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Advances in Experimental Medicine and Biology 1265

Guoyao Wu Editor

Amino Acids
in Nutrition
and Health
Amino acids in systems function and health
Advances in Experimental Medicine
and Biology

Volume 1265

Series Editors
Wim E. Crusio, Institut de Neurosciences Cognitives et Intégratives
d’Aquitaine, CNRS and University of Bordeaux UMR 5287,
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Mayo Clinic, Rochester, MN, USA
Heinfried H. Radeke, Institute of Pharmacology & Toxicology,
Clinic of the Goethe University Frankfurt Main,
Frankfurt am Main, Hessen, Germany
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Center, Tehran University of Medical Sciences, Tehran, Iran
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Guoyao Wu
Editor

Amino Acids in Nutrition

and Health
Amino acids in systems function
and health
Editor
Guoyao Wu
Department of Animal Science
Texas A&M University
College Station, TX, USA

ISSN 0065-2598     ISSN 2214-8019 (electronic)

Advances in Experimental Medicine and Biology
ISBN 978-3-030-45327-5    ISBN 978-3-030-45328-2 (eBook)
https://doi.org/10.1007/978-3-030-45328-2

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Contents

1 Amino Acids in Intestinal Physiology and Health������������������������   1

Martin Beaumont and François Blachier
2 Amino Acid Metabolism in the Liver: Nutritional
and Physiological Significance�������������������������������������������������������� 21
Yongqing Hou, Shengdi Hu, Xinyu Li, Wenliang He,
and Guoyao Wu
3 Amino Acids in Circulatory Function and Health������������������������ 39
William Durante
4 Epithelial Dysfunction in Lung Diseases: Effects
of Amino Acids and Potential Mechanisms����������������������������������� 57
Jingqing Chen, Yuhang Jin, Ying Yang, Zhenlong Wu,
and Guoyao Wu
5 Amino Acid Metabolism in the Kidneys: Nutritional and
Physiological Significance���������������������������������������������������������������� 71
Xinyu Li, Shixuan Zheng, and Guoyao Wu
6 Amino Acids in Health and Endocrine Function�������������������������� 97
Nick E. Flynn, Max H. Shaw, and Jace T. Becker
7 Amino Acids in Reproductive Nutrition and Health�������������������� 111
Haijun Gao
8 Impacts of Amino Acids on the Intestinal
Defensive System������������������������������������������������������������������������������ 133
Wenkai Ren, Peng Bin, Yulong Yin, and Guoyao Wu
9 Maternal Nutrient Restriction and Skeletal Muscle
Development: Consequences for Postnatal Health ���������������������� 153
Camila Sandoval, Guoyao Wu, Stephen B. Smith, Kathrin A.
Dunlap, and M. Carey Satterfield
10 Metabolism of Amino Acids in the Brain and Their
Roles in Regulating Food Intake���������������������������������������������������� 167
Wenliang He and Guoyao Wu

v
vi Contents

11 Metabolism and Functions of Amino Acids in the Skin��������������� 187

F. Solano
12 Metabolism and Functions of Amino Acids
in Sense Organs�������������������������������������������������������������������������������� 201
Guoyao Wu

Index���������������������������������������������������������������������������������������������������������� 219
 Amino Acids in Intestinal
Physiology and Health 1
Martin Beaumont and François Blachier

Abstract may participate in mucosal inflammation

when present in excess, while others (e.g.
Dietary protein digestion is an efficient pro- indole derivatives) prevent gut barrier dys-
cess resulting in the absorption of amino acids function or regulate enteroendocrine func-
by epithelial cells, mainly in the jejunum. tions. Lastly, some recent data suggest that
Some amino acids are extensively metabo- dietary amino acids might regulate the compo-
lized in enterocytes supporting their high sition of the gut microbiota, but the relevance
energy demand and/or production of bioactive for the intestinal health remains to be deter-
metabolites such as glutathione or nitric oxide. mined. In summary, amino acid utilization by
In contrast, other amino acids are mainly used epithelial cells or by intestinal bacteria appears
as building blocks for the intense protein syn- to play a pivotal regulator role for intestinal
thesis associated with the rapid epithelium homeostasis. Thus, adequate dietary supply of
renewal and mucin production. Several amino amino acids represents a key determinant of
acids have been shown to support the intesti- gut health and functions.
nal barrier function and the intestinal endo-
crine function. In addition, amino acids are Keywords
metabolized by the gut microbiota that use
them for their own protein synthesis and in Amino acids · Intestinal epithelial cells ·
catabolic pathways releasing in the intestinal Intracellular metabolism · Microbiota ·
lumen numerous metabolites such as ammo- Bacterial metabolites · Intestinal barrier
nia, hydrogen sulfide, branched-chain amino
acids, polyamines, phenolic and indolic com-
pounds. Some of them (e.g. hydrogen sulfide)
disrupts epithelial energy metabolism and 1.1 Introduction

The quantities of dietary proteins ingested every

M. Beaumont
GenPhySE, Université de Toulouse, INRA, INPT, day by Humans, whatever their animal or plant
ENVT, Toulouse, France origin, are vastly different according to food
e-mail: martin.beaumont@inrae.fr availability and cultural dietary habits. In Western
F. Blachier (*) Europe and United States for instance, protein
Université Paris-Saclay, AgroParisTech, INRAE, consumption averages approximately 1.5-fold
UMR PNCA, Paris, France the recommended daily amount (Rand et al.
e-mail: francois.blachier@agroparistech.fr

