes are ‘‘exceedingly
FUNCTION AND EVOLUTION OF THE CECAL APPENDIX
common and phylogenetically widespread,’’ and have
been described by a number of terms, including analogous variations, apomorphic tendencies, homiology, and
underlying synapomorphy, among others (West-Eberhard, 2003, 2005). Such phenotypes are ‘‘similar or identical phenotypic traits with discontinuous phylogenetic
distributions, which owe their similarity to common
ancestry (homology)’’ (West-Eberhard, 2003). The cecal
appendix has properties that are generally characteristic
of recurrent phenotypes, including the following: (a) The
appendix occurs sometimes as a fixed character and
sometimes as an alternative morphotype within a given
species (Smith et al., 2009). Variability in the expression
of the appendix will be described below. (b) The appendix
not only shows variability in expression within some
species, but when it is expressed, considerable variation
in morphology within the same species, sex, and life
stage can be observed, as will be described in detail
below. (c) The distribution of the appendix within the
clades in which it occurs (Euarchontoglires and Diprotodontia) does not necessarily reflect the phylogeny. This
lack of a statistically significant phylogenetic signal in
these clades (Fig. 2) is not surprising given that 45% of
the taxa traditionally ranked as families that contain
species with an appendix also contain species without an
appendix (Smith et al., 2009).
It is thus possible that the appendices found in Euarchontoglires and perhaps also in Diprotodontia are homologous within their respective clades, due to common
descent from an ancestor which had either developed a
cecal appendix or perhaps a ‘‘constitutional responsiveness’’ (inherited ability to respond to environmental variation) (Darwin, 1859; West-Eberhard, 2003), which
facilitates the relatively rapid evolution of a cecal appendix. At the same time, the appendix is apparently a highly
labile character in Diprotodontia and Euarchontoglires, as
with all recurrent traits (West-Eberhard, 2003), appearing
to ‘‘blink on and off during evolution’’ within those clades
with a propensity to possess the trait.
The appendix or perhaps the constitutional responsiveness that facilitates the evolution of the appendix
would potentially have evolved twice during the course
of evolution, once near the base of Euarchontoglires, and
once again at the base of Diprotodontia (Fig. 2). In this
scenario, the appearance of the character that facilitated
evolution of the appendix in marsupials probably
occurred more than 50 million years ago, after the
Diprotodont marsupial lineage split from other marsupial lineages (Nilsson et al., 2003; Bininda-Emonds
et al., 2007). Of particular interest is the koala (Phascolarctos cinereus), a phascolarctid Diprotodont marsupial,
which has an ‘‘appendix-like structure’’ that is long and
narrow, with a closed end, like a true appendix. Like the
human appendix, the koala’s appendix-like structure is
full of microbial biofilms (McKenzie, 1978). In the case of
the koala, these biofilms are formed by bacteria that are
necessary for the koala to digest the eucalyptus leaf, its
primary food source. However, the koala’s appendix-like
structure is not a true appendix, since it is formed by a
uniquely long and tapering cecum without a clear junction having been identified that would separate the cecum and the appendix. This unique structure may
represent the evolution of a new morphotype derived
from the much more common cecum with a true appendix that is present in some Diprotodont marsupials.
573
The appearance of the appendix or perhaps the constitutional responsiveness that facilitates the evolution of
the appendix in Euarchontoglires was probably earlier
than in marsupials. In one scenario, the acquisition
potentially occurred between 85 and 120 million years
ago, according to some molecular dating studies (Kumar
and Hedges, 1998; Douzery et al., 2003), or between 60
and 65 Ma ago, according to the fossil record (Wible
et al., 2007), before the Euarchonta separated from the
Glires. Thus, the cecal appendix or the character causing
its recurrence may have been preserved during natural
selection for a large portion of mammalian evolutionary
time, perhaps extending through the K–T extinction
event and being maintained within at least three orders
of extant mammals (primates, lagomorphs, and rodents).
Although the morphology or morphologies that preceded the cecal appendices found in Euarchontoglires
and in Diprotodontia remains unknown, observations
made in monotremes indicate that a narrow, appendixlike structure might possibly precede the evolution of a
larger cecum with an effective digestive function. Both
extant monotremes, the platypus and the echidna, have
small, tubular ceca that resemble an appendix in shape.
The structure of the platypus cecum, for example, is 2.5
cm long and about 3 mm in diameter (Krause, 1975),
about one-third the size but approximately equivalent in
shape to the human appendix. The structure in the
echidna cecum is even smaller, being slightly over 1 cm
in length and 3–4 mm in diameter (Stevens and Hume,
1995). These structures are so small that it is unlikely
that they contribute substantially to digestion as fermentation chambers. Thus, it seems possible that acquisition of a cecum with primarily a fermentation function
might not be a prerequisite for the evolution of an appendix-like structure with primarily an immunologic
function involving maintenance of the host–microbial
relationship.
Regardless of the morphological transitions that might
occur during the evolution of the cecal appendix, the appendix appears to be ancient in origin (Fig. 2), apparently supporting a mutualistic relationship between
bacteria and animals that is even more ancient. A centerpiece in this relationship, microbial biofilms in the
normal bowel, has been observed in the gut of earthworms (Jolly et al., 1993; Vinceslas-Akpa and Loquet,
1995; Mendez et al., 2003), in at least one amphibian,
and in a variety of mammals ranging from koalas to
mice and humans (Smith et al., 2009).
