A Common Origin for Immunity and Digestion

Abstract

Historically, the digestive and immune systems were viewed and studied as separate entities. However, there are remarkable similarities and shared functions in both nutrient acquisition and host defense. Here, I propose a common origin for both systems. This association provides a new prism for viewing the emergence and evolution of host defense mechanisms.

Full text

HYPOTHESIS ANDTHEORY ARTICLE
published: 19 February 2015
doi: 10.3389/fimmu.2015.00072
A common origin for immunity and digestion
Nichole A. Broderick*
Department of Molecular, Cellular, and Developmental Biology,Yale University, New Haven, CT, USA
Edited by:
Abhay Satoskar,The Ohio State
University, USA
Reviewed by:
Laurel L. Lenz, University of Colorado
School of Medicine, USA
Dina Weilhammer, Lawrence
Livermore National Laboratory, USA
*Correspondence:
Nichole A. Broderick, Department of
Molecular, Cellular, and
Developmental Biology, Yale
University, PO Box 208103, MCDB
KBT 908, New Haven, CT 06520, USA
e-mail: nabroderick@gmail.com
Historically, the digestive and immune systems were viewed and studied as separate
entities. However, there are remarkable similarities and shared functions in both nutri-
ent acquisition and host defense. Here, I propose a common origin for both systems. This
association provides a new prism for viewing the emergence and evolution of host defense
mechanisms.
Keywords: innate immunity, host-microbe interactions, gut microbiome, evolution, metabolism, digestion
physiology
The immune system appeared early in the evolution of metazoa
and is thought to have originated to protect the greater investment
of multi-cellularity (1,2). Currently, two views have been sug-
gested for the origin of the immune system. One view is that the
immune system emerged to protect against invasive microbes (3,
4). Recently, an alternative hypothesis proposed that the immune
system emerged to manage the microbiota (5–7). In this essay, I
suggest a third selection pressure, not exclusionary of the other
views that focus on function. I propose a common origin for the
digestive and immune systems that traces their ancestry to the
quest for more efficient energy acquisition.
IN THE BEGINNING, DIGESTION AND IMMUNITY WERE
ONE . . .
Over a century ago, Metchnikoff proposed that phagocytic
immune cells evolved first as nutritive cells (8). He noted that,
across phylogeny, the universal function of digestion was main-
tained in the process of phagocytosis, irrespective of whether it
occurred in the case of food acquisition (intracellular digestion)
or in an immune role. Moreover, for single-celled organisms like
amoebae, the process of infection and food acquisition are indis-
tinguishable in the initial stages, with the two being separable only
by outcome. The evolution of multi-cellularity permitted special-
ization, including cells devoted to the acquisition of nutrients and
defense. In the event of infection, phagocytic cells ingest, destroy,
and digest microbes resulting in an outcome that is indistinguish-
able from single-celled predation. As proposed by Metchnikoff,
these cells retain the primordial mechanism of nutrient acqui-
sition, providing continuity between nutritional and defensive
roles.
While Metchnikoff saw the connection between digestion
and defense, the immune system is composed of many diverse
processes beyond the cellular response of phagocytosis and indeed
animals most commonly interact with the microbes in their envi-
ronment through contact with epithelial surfaces. Analysis of such
immune and digestive components across animals reveals several
remarkable parallels (Table 1), with many enzymes involved in
immune responses also having roles in digestion. Given the gut was
a major early step in the evolution of metazoa, this tissue is a logical
starting point for an analysis of common function.
THE GUT – CONSERVATION AND DIVERGENCE OF DIGESTIVE
AND IMMUNE FUNCTIONS
The gut is ancient in the animal lineage and arose shortly after the
emergence of multi-cellularity. The gut is thought to have begun
with the formation of a true epithelium, which allowed extracellu-
lar digestion, followed by invagination of the epithelium to provide
an enclosed space to facilitate the digestive process. The gut later
progressed from a one-way digestive tube to the highly organized
and specialized organ that is found today in most animals [for
more details on the evolution of the gut, see Ref. (9,10) and ref-
erences therein]. Multiple evolutionary advances of metazoa are
attributed to the development and adaptation of the gut (9), as it
permitted extracellular digestion and the capacity to digest larger
volumes without losing nutrients to diffusion (11). Consequently,
the emergence of the gut is thought to have increased energy avail-
ability, which in turn may have driven the development of other
organ systems.
The gut evolved in a sea of microbes, which posed new chal-
lenges and provided new opportunities for nutrition (7). In its
most primitive stages, the gut would have provided a new niche
that allowed or even invited colonization bymicrobes. Hosts had to
contend with these microbes, either through indifference, forming
beneficial associations, eating them, or controlling them to reduce
microbial-mediated damage and/or competition for nutrients.
While both invertebrates and vertebrates possess innate immune
functions, only the latter have adaptive immunity. For this reason,
it is thought that the evolution of the immune system paralleled
the evolution of the gut, with immunological complexity emerging
to protect an increasingly sophisticated digestive tract. In con-
trast, this essay proposes the alternative view that innate immune
defense and digestion were indistinguishable in the primitive gut.
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Broderick A common origin for immunity and digestion
Table 1 | Examples of dual-use action in digestion and immunity.
Component Type Digestion/metabolism Immunity
Enzymes Proteases Protein break down IgA cleavage, toll signal processing
Lysozymes Cell wall break down Microbial lysis
Chitinases Chitin digestion Microbial lysis, augment adaptive responses,
wound healing
Phenoloxidases Lignin degradation (fungi, invertebrates) Melanin synthesis
β1,3-glucanases Sugar break down Pattern recognition receptor
Amidases Cell wall break down Microbial lysis
Antimicrobial peptides Cellular break down Microbial lysis
Receptors/signaling TIR domain proteins Foraging Toxin sequestration
Response to nutrients Immune effectors, pathogen avoidance