© Springer Nature Switzerland AG 2020 1

G. Wu (ed.), Amino Acids in Nutrition and Health, Advances in Experimental Medicine
and Biology 1265, https://doi.org/10.1007/978-3-030-45328-2_1
2 M. Beaumont and F. Blachier

2003; Dubuisson et al. 2010; Pasiakos et al. 1.2  mino Acid Metabolism by
A
2015). In sharp contrast, for instance in Southern the Intestinal Cells
Ethiopia, the prevalence of inadequate dietary and Functional Implications
protein intake represents as much as 94% in
women (Asayehu et al. 2017). From experimental works performed in animal
Protein digestion in the mammalian digestive models, mostly rodents and pigs, and from more
tract is globally a very efficient process, being limited clinical studies with human volunteers, it
generally higher than 90% (Bos et al. 2005; Tomé appears clearly that a significant part of several
2012); even if some dietary proteins, like for dispensable and indispensable amino acids pres-
instance proteins in rapeseed, are digested with ent in the small intestine content are metabolized
lower efficiency (Bos et al. 2007). The amino during their journey from the luminal side of the
acids and oligopeptides that are released from intestinal epithelium to the portal bloodstream
dietary and endogenous proteins in the lumen of (Baracos 2004). The in vitro studies of amino
the small intestine are absorbed mainly in the acid metabolism in the small and large intestine
proximal jejunum through the enterocytes by a epithelial cells generally used isolated living
variety of transporters present in the brush-border absorptive enterocytes (Blachier et al. 1993) and
and baso-lateral membranes of enterocytes colonocytes (Cherbuy et al. 1995) for determin-
(Bröer 2008; Mailliard et al. 1995). The intestinal ing their metabolic capacities towards the differ-
epithelium can be viewed as a selective barrier ent amino acids and their metabolites produced
towards luminal compounds in a context of a within the luminal content. This in vitro design
renewal of the intestinal epithelium that is com- allows to document the metabolic capacity of
plete within a few days (Potten and Allen 1977; intestinal cells towards amino acids, but not to
Potten 1997) through mitosis of pluripotent stem fully extrapolate to the in vivo situation when
cells and differentiation in different phenotypes numerous substrates are present at the same time
with specialized functions (Lin 2003; Barker in the luminal content. A major in vivo experi-
et al. 2008; Moore and Lemischka 2006). mental design used to estimate the apparent
In this chapter, we will present how some amino acid intestinal absorption and metabolism
amino acids are metabolized by the intestinal epi- consists of measuring the amino acid concentra-
thelial cells during their transcellular journey tions at different time after a meal in both the
from the lumen to the bloodstream. The conse- arterial and portal blood, as well as measuring
quences of these processes for enterocyte func- continuously the blood flow in the portal vein
tionality will be presented. Then, the regulatory (Rérat et al. 1988). These experiments help to
roles of amino acids in intestinal homeostasis determine if a given amino acid is globally
will be described with a focus on the gut barrier degraded (e.g. glutamine and glutamate) or pro-
and endocrine functions. We will also give an duced (e.g. aspartate and alanine) in the intestinal
overview on the ways by which the intestinal mucosa (Blachier et al. 1999). The limitation of
microbiota metabolizes amino acids; and how such experiments resides in the fact that the por-
such metabolic capacity is linked to functional tal vein does not exclusively drain amino acids
implications in both the small and large intestine. from the intestine, but also from several other
Then, we will examine how dietary amino acids visceral tissues. The utilization of alimentary
have an impact on the intestinal microbiota com- proteins labelled with stable isotope allows for
position. The aim of the authors is not to cover in following more precisely the metabolic fate of
an exhaustive way the different topics presented amino acids during their intestinal absorption
in this chapter, but rather to give some represen- (Morens et al. 2003). Utilization of amino acids
tative examples illustrating how amino acid and in intestinal epithelial cells supports not only pro-
their derived compounds may have an impact on tein and nucleotide synthesis, but also the synthe-
intestinal physiology. sis of various compounds with important
biological functions like for instance the tripep-
1 Amino Acids in Intestinal Physiology and Health 3

tide glutathione (Reeds et al. 1997). It is worth and colonocytes (Darcy-Vrillon et al. 1993).
noting that in the enterocytes from the small Glutamate can be used in enterocytes for protein
intestine, the amino acids can be supplied from synthesis or can be extensively metabolized in
both the luminal route (notably in the post-­ other pathways including those involved in
prandial period), but also from the baso-lateral enterocyte ATP production (Blachier et al. 2009)
(blood) side (Windmuller and Spaeth 1975); (Fig. 1.1). Indeed, glutamine and glutamate are
while for the colonocytes, the amino acid supply among the most important contributors for energy
is believed to be from the blood side exclusively metabolism in mammalian enterocytes (Ashy
(Darragh et al. 1994), even if this latter point et al. 1988) and colonocytes (Ardawi and
remains somewhat controversial as some amino Newsholme 1985). ATP production and utiliza-
acid transporters have been identified on the tion are intense in enterocytes. This corresponds
luminal side of colonocytes (van der Wielen et al. to the fact that although the gastrointestinal tract
2017). represents approximately 5% of the body weight,
it is responsible for around 20% of whole body
oxygen consumption (Vaugelade et al. 1994; Yen
1.2.1 Glutamate, Glutamine, et al. 1989). The intestinal epithelium presents a
Arginine and Related Amino high energy demand (Watford et al. 1979) due to
Acid Metabolism in Intestinal the rapid renewal of the epithelium, thus requir-
Absorptive Cells ing intense anabolic metabolism. In addition,
sodium extrusion through the Na/K ATPase
Glutamate and glutamine are extensively metab- activity following nutrient and electrolyte absorp-
olized in enterocytes (Darcy-Vrillon et al. 1994) tion is likely to represent a major ATP-consuming