SUBSTANTIAL VARIATION IN THE
STRUCTURE OF THE APPENDIX
One of the hallmarks of the cecal appendage is variability in its size. Such variability was suggested by Darwin as being an indicator that the appendix was a
vestige. This argument is not especially strong, since
high degrees of variability not related to vestigial structures are often observed. In humans, for example, substantial variation is seen in the size of the torso, several
parameters associated with hair, pigmentation in the
skin and eyes, and foot and hand size to name only a
few. Nevertheless, considering the variability in size of
the cecal appendix is potentially important and may provide insight into its function, and, as pointed out above,
into the potentially recurrent nature of the structure in
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LAURIN ET AL.
evolution. The variability observed in the structure of
the human appendix is less striking than variability
observed in the appendix of some other species. In at
least four primate species and in the laboratory mouse,
the appendix is present in some individuals and absent
in others (Smith et al., 2009). Most mammals with an
appendix, however, express the appendix with more regularity, although this may, to an extent, reflect the much
smaller sample size of studied individuals in those species. In humans, even though several dozen individuals
have been identified who have been born without an appendix (Pester, 1965), the overwhelming majority of individuals do have an appendix.
Although the length of the human appendix is thought
to be highly variable, the diameter is considered to be
relatively consistent (Odze and Goldblum, 2008). A relatively consistent diameter has been supported by several
studies using computed tomography (CT) to evaluate the
appendix size. For example, one study of the normal appendix in 167 patients revealed that the mean diameter
of the normal appendix without apparent intraluminal
content is 6.6 mm with a standard deviation of 1.0 mm.
(Benjaminov et al., 2002). Another study of 305 patients
showed that about 80% of all normal appendices have a
diameter between 4 and 7 mm, and >90% have a diameter between 4 and 8 mm (Tamburrini et al., 2005). The
degree of variation observed depended to some extent on
the presence or absence of fecal material in the appendix, and thus some of the observed variation is not inherent in the tissue itself. Further, differences in body
size or mass, which are generally not taken into account
in reports of appendix size, may account to some extent
for variation in appendix size. With this information in
hand, it seems not unreasonable to conclude that the
narrow lumen of the appendix, which is likely important
in its apparent role as a safe house for beneficial bacteria, is consistently maintained in the human population.
In contrast to diameter, the length of the normal appendix is thought to be highly variable, with both very
long (>20 cm) and very short (<2 cm) lengths being
reported. A reasonably detailed discussion concerning
the length of the appendix, as well as some quantitative
assessment of its variability in length, was provided by
Kelynack (1893) and again by Lake (1920). As described
by Kelynack and again by Lake, several surgeons had
reported the longest appendix they had encountered during the course of their work. Kelynack himself had found
the maximum length of any appendix he had encountered to be about 15 cm, whereas three of his colleagues
had identified maximum lengths of 15, 17, and 23 cm,
respectively. Appendices reported by Lake as being ‘‘of
such extreme length as to be worthy of particular notice’’
included structures with lengths of 21.5 cm, 22 cm, 23
cm, 29.4 cm, and 33 cm. On the basis of these observations, it seems likely that appendices longer than 17–20
cm are very rare. When examining the frequency of very
short appendices, Kelynack reported that only two out of
177 (about 1%) of the appendices in his practice had a
length of <2.54 cm. Thus, both very long (>15 cm) and
very short (<2.54 cm) appendices are apparently uncommon. Although extremes in length are apparently rare,
Kelynack did observe a substantial degree of variation
in typical lengths, with about 7% of the appendices in
his study being >12.7 cm in length, and about 11% being
<5.1 cm in length. Although this variation in length
might be seen as an indication that the function of the
appendix is of little biological importance, the range of
appendix lengths found throughout phylogeny (from
about 1 cm in length in the lemming to >15 cm in the
brushtail possum) is consistent with the idea that
appendices with a wide range of lengths may all be quite
functional. Thus, the quintessential structural feature of
the appendix may well be the relatively narrow lumen
rather than any particular length. With this in mind,
there appears to be substantial selective pressure to
keep the diameter of the appendix relatively constant,
whereas its length appears to be under much less evolutionary pressure.
IS THE APPENDIX A ‘‘VESTIGE?’’
Whether the cecal appendix should be considered a
‘‘vestige’’ of a larger cecum has been hotly debated, and
the discovery of a function for which the appendix is
well adapted brings renewed interest to this debate. By
definition, a vestige has a reduced function, if any function at all, compared to the structure from which it
evolved (Darwin, 1871; Fong et al., 1995). In addition,
vestiges are typically reduced in size compared to their
fully functional predecessors (Fong et al., 1995). However, simply because the size of a given structure is
decreased and even the function has decreased does not
necessarily indicate that a structure is a vestige. For
example, when considering an ancestor with arms used
for collecting food, grooming, and locomotion in an arboreal habitat, and a descendent with relatively smaller
arms that are used for collecting food, grooming, but no
longer for locomotion, the arms of the descendent would
not be considered vestiges despite the fact that the relative size of the arm has decreased and at least one function has been lost. The same might be said of a cecum in
an omnivore, which, although still of perfect utility and
even necessity for the digestion of food, is smaller and of
relatively less significance for the omnivore than a
larger cecum was for a putative folivore ancestor of that
omnivore. By the same token, although the cecal appendix of humans has been considered a vestige, the cecum
itself has not been considered a vestige in humans, despite its relatively small size. Thus, to some extent, the
idea of a vestige is tied not so much to a decrease in size
or even function, but to the idea that the phenotype is
driven by evolutionary history at the expense of present
utility. In other words, a vestige may well have some
utility and may even be adapted to perform new functions, but the morphology is better explained when considering the function as seen in an ancestor rather than
the function at present. In keeping with this idea, the
reason that the identification of vestigial structures
played an important role in the founding of evolutionary
theory was that those structures provided tangible
traces of past generations (Müller, 2002).