Starvation resistance Pattern recognition receptor
Cellular processes Phagocytosis autophagy Food acquisition Microbial clearance
Intracellular digestion of food Microbial clearance
This hypothesis has a number of implications for our under-
standing of the evolution of the immune system. What today are
presumed to be disparate primordial functions may not be so. For
example, one immediate implication is that intersections between
immunity and metabolism may be more intricately linked than
previously appreciated (12,13). An immediate parallel is that both
pathogen clearance and digestion involve microbial destruction.
Hence, enzymes produced for digestion have dual-use function in
protection and subsequent evolution of the genes could promote
specialization and divergence. For example, β1,3-glucanases are
digestive enzymes, but one subfamily lost catalytic activity and is a
pattern recognition receptor. Similarly,toll-interleukin-1 receptor
(TIR) domain proteins in amoebae and an ortholog in C. elegans
have dual roles in nutritional foraging and defense (14,15). These
dual roles suggest contexts when these functions cannot be dis-
tinguished. This may be especially true amongst animals where
bacterivory, or the feeding on bacteria as an energy source, pro-
vides a major source of nutrition. The role of bacterivory in the
origin and evolution of animals is important due to its potential
in providing for the acquisition of novel functions through lateral
gene transfer (16,17). In this regard, lateral transfer of genes with
putative defensive function could have been maintained due to
their role as digestive enzymes. For example, two recent reports
of genes transferred from bacteria to eukaryotes that were asso-
ciated with antibacterial activity (one a lysozyme, the other an
amidase) could easily function in the digestion of bacteria for
nutrient acquisition (18,19). In this regard, lysozymes have his-
torically been categorized into groups as either having defensive or
digestive functions, yet they are essentially identical. By and large,
the digestive and immune functions of these enzymes has been
assigned based on the tissues in which they are expressed, gut or
stomach versus immune cells, respectively. However, recent stud-
ies have argued that they were preserved through common descent
with true homology (20,21).
This hypothesis also suggests alternative views to how the
microbiota and the defensive function of the immune system
evolved. Considering the emergence of the microbiota, one might
envision how microbes that were not digested could be maintained
in the gut. In this regard, microbes that contributed to host nutri-
tion by producing a byproduct or transforming compounds could
reduce host requirements for microbes as direct food sources, thus
permitting their retention. In addition, microbes that are able to
resist the digestive processes would have been able to persist in the
gut and form potential associations with the host. Alternatively,
hosts that evolved gut attributes (physical/physiological) or the
ability to selectively digest microbes would be able to maintain
a microbiota, which would have been selected for if it provided
an advantage. McFall-Ngai (22) has proposed that the evolution
of the adaptive immune system may have permitted greater flex-
ibility in the diversity of microbes associated with the gut. Along
these lines, the reduced reliance of microbes as direct food sources
may have permitted greater diversity of the microbiota and fur-
ther specialization of epithelial immune responses. In addition,
the microbiota is a potential food reserve. Axenic mice are more
susceptible to starvation, and starvation of many animals reduces
microbiota density, suggesting utilization as food (23–25) More-
over, such phenomenon as termite trophallaxis and digestion of
microbiota by nitrogen-deprived herbivores supports the notion
that the microbiota can provide a nutritional reserve (26). It is
noteworthy that there are 20% more calories in a gram of microbes
than a gram of carbohydrate (27). However, the same microbiota
that can serve as food also poses a potential danger to the host
as a source of infectious disease. Consequently, these interactions
between host and microbiota illustrate the continuity between
digestion and immunity.
CONCLUSION
This hypothesis proposes a common origin for two fundamental
physiological systems that are currently viewed as separate and
disparate. While the interplay between metabolic and immune
pathways, including genes that function in both systems (28) [i.e.,
foxo (29), MyD88 (30,31), TGF-β(32), mef2 (33), atf3 (34), . . .]
is an area of intense study, these similarities are generally viewed
as convergent. In contrast, this hypothesis posits a common origin
for these functions, thus providing an explanation for the main-
tenance of dual functions. I note similar associations in other
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Broderick A common origin for immunity and digestion
systems, such as Toll having roles in both immunity and devel-
opment. Underlying these associations is the fact that the ancient
function of proteins might be conserved, but can also be co-opted
for new roles.
The hypothesis has some practical applications for the inter-
pretation of experiments involving mutants of either metabolic
or immune pathways. For example, phenotypes attributed to
immune deficiencies, which are often associated with higher
microbial burden, could also represent a digestive or metabolic
deficiency. An approach to test the hypothesis may be to delete
genes that are putatively associated with an immune or digestive
function and assess the resulting phenotypes of the other system.
By considering a common origin for immunity and digestion, it is
possible to integrate metabolic, physiological, and immune infor-
mation and interpret those data in the context of a unified view.
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Conflict of Interest Statement: The author declares that the researchwas conducted
in the absence of any commercial or financial relationships that could be construed
as a potential conflict of interest.
Received: 04 November 2014; accepted: 04 February 2015; published online: 19
February 2015.
Citation: Broderick NA (2015) A common origin for immunity and digestion. Front.
Immunol. 6:72. doi: 10.3389/fimmu.2015.00072
This article was submitted to Microbial Immunology, a section of the journal Frontiers
in Immunology.
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