Fig. 1.1 Glutamate

metabolism in intestinal
absorptive cells
Glutamate is metabolized
to alpha ketoglutarate
(alpha KG) by transamina-
tion with pyruvate (PYR)
and oxaltoacetate (OAA).
Alpha KG then enter the
TCA cycle. Glutamate is
also a precursor for the
stepwise production of
citrulline and proline
4 M. Beaumont and F. Blachier

process in enterocytes and colonocytes (Buttgereit Stipanuk 1989); and inhibition of mucosal gluta-
and Brand 1995). The metabolic steps involved in thione synthesis is associated with alteration of
glutamate utilization in enterocytes involve trans- intestinal functions that can be prevented by giv-
amination with oxaloacetate to produce alpha-­ ing glutathione monoester orally (Martensson
ketoglutarate and aspartate (Fig. 1.1). Incidentally et al. 1990). In addition to their capacity to syn-
aspartate, in addition to glutamine and glutamate, thesize glutathione, human enterocytes take up
represent a major fuel for the absorptive entero- extracellular glutathione (Iantomasi et al. 1997).
cytes (Windmueller and Spaeth 1976). Glutamate Glutathione in intestinal mucosa appears to
can also be transaminated in the presence of derive largely from the metabolism of enteral
pyruvate to produce alanine and alpha-­ glutamate (Reeds et al. 1997). The ratio of
ketoglutarate, these latter compounds entering reduced to oxidized glutathione is an important
the tricarboxylic cycle in the mitochondria. In parameter for fixing the intracellular redox status
contrast, for glutamine oxidation, an initial con- and controlling the intracellular concentrations of
version of glutamine into glutamate and ammo- both oxygen-reactive and nitrogen-reactive spe-
nia by the phosphate-dependent glutaminase cies (Chakravarthi et al. 2006; Kemp et al. 2008).
activity has to proceed in the mitochondria of Glutamate and glutamine allow the net pro-
enterocytes (Pinkus and Windmueller 1977, duction of of proline (Wu et al. 1994a), ornithine
Duée et al. 1995) (Fig. 1.2). (Henslee and Jones 1982), and citrulline (Wu
Glutamate, together with cysteine and gly- et al. 1994b) (Fig. 1.1). Although neither orni-
cine, are the amino acid precursors for the syn- thine nor citrulline are present in proteins, they
thesis of glutathione in mammalian cells represent important compounds for inter-organ
including intestinal epithelial cells (Coloso and metabolism. Ornithine that is mainly produced

Fig. 1.2 Glutamine

metabolism in intestinal
absorptive cells
Glutamine is converted to
glutamate and ammonia.
Then glutamate is
converted to alpha
ketoglutarate (alpha KG)
that enter the TCA cycle
1 Amino Acids in Intestinal Physiology and Health 5

Fig. 1.3 Arginine

metabolism in intestinal
absorptive cells
Arginine is converted to
ornithine and urea, and to a
much lower extent to nitric
oxide (NO) and citrulline.
Citrulline can also be
produced by condensation
of ornithine with carbamo-
ylphosphate (CP). A minor
part of ornithine can be
used for putrescine
(PUTR), spermidine
(SPMD), and spermine
(SPM) synthesis

together with urea from arginine by the arginase and, since the polyamine circulating concentra-
activity in enterocytes (Mouillé et al. 2004), can tion are below micromolar concentrations (Bartos
be exported in the portal vein and be used in the et al. 1977), the enterocyte and colonocyte poly-
liver as an intermediate in the urea cycle (Lund amine content depends almost exclusively on the
and Wiggins 1986). A part of ornithine released polyamines in the luminal contents (Kumagai
from the amino precursors is converted to citrul- and Johnson 1988; Osborne and Seidel 1990),
line in enterocytes (Blachier et al. 1991) either from dietary or microbiota origin (detailed
(Fig. 1.3). Then, citrulline is released in the portal below) (Bardocz 1993; Blachier et al. 1991)
vein, and passes through the liver without major (Fig. 1.3).
uptake, and is then used for de novo synthesis of Arginine, apart from being a precursor of
arginine in kidneys (Cynober 1994; Dhanakoti ornithine, is also a precursor of nitric oxide
et al. 1990). In addition, a minor part of ornithine (NO) and citrulline in both enterocytes and
released from arginine and glutamine can be used colonocytes (Blachier et al. 2011, 1991, 1993;
by enterocytes and colonocytes for the stepwise M’Rabet-Touil et al. 1993) (Fig. 1.3). The pro-
production of the polyamines putrescine, spermi- duction of NO by the enterocytes appears to be
dine and spermine (Fig. 1.3). These amino acid-­ involved in the protection of the gastrointesti-
derived compounds are necessary for intestinal nal mucosa (Stark and Szurszewski 1992;
epithelial cells mitosis (Ray et al. 2001). However, Miller et al. 1993; Quintero and Guth 1992;
except in the neonatal period, the endogenous Konturek et al. 1992; MacKendrick et al. 1993),
production of polyamines by enterocytes and the regulation of the intestinal motility
colonocytes appears barely detectable in mam- (Calignano et al. 1992; Hata et al. 1990), and
mals (Blachier et al. 1992; Mouillé et al. 2004), the modulation of the intestinal epithelial per-
6 M. Beaumont and F. Blachier