With that in mind, one indication that the appendix is
not a vestige is that, based on what we know of the
apparent function of the appendix, the narrow diameter
is more effective than a large cecum in terms of efficiently providing a bacterial safe-house. It is the apparent improvement of this function as seen in the shape
of the appendix, not so much the presence of some function, which is important in this discussion. Although
vestiges can adapt to new functions, many structures
FUNCTION AND EVOLUTION OF THE CECAL APPENDIX
575
(arms in land-dwelling vertebrates, for example) are in
fact derived from structures that had different functions
(lobe-fins used for swimming, for example). Because
such structures are apparently well adapted for their
present function, they are not considered vestiges. On
the other hand, because it is not known to what extent
the function of the cecal appendix as a microbial safe
house is improved over the same function which might
be carried out by the cecum, it may be impossible to
determine whether or not the appendix should be classified as a vestige of a larger cecum based strictly on considerations of function. However, evidence regarding
function is not the only evidence which has a bearing on
the issue.
A second, more telling, indicator that the cecal appendix is not a vestige is the fact that a cecal appendix is in
many cases associated with a large cecum used for digestion. In fact, the majority of species with an appendix,
including most rodents with an appendix as well as
some primates, possess this morphology (Smith et al.,
2009). As pointed out by Darwin, if the appendix is a
vestige of a larger cecum used for digestion, then the appendix and a large cecum should not co-occur in any species, since the vestige and the structure from which the
vestige is derived should not exist simultaneously.
Third, as described above, a modern analysis of the
phylogenetic distribution, comparative anatomy, and
evolution of the appendix refute the idea that a large cecum gives rise to an appendix plus a smaller cecum
(Smith et al., 2009). In fact, those analyses indicate that
a narrow, appendix-like structure may well have evolved
in some cases prior to the evolution of a cecum used for
fermentation.
When considering the evolution of the appendix, the
several phenotypes associated with the proximal large
bowel can be considered. These phenotypes can be
roughly classified into five categories, each expected to
have unique functional properties:
1. A cecal appendix or appendix-like structure, with no
evident cecum. This morphology appears sporadically
in vertebrates, with all monotremes, some actinopterygians, some birds, and at least one marsupial
having this morphology (Smith et al., 2009). Examples (Fig. 3A) include Ornithorhynchus anatinus (the
platypus) and the Lasiorhinus latifrons (Southern
hairy-nosed wombat). The morphology is consistent
with an immunological function and a minimal digestive function.
2. A cecal appendix with a small cecum. This morphology is characteristic of hominids (Smith et al., 2009).
Examples (Fig. 3B) include Homo sapiens (humans)
and Pongo pygmaeus (orangutans). The morphology is
consistent with an immunological function and a modest digestive function.
3. A cecal appendix with a long cecum. This morphology
is found in those rodents that have an appendix, in
all lagomorphs, in a few marsupials, and in primates
other than hominids with an appendix (Smith et al.,
2009). Examples (Fig. 3C) include Lemmus lemmus
(lemmings) and Lepilemur leucopus (sportive lemurs).
The morphology is consistent with an immunological
function of the appendix coupled with an extensive digestive function of the cecum.
Fig. 3. Five morphotypes at the junction between the large and
small bowel. A: Cecal appendix or appendix-like structure, with no
evident cecum of Ornithorhynchus anatinus, the platypus (a monotreme, left), and Lasiorhinus latifrons, the Southern hairynosed wombat (a marsupial, right). B: Cecal appendix with a small cecum, as
seen in Homo sapiens (humans, left) and Pongo pygmaeus (orangutans, right). C: Cecal appendix with a long cecum, in Lepilemur leucopus (sportive lemurs, left) and Lemmus lemmus (lemmings, right). D:
Cecum with no appendix of Rattus norvegicus (rats, left) and Sus
scrofa (pigs, right). E: No cecum and no appendix, as in Desmodus
rufus (vampire bats, left) and Physeter catodon (sperm whales, right).
Drawings of the bowel of the platypus, the wombat, the human, the
orangutan, and the sportive lemur are from Smith et al. (2009). The
drawing of the bowel of the lemur is adapted from Behmann (Behmann, 1973). The drawings of the bowel from the rat, the pig, sperm
whale, and the vampire bat are adapted from Stephens and Hume
(1995).
4. A cecum with no appendix. This morphology is common in a wide range of mammals, and occurs in
many birds. Examples (Fig. 3D) include Rattus norvegicus (rats) and Sus scrofa (pigs). This morphology is
consistent with a limited immunological function and
a digestive function dependent on cecum size.
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LAURIN ET AL.
5. No cecum and no appendix. This morphology appears
in a range of mammals, as well as in actinopterygians, reptiles and amphibians. Examples (Fig. 3E)
include Desmodus rufus (vampire bats) and Physeter
catodon (sperm whales). The morphology is consistent
with a minimum cost to produce, although immunological and digestive functions must be maintained
without a blind sac or pouch.
Given these five morphological states and the potential for any one of these states to be most advantageous
in a suitable environment, there is no reason to suppose
that any one state must necessarily be preceded by
another state; rather, the states may evolve as needed.
Thus, a linear evolution leading from a large cecum to a
smaller cecum plus an appendix may be only one possible scenario out of several by which an appendix may
have evolved (Smith et al., 2009). This observation has a
bearing on the vestigiality of the appendix: As pointed
out by Müller, vestigial structures must be identified by
the comparative method: ‘‘homology of the reduced character with a more fully developed, ancestral counterpart
must be established, not only on the basis of structural
and positional criteria, but also with regard to the continuous presence of the structure in the lineage leading
from the ancestral to the derived form’’ (Müller, 2002).
Our comparative data suggest such a continuous presence in human ancestors, going back at least to early
apes in the Miocene (Fig. 2), but they do not suggest
reduction in size, which is typical of vestigial structures
(Darwin, 1859). The same data suggests multiple
appearances of the appendix, and fewer losses, which in
turn suggests a selective advantage of the appendix, an
idea supported by epidemiological, immunological, and
microbiological data. Thus, the cecal appendix of
humans cannot be considered a vestige.