meability (Kubes 1992, 1993). Although a lim- 1.2.3  ulfur-Containing Amino Acid
S
ited amount of NO may play a protective role Metabolism in Intestinal
during active intestinal mucosal inflammation Absorptive Cells
(Dijkstra et al. 1998; Perner and Rask-Madsen
1999; Guslandi, 1998), numerous studies As indicated above, cysteine is a precursor for the
reported increased production of NO in colon synthesis of glutathione, and it has been deter-
of patients suffering from ulcerative colitis and mined that between 30% and 50% of the total
Crohn’s disease (Guihot et al. 2000; Lundberg utilization of this amino acid by the body is
et al. 1994; Boughton-Smith et al. 1993; devoted to the overall glutathione synthesis
Rachmilewitz et al. 1995; Singer et al. 1996; (Fukagawa et al. 1996; Malmezat et al. 1998). If
Leonard et al. 1998; Mc Laughlan et al. 1997; we consider the utilization of sulfur-containing
Zhang et al. 1998). Excessive NO, by itself or amino acids in enterocytes, the net portal balance
through reactions with oxygen species (e.g. for methionine represents as much as 48% of
leading to the production of the oxidant per- intake in piglets, suggesting that a relatively large
oxynitrite) is likely to play a role in the genesis part of the dietary methionine is consumed by the
of the colonic mucosa lesions as observed in portal-drained viscera for protein synthesis and
inflammatory bowel diseases (Beckman and catabolism (Stoll et al. 1998). More precisely, the
Koppenol 1996; Banan et al. 2001; Kubes and piglet gastrointestinal tract consumes approxi-
McCafferty 2000). mately 20% of the dietary methionine (Riedijk
et al. 2007). Cysteine, fed enterally or parenter-
ally appears effective for sparing dietary methio-
1.2.2  ranched-Chain Amino Acid
B nine (Shoveller et al. 2003). In the neonatal piglet
Metabolism in Intestinal model, sulfur-containing amino acid deficiency
Absorptive Cells results in small intestine atrophy with lower gob-
let cells and lower glutathione intestinal content
Regarding the metabolic fate of branched-chain (Bauchart-Thevret et al. 2009). These effects
amino acids (i.e. leucine, isoleucine, and were associated with upregulation of the intesti-
valine), it has been determined in the pig model nal methionine cycle activity. Furthermore, in
that 32% of leucine in the diet is extracted by young pig, the gastrointestinal tract appears to be
the portal-­drained viscera in the first pass, with a site for whole-body transmethylation and trans-
21% of the extracted leucine being utilized for sulfuration, these two metabolic pathways being
the intestinal mucosa protein synthesis (Stoll responsible for a majority of methionine utiliza-
et al. 1998), the rest of leucine being presum- tion by the gastrointestinal tract (Riedijk et al.
ably catabolized. Overall, 44% of total 2007). However, as previously said, despite large
branched-chain amino acids are extracted by utilization by the intestine, methionine is little
first-pass splanchnic metabolism in neonatal catabolized in enterocytes suggesting that this
piglets (Elango et al. 2002). The catabolism of amino acid may be substantially consumed in
the branched-chain amino acids in enterocytes other cells of the portal-drained viscera, and/or
appears to imply extensive transamination and by the intestinal microbiota.
decarboxylation (Chen et al. 2009). In contrast,
other essential amino acids (i.e. histidine,
lysine, methionine, phenylalanine, threonine, 1.2.4 Threonine Metabolism
and tryptophan) that are used for protein syn- in Intestinal Absorptive Cells
thesis in the intestinal mucosa are apparently
little catabolized in enterocytes (Chen et al. As noted above, the metabolic capacity of entero-
2009). Metabolism of essential amino acids in cytes for threonine catabolism is close to the limit
colonic epithelial cells remains to be of detection (Chen et al. 2009). The intestinal
determined. mucins are glycoproteins very rich in threonine
1 Amino Acids in Intestinal Physiology and Health 7