CONFIDENCE REGARDING THE APPARENT
FUNCTION OF THE CECAL APPENDIX, AND
FUTURE WORK ON THAT FUNCTION
The observation that microbial biofilms are most concentrated in the proximal large bowel, in conjunction
with information that has been widely known for some
time, including the relative seclusion of the cecal appendix and the protective nature of biofilms for resident bacteria, provides the means for a ‘‘proof by deduction’’ that
the cecal appendix is a safe-house for bacteria. In light
of current knowledge regarding the nature of microbial
biofilms, it would in fact be difficult to imagine that
regions of the bowel which harbor biofilms provide no
sanctuary for bacteria. Indeed, the deduced function of
the cecal appendix as an immune-supported safe-house
for beneficial bacteria is supported by a host of observations in immunology and microbiology, and is consistent
with observations made by medical science. Further, a
wide range of clinical observations and experimental
studies point toward the vital role of the normal flora in
protection against infection and disease, thus providing
a biological motive for the maintenance of that flora.
Finally, studies in comparative anatomy as well as evolutionary biology demonstrate that some function must
exist which at least compensates for the cost of producing the structure.
Although some degree of confidence can be ascribed to
the idea that the cecal appendix is a safe-house for beneficial bacteria, no experiment or study has directly demonstrated the function of the appendix. The study of
patients in developing countries following appendectomy
is one potential way to obtain direct evidence for a function, but hurdles to such studies abound. Finding appropriate patients may prove difficult for several reasons.
First, appendicitis in developing countries is relatively
rare (see discussion above), and second, access to such
patient populations for purposes of long-term studies is
often difficult. Third, the function of the appendix may
be most important in children <5 years of age, when
death due to diarrheal illness is most common, thus providing a considerable restriction on which patients may
be important for such a study. Fifth, if the age-association of appendicitis in developing countries is similar to
that seen in developed countries, then appendicitis is
most common from 10 to 14 years of age. At that age,
the function of the appendix may be less important
because death due to diarrheal illness is less during
those years than in younger years. To complicate the picture, the relatively rare cases of appendicitis that do
occur in developing countries may have a much different
root cause and pathogenesis than cases of appendicitis
in developed countries, since appendicitis in developed
countries is apparently due to hygiene-associated
immune over-reactivity, which does not exist in developing countries. Further, even if it were possible to monitor the effects of appendectomy in developing countries,
it would be difficult to distinguish cause from effect: It is
likely that the factors associated with appendicitis in
developing countries may also have an effect on
mortality.
Although the design of studies in humans aimed at
direct observation of the apparent function of the appendix seem problematic, studies in laboratory animals
could be conducted. However, such studies might be expensive, and a suitable animal model with a human-like
appendix may need to be found. Although the rabbit is
commonly used in the laboratory and does have a cecal
appendix, the morphology of the intestine as well as the
nature of digestion in the herbivorous rabbit is substantially different than that found in humans, some other
primates, and a variety of rodents. Further, removal of
the rabbit’s appendix results in a relatively much more
substantial reduction in immune tissue than does removal of a human appendix, and can have profound systemic effects (Dasso and Howell, 1997). Thus, the
relative importance of the cecal appendix to the immune
systems of rabbits and humans may be profoundly different, and removal of the rabbit appendix may have substantial effects on the immune system that are not
evident in humans following appendectomy. With this in
mind, it may prove difficult to test directly the function
of the appendix in humans given currently available laboratory animal models.
Perhaps, one of the most interesting and promising
approaches by which the function of the appendix may
be further evaluated is through comparative anatomy
and evolutionary biology. As described above, it was this
approach which first demonstrated conclusively that the
appendix is indeed adapted for a specific function, and is
in fact not a vestige of evolution. Several scenarios
regarding the origins and function of the appendix may
FUNCTION AND EVOLUTION OF THE CECAL APPENDIX
lend themselves to direct testing by current approaches
in evolutionary biology because they make different predictions about the order in which a caecum used for fermentation and an appendix appeared, and comparative
data can be used to determine the order of appearance
in various taxa, and reveal a regularity (if any) in such
appearances.
THE CECAL APPENDIX AS A COMPONENT
OF THE IMMUNE SYSTEM UPENDED BY
FACTORS ASSOCIATED WITH
POST-INDUSTRIAL CULTURE
Given a wide range of observations from medical science, evolutionary biology, immunology, and comparative
anatomy described above, it seems likely that the appendix, like other components of the immune system
designed to fight threats that no longer apply to many
humans, is not only made obsolete by factors associated
with post-industrialized culture, but is overly reactive or
sensitive due to an absence of stimulation. Indeed, given
the ever-increasing evidence supporting the hygiene hypothesis and the fact that all of that evidence points
towards certain biological components such as helminths
and mutualistic bacteria as the critical factors mediating
immunity (Matricardi et al., 2000; Kalliomaki et al.,
2001; Schiffrin and Blum, 2002; Yazdanbakhsh et al.,
2002; Capron et al., 2004; Imai and Fujita, 2004; Wilson
and Maizels, 2004; Rook and Brunet, 2005; Hewitson
et al., 2009; Rook, 2009), it could be argued that the traditional term ‘‘hygiene hypothesis’’ would be more
descriptively labeled as the ‘‘biome depletion theory of
immune disorders.’’ Examples of immune components
other than the appendix which are apparently maladapted to the post-industrialized culture are the components designed to produce immunoglobulin E (IgE): production of ‘‘high’’ levels of IgE leads to detrimental side
effects (allergy) in industrialized countries, but levels of
IgE much greater than those found in allergic patients
are generally present in pre-industrial populations as a
response to parasitic infections (Scaglia et al., 1979;
Gale, 2002; Devalapalli et al., 2006), and no allergy is
produced. Thus, the appendix is apparently another
immune component ill-suited to post-industrial culture.
It is now on the shoulders of medical science to devise a
way to stimulate the immune system in a way that
averts diseases associated with biome depletion and
avoids profound side effects.
CONCLUSIONS
The cecal appendix appears to be a ‘‘recurrent’’ trait,
variably expressed in Euarchontoglires and in Diprotodontia. Changes in selection pressure which influence
the presence or absence of the appendix could involve
changes in such factors as diet and social behavior that
decrease the impact of intestinal pathogens on the
health of the population, but the exact nature of such
factors remains unknown. Given the wide range of
observations from medical science, evolutionary biology,
immunology, and comparative anatomy described in this
review, it seems likely that the appendix, like other components of the immune system designed to fight threats
that no longer apply to humans in a post-industrial soci-
577
ety has been made obsolete and even rendered harmful
by factors associated with post-industrial culture.
The appendix is ancient in origin, apparently supporting a mutualistic relationship between bacteria and animals that is even older. The support of the bacterial
biofilms within the appendix is mediated in large part
by the innate and adaptive immune systems, which
actively facilitate growth of beneficial bacterial in the
gut. Given the ancient nature of immune interactions
with gut bacteria, it may be hypothesized that a small,
appendix-like pouch which functioned primarily as an
immune structure maintaining the gut flora evolved
prior to the evolution of a cecum that functioned effectively as a digestive structure. Although the morphology
that preceded the cecal appendices found in Euarchontoglires and in Diprotodontia remains unknown, data on
monotremes indicate that a narrow, appendix-like structure may have preceded the evolution of a larger cecum
with an effective digestive function.
In the gut of several mammals, including humans,
mice, and rats, microbial biofilms are associated with
the proximal large bowel but not the small bowel or the
distal large bowel. In those animals having a cecum but
no cecal appendix, the apex of the cecum is associated
with GALT, has the greatest concentration of microbial
biofilms within the gut, and is thought to perform the
function performed by the cecal appendix (Berry, 1900;
Smith et al., 2009). The distribution of microbial biofilms
in the gut of a frog, which lacks a cecum, reveals a pattern surprisingly similar to that seen in mammals with
a cecum or an appendix (Smith et al., 2009). Thus, the
proximal large bowel, even in the absence of a cecum or
appendix, is apparently the region most used for support
of mutualistic microbial biofilms, and the observation of
this pattern in an amphibian suggests the possibility of
an ancient origin for the pattern, since the last common
ancestor of lissamphibians and amniotes lived between
332 and 360 million years ago (Marjanovic and Laurin,
2007). Most importantly, the compilation of evidence
from a wide range of scientific fields, including ecology,
microbiology, immunology, and evolutionary biology
points toward host–microbial interactions as one of the
primary driving forces for the evolution of the gut. Thus,
the morphology of the gut must be understood in light of
not only digestive function, but also of immunologic
function and the maintenance of host–microbial
interactions.
LITERATURE CITED
Backhed F, Ley RE, Sonnenburg JL, Peterson DA, Gordon JI. 2005.
Host–bacterial mutualism in the human intestine. Science 307:
1915–1920.
Barker DJ, Morris J. 1988. Acute appendicitis, bathrooms, and diet
in Britain and Ireland. Brit Med J Clin Res Ed 296:953–955.
Barker DJ, Morris JA, Simmonds SJ, Oliver RH. 1988a. Appendicitis epidemic following introduction of piped water to Anglesey.
J Epidemiol Commun H 42:144–148.
Barker DJ, Osmond C, Golding J, Wadsworth ME. 1988b. Acute
appendicitis and bathrooms in three samples of British children.
Br Med J Clin Res Ed 296:956–958.
Behmann H. 1973. Vergleichend- und funktionell-anatomische
Untersuchungen am Caecum und Colon myomorpher Nagetiere.
Zeitschrift fur Wissenschaftlich Zoologie 186:173–294.
578
LAURIN ET AL.
Benjaminov O, Atri M, Hamilton P, Rappaport D. 2002. Frequency
of visualization and thickness of normal appendix at nonenhanced
helical CT. Radiology 225:400–406.
Berry RJA. 1900. The true caecal apex, or the vermiform appendix:
its minute and comparative anatomy. J Anat Physiol 35:83.
Bickler SW, DeMaio A. 2008. Western diseases: current concepts
and implications for pediatric surgery research and practice.
Pediatr Surg Int 24:251–255.
Bininda-Emonds OR, Cardillo M, Jones KE, MacPhee RD, Beck
RM, Grenyer R, Price SA, Vos RA, Gittleman JL, Purvis A. 2007.
The delayed rise of present-day mammals. Nature 446:507–512.
Bjorksten B. 2009. The hygiene hypothesis: do we still believe in it?
Nestle Nutrition Workshop Series Paediatric Programme 64:11–18.
Bolin TD, Wong S, Crouch R, Engelman JL, Riordan SM. 2009.
Appendicectomy as a therapy for ulcerative proctitis. Am J Gastroenterol 104:2476–2482.
Bollinger RB, Barbas AS, Bush EL, Lin SS, Parker W. 2007. Biofilms in the large bowel suggest an apparent function of the
human vermiform appendix. J Theor Biol 249:826–831.
Bollinger RB, Everett ML, Wahl S, Lee Y-H, Orndorff PE, Parker
W. 2005. Secretory IgA and mucin-mediated biofilm formation by
environmental strains of Escherichia coli: role of type 1 pili. Mol
Immunol 43:378–387.