(Fogg et al. 1996). In a model of experimental 1.3  egulatory Roles of Amino

R
colitis, the intestinal inflammation increases the Acids in Endocrine
gastrointestinal uptake of threonine and mucin and Intestinal Barrier
synthesis (Rémond et al. 2009). Dietary threo- Functions
nine extraction by the small intestine is likely to
reduce threonine availability for other tissues 1.3.1 Amino Acids
when mammals are fed a diet marginally defi- and Enteroendocrine
cient in threonine (Hamard et al. 2009). Function
Interestingly, a moderate threonine deficiency
was responsible for an alteration of the intestinal Enteroendocrine cells are one type of polarized
functionality in terms of paracellular permeabil- differentiated intestinal epithelial cells. These
ity (Hamard et al. 2010). The high rate of utiliza- cells that are the hormone-producing cells of the
tion by the intestinal mucosa appears largely due intestine, represent not more than 1% of the
to the incorporation of this amino acid in the pro- intestinal epithelial cells, and are present all
teins of the mucosa, notably in the proteins along the gastro-intestinal tract, where they are
secreted by the mucous (goblet) cells (Schaart located in the intestinal villi, but also in the crypts
et al. 2005). (Janssen and Depoortere 2013). The hormones
secreted by the entero-endocrine cells present a
broad spectrum of physiological effects. For
1.2.5 Lysine and Phenylalanine instance, the effects of cholecystokinin (CCK)
Metabolism in Intestinal include stimulation of endocrine pancreas secre-
Absorptive Cells tion (Hermansen 1984), intestinal motility
(Meyer et al. 1989), regulation of gastric empty-
In the piglet model, when expressed as a percent- ing (Liddle et al. 1986), and food intake (Lo et al.
age of the enteral tracer input, it has been deter- 2014). A wide range of luminal compounds, such
mined that the first-pass metabolism of lysine is as nutrients (Furness et al. 2013), bacterial
substantial, averaging 35% (Stoll et al. 1998). metabolites (e.g. short-chain fatty acids
However, only 18% of what is used in the first-­ (Christiansen et al. 2018)), and microbial compo-
pass metabolism is recovered in the intestinal nents (Bugunovic et al. 2007; Lebrun et al. 2017)
mucosa proteins. This may be due to lysine utili- are able to stimulate the expression and the secre-
zation by the microbiota. However, there are also tion of gut enterohormones. Among these com-
evidences in favor of de novo synthesis of lysine pounds, protein hydrolysates and amino acids are
by the intestinal microbiota (Torrallardona et al. known to stimulate the release of CCK through
1996; Backes et al. 2002). However, the net result numerous type of receptors (Choi et al. 2007).
of lysine production and utilization by the intesti- The aromatic amino acids phenylalanine and
nal microbiota in different contexts remains to be tryptophan have been identified as the most effec-
determined (Davila et al. 2013). Interestingly, it tive for increasing CCK release (Hira et al. 2008;
has been shown that dietary lysine used by the Liou et al. 2011; Wang et al. 2011). The taste
portal-drained viscera is driven by its luminal receptor T1R1 and T1R3 expressed in CCK-­
bioavailability; and this utilization is stimulated secreting cells have been shown to be implicated
immediately after meal ingestion (Bos et al. in the CCK secretion in response to phenylala-
2003). nine, leucine, and glutamate (Daly et al. 2013). In
In the piglet model, when expressed as a per- the small intestine, amino acids sensing by
centage of the enteral tracer, a marked first pass enteroendocrine cells via G protein-coupled
metabolism of phenylalanine is measured averag- receptors (GPCR) such as calcium-sensing recep-
ing 35%, with 18% of what is used in the total tor (CaSR) and GPR142 induces the releases of
first-pass metabolism being recovered in mucosal hormones such as glucagon-like peptide 1
proteins (Stoll et al. 1998). (GLP1) (Gribble and Reimann 2016).
8 M. Beaumont and F. Blachier

1.3.2  mino Acids and Intestinal

A supplementation also prevented intestinal inflam-
Barrier Function mation through activation of the aryl hydrocar-
bon receptor (AhR) (Islam et al. 2017). Indeed,
The intestinal mucosa is a physicochemical and several tryptophan catabolites produced by the
immunological barrier against luminal antigens gut microbiota (detailed bellow) activate the AhR
and enteric pathogens. Besides their role as build- pathway that is a master regulator of the gut bar-
ing blocks for protein synthesis, amino acids rier function (Agus et al. 2018). Tryptophan sup-
regulate critical functions of the intestinal barrier plementation also upregulated the gene
such as epithelial permeability, tight junction for- expression of AhR target genes and downregu-
mation, antimicrobial peptides secretion, mucus lated the expression of interleukin 8 in piglets
production and innate immune responses (Vidal-­ (Liang et al. 2018). Moreover, some of the bene-
Lletjos et al. 2017; Coëffier et al. 2010). Herein, ficial effects of tryptophan for gut health might
we summarize the main effects on the gut barrier be related to its metabolism by epithelial indole-
of amino acids individually or in combination amine 2,3 oxygenase (IDO) that produces the
(Fig. 1.4). immune regulator metabolite kynurenine (Agus
Tryptophan plays a key role in mucosal et al. 2018).
homeostasis, as exemplified by the detrimental The beneficial effects of glutamine for mucosal
effects of a tryptophan deficient diet in a colitis homeostasis have been demonstrated by numerous
mouse model, notably through the down regula- studies. Glutamine limits intestinal inflammation
tion of multiple antimicrobial peptides in a mam- by downregulating the production of cytokines by
malian target of rapamycin (mTOR)-dependent immune (macrophages, lymphocytes) and epithe-
manner (Hashimoto et al. 2012). Beneficial lial cells notably through nuclear factor-κB (Nf-
effects of dietary tryptophan supplementation κB) pathway inhibition (Achamrah et al. 2017).
were observed in a porcine model of colitis, with Additionally, glutamine prevents oxidative stress
a reduction of intestinal permeability and of pro-­ by regulating intracellular glutathione (Coëffier
inflammatory cytokine production (Kim et al. et al. 2010). Glutamine also regulates the epithelial
2010). In a mouse model of colitis, tryptophan permeability through an upregulation of the

Fig. 1.4 Main effects of amino acids on the intestinal epithelium

The effects of amino acids (either positive or negative) are indicated in regards (left to right) to hormone secretion,
innate immune functions, mucosal inflammation, antimicrobial peptide secretion, epithelial permeability, and mucus
secretion
1 Amino Acids in Intestinal Physiology and Health 9

expression of tight junction proteins such as occlu- 2001). In septic patients, the sodium-dependent
din, claudin-1, zonula occludens-1 (Achamrah glutamine transport is decreased in both jejunum
et al. 2017). Glutamine supplementation in mice and ileon (Salloum et al. 1991). Furthermore, gut
upregulated the expression of Toll-Like receptor 4 glutamine and oxygen consumption are markedly
(Tlr4) and pro-­ inflammatory cytokines in the diminished in such patients (Souba et al. 1990). In
ileum, while in the jejunum, glutamine upregu- rats receiving an intraperitoneal injection of LPS,
lated the expression of Mucin 4 and of several anti- transport measurement indicated a decreased
microbial peptides (Ren et al. 2014a). These activity in the jejunum of the sodium-dependent
results suggest that the effects of glutamine sup- glutamine uptake and glutaminase activity
plementation on immune responses are dependent (Salloum et al. 1991; Souba et al. 1990; Haque
of the intestinal segment considered. It remains to et al. 1997), suggesting less glutamine being
be investigated whether this activation of immune available for enterocyte metabolism. In the model
response in the mucosa, depending on the overall of sepsis provoked experimentally by caecal liga-
context, is beneficial or not for gut health. Another tion and puncture, the capacity of enterocytes for
study in mice showed that glutamine supplementa- oxidation and the intestinal mucosa glutaminase
tion increased the number of immunoglobulin A activity are decreased (Ardawi et al. 1990), with a
(IgA)+plasma cells, upregulated the expression of concomitant negative nitrogen balance. Although
the polymeric immunoglobulin receptor (Pigr), the mechanisms underlying decreased glutamine
and increased IgA secretion in intestine of mice metabolism in enterocytes in septic animals
(Wu et al. 2016). These effects were associated remain unclear, interleukin-1 (IL-1) has been
with an upregulation of the expression of genes shown to act as a mediator of the alterations in gut
involved in plasma cells maturation (TGF-B pro- glutamine in endotoxemia and sepsis (Augsten
teins, Th2 cytokines, BAFF and APRIL), but were et al. 1991; Mester et al. 1993). However, it is
not observed after an antibiotic treatment, suggest- worth noting that the effect of endotoxemia and
ing a potential involvement of the microbiota in sepsis on glutamine metabolism in the intestinal
the regulation of IgA secretion by glutamate. mucosa is likely unspecific since absorption of
Endotoxemia and sepsis have been shown to several other amino acids, including leucine, pro-
represent situations of markedly impaired gluta- line, glutamate and arginine, are also affected
mine metabolism in intestine. Endotoxemia that is (Salloum et al. 1991; Abad et al. 2001; Gardiner
defined as the presence of endotoxin in blood may et al. 1995; Sodeyama et al. 1993). Indeed, fol-
result from a transfer of a pathological amount of lowing endotoxemia, almost all circulating amino
endotoxin (also called bacterial lipopolysaccha- acids are markedly decreased suggesting a marked
ride, LPS) from the intestinal lumen to the blood- decrease of the intestinal functions, notably the
stream due to impaired gut selective barrier function of absorption (Boutry et al. 2012), even
function. Major endotoxemia can lead to sepsis if the associated anorexia may contribute to the
that is characterized by a whole-body inflamma- decrease of amino acid concentration in blood.
tory state (Tsiotou et al. 2005). Sepsis shock can Several other amino acids showed protective
lead to multiple organ dysfunction syndrome effects for the intestinal mucosa when tested indi-
(Nardi et al. 2013; Venkatesh et al. 2013). In criti- vidually. Arginine can modulate the intestinal
cally ill patients, the gastrointestinal tract is immune response through regulation of nitric
believed to play a central role in the pathogenesis oxide production, polyamine synthesis or by
of septic shock (Hassoun et al. 2001; Swank and upregulating the expression of antimicrobial pep-
Deitch 1996). Indeed, increased gut permeability tides (Coëffier et al. 2010). In mice, arginine
and bacterial translocation play an active role in supplementation upregulated the expression of
multiple organ failure by inducing a vicious cycle Tlr4, pro-inflammatory cytokines, and antimicro-
of increased intestinal permeability, leading to bial peptides in the ileum (Ren et al. 2014b).
increased transfer of luminal compounds in the Here again, the consequences for gut health of
bloodstream (Deitch et al. 1987; Hassoun et al. these latter modifications remained to be deter-
10 M. Beaumont and F. Blachier