Bollinger RR, Everett ML, Palestrant D, Love SD, Lin SS, Parker
W. 2003. Human secretory immunoglobulin A may contribute to
biofilm formation in the gut. Immunology 109:580–587.
Campbell R, Greaves MP. 1990. Anatomy and community structure
of the rhizosphere. West Sussex, UK: Wiley & Sons.
Capron A, Dombrowicz D, Capron M. 2004. Helminth infections and
allergic diseases. Clin Rev Allergy Immunol 26:25–34.
Correale J, Farez M, Razzitte G. 2008. Helminth infections associated with multiple sclerosis induce regulatory B cells. Ann Neurol
64:187–199.
Costerton JW. 1995. Overview of microbial biofilms. J Ind Microbiol
15:137–140.
Costerton JW, Cheng KJ, Geesey GG, Ladd TI, Nickel JC, Dasgupta
M, Marrie TJ. 1987. Bacterial biofilms in nature and disease.
Annu Rev Microbiol 41:435–464.
Costerton JW, Lewandowski Z, Caldwell DE, Korber DR, Lappin-Scott
HM. 1995. Microbial biofilms. Annu Rev Microbiol 49:711–745.
Darwin C. 1859. On the origin of species by means of natural selection,
or the preservation of favoured races in the struggle for life (1st edition). London: John Murray.
Darwin C. 1871. The descent of man and selection in relation to
sex. London: John Murray.
Dasso JF, Howell MD. 1997. Neonatal appendectomy impairs mucosal immunity in rabbits. Cell Immunol 182:29–37.
Davies D. 2003. Understanding biofilm resistance to antibacterial
agents. Nat Rev Drug Discov 2:114–122.
De Bary A. 1879. Die Erscheinung der Symbiose. Vortrag aut der
Versammlung der naturforscher und Aerzte zu Casse. Strassburg:
Trubner. p 21–22.
Devalapalli AP, Lesher A, Shieh K, Solow JS, Everett ML, Edala AS,
Whitt P, Long RR, Newton N, Parker W. 2006. Increased levels of
IgE and autoreactive, polyreactive IgG in wild rodents: implications
for the hygiene hypothesis. Scand J Immunol 64:125–136.
Donaldson RM, Jr. 1964. Normal bacterial populations of the intestine and their relation to intestinal function. N Engl J Med
270:994–1001.
Douzery EJP, Delsuc F, Stanhope MJ, Huchon D. 2003. Local molecular clocks in three nuclear genes: divergence times for rodents
and other mammals and incompatibility among fossil calibrations.
J Mol Evol 57(Supplement 1):S201–S213.
Drinkwater H. 1924. Fifty years of medical progress, 1873-1922.
New York: Macmillan.
Dykes GA, Sampathkumar B, Korber DR. 2003. Planktonic or biofilm growth affects survival, hydrophobicity and protein expression patterns of a pathogenic Campylobacter jejuni strain. Int J
Food Microbiol 89:1–10.
Falcone FH, Loukas A, Quinnell RJ, Pritchard DI. 2004. The innate
allergenicity of helminth parasites. Clin Rev Allergy Immunology
26:61–72.
Fisher RE. 2000. The primate appendix: a reassessment. Anat Rec
261 B:228–236.
Fong DW, Kane TC, Culver DC. 1995. Vestigialization and loss of
nonfunctional characters. Annu Rev Ecol Syst 26:249–268.
Fraysse N, Couderc F, Poinsot V. 2003. Surface polysaccharide
involvement in establishing the rhizobium-legume symbiosis. Eur
J Biochem 270:1365–1380.
Fumagalli M, Pozzoli U, Cagliani R, Comi GP, Riva S, Clerici M,
Bresolin N, Sironi M. 2009. Parasites represent a major selective
force for interleukin genes and shape the genetic predisposition to
autoimmune conditions. J Exp Med 206:1395–1408.
Gale EA. 2002. A missing link in the hygiene hypothesis? Diabetologia 45:588–594.
Germain D, Laurin M. 2005. Microanatomy of the radius and lifestyle in amniotes (Vertebrata, Tetrapoda). Zool Scr 34:335–350.
Gilbert P, McBain AJ. 2001. Biofilms: their impact on health and their
recalcitrance toward biocides. Am J Infect Control 29:252–255.
Gordon HA, Pesti L. 1971. The gnotobiotic animal as a tool in the
study of host microbial relationships. Bacteriol Rev 35:390–429.
Gorgollon P. 1978. The normal human appendix: a light and electron microscopic study. J Anat 126:87–101.
Gradstein FM, Ogg JG, Smith AG. 2004. A geologic time scale.
Cambridge: Cambridge University Press.
Gupta A, Gopal M, Tilak KV. 2000. Mechanism of plant growth promotion by rhizobacteria. Ind J Exp Biol 38:856–862.
Hattori M, Taylor TD. 2009. The human intestinal microbiome: a
new frontier of human biology. DNA Res 16:1–12.
Hewitson JP, Grainger JR, Maizels RM. 2009. Helminth immunoregulation: the role of parasite secreted proteins in modulating host
immunity. Mol Biochem Parasitol 167:1–11.
Honnegger R. 2000. Great discoveries in bryology and lichenology:
Simon Schwendener (1829-1919) and the dual hypothesis of
lichens. Bryologist 103:307–313.
Imai S, Fujita K. 2004. Molecules of parasites as immunomodulatory drugs. Curr Top Med Chem 4:539–552.
Jolly JM, Lappinscott HM, Anderson JM, Clegg CD. 1993. Scanning
electron-microscopy of the gut microflora of 2 earthworms—
Lumbicus terrestris and Octolasion cyaneum. Microb Ecol 26:
235–245.