mined, but could represent, depending on the maintenance of intestinal barrier. Although direct
context, either a reinforcement of the innate effects of amino acids are involved in their bene-
immunity or a detrimental inflammatory ficial role on the mucosa, it has been recently
response. In a pig model of colitis, cysteine sup- hypothesized that the gut microbiota could medi-
plementation reduced intestinal permeability and ate some of the health effects of amino acids.
mucosal inflammation (Kim et al. 2009).
Histidine reduced histologic damages and pro-­
inflammatory cytokines levels in a mouse model 1.4  mino Acid Metabolism by
A
of colitis, (Andou et al. 2009). Glycine is able to the Intestinal Microbiota
reduce the myeloperoxidase activity and pro-­ and Functional Implications
inflammatory cytokines in the colonic mucosa in
a rodent model of colitis (Tsune et al. 2003). Although the microbiota is not abundant in the
The mucus layers that are part of the intestinal proximal part of the small intestine, and the intes-
barrier function protect the intestinal epithelium tinal transit is relatively rapid there (Schippa and
from luminal aggression (Birchenough et al. Conte 2014; Dinning 2016), some recent data
2015). Intestinal goblet cells, the cells responsi- suggest that the microbiota could play a role in
ble for mucus secretion, are polarized differenti- the utilization and production of amino acids,
ated epithelial cells. Their density increases from even if, as said above, the balance between both
the duodenum to the colon and this increase par- processes is not fully understood (Portune et al.
allels the increase in the number of bacteria 2016).
(Deplancke and Gaskins 2001). In the piglet The situation is further complicated by the
model, an adequate dietary threonine consump- fact that a part of both endogenous and dietary
tion appears critical for the production of the proteins present in the small intestine luminal
intestinal mucus, and parenteral threonine supply content can be transferred to the large intestine
can ameliorate different signs of threonine defi- through the ileocaecal junction (Gibson et al.
ciency (Law et al. 2007). Under pathological 1976). In the large intestine, the microbiota,
conditions such as ileitis, threonine requirement thanks to its protease and peptidase activities,
is presumably increased to participate in the degrade these undigested or not fully digested
maintenance and/or the recovery of intestinal proteins in peptides and amino acids (Portune
morphology and physiology (Mao et al. 2011). et al. 2016). Amino acids are not believed to be
Lastly, some studies reported beneficial effects absorbed by the large intestine epithelium to
of amino acids mixtures on mucosal healing after any significant extent, except during a short
an inflammatory episode. In a rat model of colitis, period following birth (Fuller 2012; van der
dietary supplementation with amino acids highly Wielen et al. 2017). Then, amino acids are used
represented in mucins (threonine, cysteine, pro- by the intestinal microbiota for its own protein
line and serine) increased intestinal mucus pro- synthesis, and for utilization in catabolic path-
duction and thus favored mucosal healing (Faure ways that generates numerous metabolic end
et al. 2006). In another rodent study, dietary sup- products (Libao-Mercado et al. 2009, Dai et al.
plementation after colitis induction with a mix- 2010, Blachier et al. 2007). Some of these
ture of three amino acids (glutamate, methionine metabolites are absorbed through the colonic
and threonine) improved mucosal healing while it epithelium, and during this process can be fur-
did not improved inflammatory parameters (Liu ther metabolized giving rise to the production of
et al. 2013). The beneficial effects of this amino co-metabolites (i.e. bacterial metabolites that
acid mixture might be related to their involvement are modified by the host (Rajani and Jia 2018)).
in energy metabolism, and glutathione and mucus Some of these amino acid-derived bacterial
synthesis. metabolites and co-­ metabolites have been
In summary, several amino acid (mainly tryp- shown to exert both beneficial and deleterious
tophan and glutamine) play a critical role in the effects, depending on their chemical structure
1 Amino Acids in Intestinal Physiology and Health 11

and concentrations, on the intestinal epithelial Table 1.1 Main metabolites produced by the gut micro-
biota from amino acids
cells (Blachier et al. 2017).
Category AA precursor Bacterial metabolites
Branched Leucine Isovalerate
AA
1.4.1  elevance for Gut Health
R Valine Isobutyrate,
of Bacterial Metabolites 2-methylbutamine
Produced from Amino Acids Isoleucine 2-methylbutyrate
Aromatic Tryptophan Indole, indole-3-pyruvate,
Bacterial metabolites are key molecular intermedi- AA indole-3-­lactate, indole-
3-propionate,
ates between the microbiota and its host. From a
indole-3-acrylic
quantitative point of view, complex carbohydrate acid,indole-3-­acetate,
(mostly dietary fibers) degradation is the most indole-3-­aldehyde,
important metabolic activity of the gut microbiota, tryptamine, skatole,
serotonin
releasing the short chain fatty acids (SCFA) acetate
Tyrosine 4-hydroxyphenyllactate,
(C2), propionate (C3) and butyrate (C4) (O’Keefe 4-hydroxyphenylpyruvate,
2016). SCFA are generally considered beneficial 4-hdyroxyphenylpropionate,
for gut health since they contribute to epithelial 4-hydroxyphenylacetate,
energy metabolism and promote the intestinal bar- 4-hydroxybenzoate,
4-ethylphenol, p-cresol,
rier function (Koh et al. 2016). Although quantita- phenol, dopamine
tively less important, the metabolic output of amino Phenylalanine Phenylpyruvate,
acid degradation by the gut microbiota is much phenyllactate,
more diverse (summarized in Table 1.1). Bacterial phenylacetate,
3-phenylpropionate,
catabolism of amino acids releases in the intestinal
benzoate,
lumen ammonia, SCFA, branched chain fatty acids, phenylethylamine
hydrogen sulfide (H2S), amines, polyamines, phe- Sulfur Cysteine Hydrogen sulfide
nolic and indolic compounds, and compounds containing
known as neurotransmitters. Strikingly, the greatest AA
Other AA Proline Valerate
diversity of metabolites is observed for aromatic
Glycine Methylamine, acetate
amino acid-derived bacterial metabolites.
Ornithine Agmatine, putrescine,
Some bacterial metabolites produced by the spermidine, spermine,
microbiota from amino acids have been identified GABA
as metabolic troublemakers (Fig. 1.5). Although Lysine Cadaverine, acetate,
at low concentration (i.e. <40 μM), the cysteine-­ butyrate
derived bacterial metabolite H2S is used as an Arginine Putrescine, spermidine,
spermine, GABA
energy substrate by colonocytes and provides Alanine Ethylamine, acetate,
ATP (Goubern et al. 2007), at a higher concentra- propionate
tion, H2S inhibits mitochondrial respiration and Histidine Histamine
inhibits SCFA oxidation, leading to an impair- Threonine Acetate, propionate
ment of epithelial energy metabolism (Blachier Glutamate Acetate, butyrate
et al. 2019). Similarly, the tyrosine-derived bac- Aspartate Acetate
terial metabolite p-cresol impairs colonocyte AA Ammonia
deamination
mitochondrial metabolism, an effect associated
with reactive oxygen species (ROS) production
(Andriamihaja et al. 2015). Last, the bacterial derived from amino acids degradation can
deamination product ammonia inhibits SCFA severely impair energy supply in the intestinal
oxidation and oxygen consumption by colono- epithelium when they reach high concentrations.
cytes (Andriamihaja et al. 2010). Collectively, Several bacterial metabolites produced by the
these data show that some bacterial metabolites gut microbiota from amino acids degradation were
12 M. Beaumont and F. Blachier