Josse S, Moreau T, Laurin M. 2006. Stratigraphic tools for Mesquite.
Available at: http://mesquiteproject.org/packages/stratigraphicTools/.
Kalliomaki M, Kirjavainen P, Eerola E, Kero P, Salminen S, Isolauri
E. 2001. Distinct patterns of neonatal gut microflora in infants in
whom atopy was and was not developing. J Allergy Clin Immunol
107:129–134.
Keith A. 1912. The functional nature of the caecum and appendix.
Br Med J 2:1599–1602.
Kelynack TN. 1893. A contribution to the pathology of the vermiform appendix. London: H. K. Lewis.
Kivity S, Agmon-Levin N, Blank M, Shoenfeld Y. 2009. Infections and autoimmunity—friends or foes? Trends Immunol 30:
409–414.
Kolenbrander PE. 2000. Oral microbial communities: biofilms, interactions, and genetic systems. Annu Rev Microbiol 54:413–437.
Koutroubakis IE, Vlachonikolis IG. 2000. Appendectomy and the development of ulcerative colitis: results of a metaanalysis of published case-control studies. Am J Gastroenterol 95:171–176.
Krause WJ. 1975. Intestinal mucosa of the platypus, Ornithorhynchus anatinus. Anat Rec 181:251–265.
Kumar S, Hedges BS. 1998. A molecular timescale for vertebrate
evolution. Nature 392:917–920.
Lake GB. 1920. Report of an extremely long vermiform appendix. J
Am Med Assoc 75:1269.
Lappin-Scott HM, Costerton JW. 1989. Bacterial biofilms and surface fouling. Biofouling 1:323–342.
Laurin M. 2004. The evolution of body size, Cope’s rule and the origin of amniotes. Syst Biol 53:594–622.
Laurin M. 2005. Embryo retention, character optimization, and the
origin of the extraembryonic membranes of the amniotic egg. J
Nat Hist 39:3151–3161.
Lewis K. 2001. Riddle of biofilm resistance. Antimicrob Agents Chemother 45:999–1007.
FUNCTION AND EVOLUTION OF THE CECAL APPENDIX
Lohr J, Knoechel B, Caretto D, Abbas AK. 2009. Balance of Th1
and Th17 effector and peripheral regulatory T cells. Microbes
Infect 11:589–593.
Lukševics E, Lebedev O, Mark-Kurik E, Karatajute-Talimaa V.
2009. The earliest evidence of host–parasite interactions in vertebrates. Acta Zool 90:335–343.
Maddison WP, Maddison DR. 2009. Mesquite: a modular system for evolutionary analysis. Version 2.72. Available at: http://mesquiteproject.org.
Marjanovic D, Laurin M. 2007. Fossils, molecules, divergence times,
and the origin of lissamphibians. Syst Biol 56:369–388.
Matricardi PM, Rosmini F, Riondino S, Fortini M, Ferrigno L, Rapicetta M, Bonini S. 2000. Exposure to foodborne and orofecal
microbes versus airborne viruses in relation to atopy and allergic
asthma: epidemiological study. BMJ 320:412–417.
McGeady SJ. 2004. Immunocompetence and allergy. Pediatrics
113:1107–1113.
McKenzie RA. 1978. The cecum of the koala phascolarctos-cinereus
light microscopic scanning electron microscopic and transmission
electron microscopic observations on its epithelium and flora.
Aust J Zool 26:249–256.
Mendez R, Borges S, Betancourt C. 2003. A microscopical view of
the intestine of Onychochaeta borincana (Oligochaeta: Glossoscolecidae). Pedobiologia 47:900–903.
Metchnikoff E. 1903. Les microbes intestinaux. Bull Inst Pasteur
1:265–282.
Mizrahi M, Ilan Y. 2009. The gut mucosa as a site for induction of
regulatory T-cells. Curr Pharm Des 15:1191–1202.
Müller GB. 2002. Vestigial organs and structures. In: Pagel M, editor. Encyclopedia of evolution. New York: Oxford University
Press. p 1131–1133.
Neese RM, Williams GC. 1996. Why we get sick: the new science of
darwinian medicine. London: Vintage.
Neiburger JB, Neiburger RG, Richardson ST, Grosfeld JL, Baehner
RL. 1976. Distribution of T and B lymphocytes in lymphoid tissue
of infants and children. Infect Immun 14:118–121.
Nencki M. 1886. Bemerkung zu einer Bemerkung Pasteur’s. Arch
Exp Pathol Pharmacol 20:385–388.
Nilsson MA, Gullberg A, Spotorno AE, Arnason U, Janke A. 2003.
Radiation of extant marsupials after the K/T boundary: evidence
from complete mitochondrial genomes. J Mol Evol 57:S3–S12.
Odze RD, Goldblum JR. 2008. Surgical pathology of the GI tract,
liver, biliary tract and pancreas. 2nd ed. Philadelphia: Saunders.
Orndorff PE, Devapali A, Palestrant S, Wyse A, Everett ML, Bollinger RB, Parker W. 2004. Immunoglobulin-mediated agglutination
and biofilm formation by Escherichia coli K-12 requires the type 1
pilus fiber. Infect Immun 72:1929–1938.
Palestrant D, Holzknecht ZE, Collins BH, Miller SE, Parker W, Bollinger RR. 2004. Microbial biofilms in the gut: visualization by
electron microscopy and by acridine orange staining. Ultrastruct
Pathol 28:23–27.
Pennisi E. 2008. Microbiology. Bacteria are picky about their homes
on human skin. Science 320:1001.
Pester GH. 1965. Congenital absence of the vermiform appendix.
AMA Arch Surg 91:461–462.
Poinar G, Jr., Boucot AJ. 2006. Evidence of intestinal parasites of
dinosaurs. Parasitology 133:245–249.
Pouydebat E, Laurin M, Gorce P, Bels V. 2008. Evolution of grasping among anthropoids. J Evol Biol 21:1732–1743.
Reddy A, Fried B. 2009. An update on the use of helminths to treat
Crohn’s and other autoimmunune diseases. Parasitol Res 104:217–221.
Reshef L, Koren O, Loya Y, Zilber-Rosenberg I, Rosenberg E. 2006.
The coral probiotic hypothesis. Environ Microbiol 8:2068–2073.
Ritchie KB. 2006. Regulation of microbial populations by coral surface
mucus and mucus-associated bacteria. Mar Ecol Prog Ser 322:1–14.
Rook GA, Brunet LR. 2005. Microbes, immunoregulation, and the
gut. Gut 54:317–320.
Rook GAW. 2009. Review series on helminths, immune modulation
and the hygiene hypothesis: the broader implications of the
hygiene hypothesis. Immunology 126:3–11.
Rosenberg E, Koren O, Reshef L, Efrony R, Zilber-Rosenberg I.
2007. The role of microorganisms in coral health, disease and evolution. Nat Rev Microbiol 5:355–362.
579
Scaglia M, Tinelli M, Revoltella R, Peracino A, Falagiani P, Jayakar
SD, Desmarais JC, Siccardi AG. 1979. Relationship between serum IgE levels and intestinal parasite load in African populations. Int Arch Allerg Appl Immunol 59:465–468.
Schiffrin EJ, Blum S. 2002. Interactions between the microbiota
and the intestinal mucosa. Eur J Clin Nutr 56:S60–S64.
Schottelius M. 1902. Die Bedeutung der Darmbakterien Fur die
Ernahrung. II. Arch fur Hygiene 42:48–70.
Schwendener S. 1868. Ueber die Beziehungen zwischen Algen und
Flechtengonidien. Botanische Zeitung 26:289–292.
Scott GB. 1980. The primate caecum and appendix vermiformis: a
comparative study. J Anat 131:549–563.
Smith HF, Fisher RE, Everett ML, Thomas AD, Bollinger RB,
Parker W. 2009. Comparative anatomy and phylogenetic distribution of the mammalian cecal appendix. J Evol Biol 22:1984–1999.
Sonnenburg JL, Angenent LT, Gordon JI. 2004. Getting a grip on
things: how do communities of bacterial symbionts become established in our intestine? Nat Immunol 5:569–573.
Spencer J, Finn T, Isaacson PG. 1985. Gut associated lymphoid tissue: a morphological and immunocytochemical study of the
human appendix. Gut 26:672–679.
Stevens CE, Hume ID. 1995. Comparative physiology of the vertebrate digestive system. Cambridge: Cambridge University Press.
Strachan DP. 1989. Hay fever, hygiene, and household size. Br Med
J 299:1259–1260.
Summers RW, Elliott DE, Qadir K, Urban JF, Jr., Thompson R,
Weinstock JV. 2003. Trichuris suis seems to be safe and possibly
effective in the treatment of inflammatory bowel disease. Am J
Gastroenterol 98:2034–2041.
Tamburrini S, Brunetti A, Brown M, Sirlin CB, Casola G. 2005. CT
appearance of the normal appendix in adults. Eur Radiol
15:2096–2103.
Van Leeuwenhoek A. 1684. An abstract of a letter from Mr. Anthony Leevvenhoek at Delft, dated September 17, 1683, Containing Some Microscopical Observations, about Animals in the Scurf
of the Teeth, the Substance Call’d Worms in the Nose, the Cuticula Consisting of Scales. Philos Trans (1683–1775) 14:568–574.
Vinceslas-Akpa M, Loquet M. 1995. In situ observation of the microflora linked to the digestive tract of Eisenia fetida andrei (Lumbricidae). Eur J Soil Biol 31:101–110.
Weller DM, Thomashow LS. 1994. Current challenges in introducing beneficial organisms into the rhizosphere. New York, NY:
VCH.
West-Eberhard MJ. 2003. Recurrence. Developmental plasticity and
evolution. Oxford: Oxford University Press. p 353–374.
West-Eberhard MJ. 2005. Developmental plasticity and the origin
of species differences. Proc Natl Acad Sci USA 102:6543–6549.
WHO. 2001. The world health report: 2001: mental health: new
understanding, new hope. Geneva, Switzerland: World Health
Organization.
Wible JR, Rougier GW, Novacek MJ, Asher RJ. 2007. Cretaceous
eutherians and Laurasian origin for placental mammals near the
K/T boundary. Nature 447:1003–1006.
Williams RC, Gibbons RJ. 1972. Inhibition of bacterial adherence
by secretory immunoglobulin A: a mechanism of antigen disposal.
Science 177:697–699.
Wilson MS, Maizels RM. 2004. Regulation of allergy and autoimmunity in helminth infection. Clin Rev Allergy Immunol 24:
35–50.
Workman CJ, Szymczak-Workman AL, Collison LW, Pillai MR,
Vignali DA. 2009. The development and function of regulatory T
cells. Cell Mol Life Sci 66:2603–2622.
Xu KD, McFeters GA, Stewart PS. 2000. Biofilm resistance to antimicrobial agents. Microbiology 146:547–549.
Yazdanbakhsh M, Kremsner PG, van Ree R. 2002. Allergy, parasites, and the hygiene hypothesis. Science 296:490–494.
Yazdanbakhsh M, van den Biggelaar A, Maizels RM. 2001. Th2
responses without atopy: immunoregulation in chronic helminth
infections and reduced allergic disease. Trends Immunol 22:
372–377.
Zahid A. 2004. The vermiform appendix: not a useless organ.
JCPSP 14:256–258.
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