Fig. 1.5 Effects of amino acid-derived bacterial metabolites on the intestinal epithelium
The effects (either positive or negative) are indicated in regards (left to right) to DNA damages, hormone secretion,
production of pro-inflammatory cytokines, mucus layer integrity, epithelial permeability, and mitochondrial energy
production

found to disrupt intestinal barrier and induce Importantly, gut microbiota derived metabolites
inflammation (Fig. 1.5). H2S in excess may disrupt produced from tryptophan recently emerged as
the mucus layer through disulfur bond reduction, major regulators of intestinal gut barrier homeosta-
leading to an increased exposure of the epithelial sis (Agus et al. 2018, Roager and Licht 2018).
cells to toxic luminal compounds, such as heme Indole, the main tryptophan derived bacterial
(Ijssennagger et al. 2015). Moreover, this metabo- metabolite (Jin et al. 2014), strengthen the epithe-
lite upregulates pro-inflammatory genes expression lial barrier in vitro (Bansal et al. 2010) and prevents
in epithelial cells in a model of intra-colonic instil- colitis-associated mucosal damages in vivo
lation in rats (Beaumont et al. 2016). The tyrosine- (Shimada, et al. 2013). However, in order to estab-
derived bacterial metabolites phenol and p-cresol lish the beneficial vs. deleterious effects of
increase epithelial permeability in vitro (Hughes increased production of indole by the gut microbi-
et al. 2008; Wong et al. 2016). Ammonia also ota, it appears important to consider that indoxyl
increases epithelial permeability and induces the sulfate, a co-metabolite derived from indole is con-
expression of the tumor necrosis factor α (Villore sidered to contribute to renal disease progression
Tudela et al. 2015). In contrast, other metabolites (Ellis et al. 2018; Leong and Sirich 2016; Tan et al.
produced from amino acids exert protective effects 2017; Ramezani and Raj 2014).
for mucosal homeostasis. A mixture of branched Indole-3-acrylic acid, produced from trypto-
chain fatty acids (isovalerate and isobutyrate), phan by Peptostreptococcus species, alleviates
respectively derived from leucine and valine, dose intestinal inflammation and upregulates Mucin 2
dependently prevented the disruption of the epithe- gene expression (Wlodarska et al. 2017). Indole-­
lial barrier in vitro (Boudry et al. 2013). 3-­propionate, produced from tryptophan by
Interestingly, disruption of the epithelial barrier Clostridium species, reduced intestinal permea-
induced by p-cresol was prevented by 3-phenylpro- bility and inflammation through pregame X
pionate and 3-(3-hydroxyphenyl)propionate, these receptor (PXR) (Venkatesh et al. 2014; Dodd
bacterial metabolites being produced notably from et al. 2017). Indole-3-aldehyde, produced from
phenylalanine or tyrosine degradation (Wong et al. tryptophan by Lactobacillus species, regulates
2016). The histidine and arginine-derived bacterial mucosal immunity through interleukin-22 pro-
metabolites histamine, putrescine and spermine duction and AhR (Zelante et al. 2013). Together,
dose dependently inhibited interleukin-18 secre- the protective effects of bacterial metabolites
tion by mice colon explants (Levy et al. 2015). derived from tryptophan on gut health might con-
1 Amino Acids in Intestinal Physiology and Health 13

tribute to the beneficial effects of tryptophan cytotoxic effects (Andriamihaja et al. 2015).
supplementation observed in colitis models Phenol that is also produced by the intestinal
(Hashimoto et al. 2012; Kim et al. 2010). microbiota from tyrosine, appears to be a precur-
Interestingly, several recent reports suggest sor of the mutagenic compounds p-diazoquinone
that bacterial amino acid derived metabolites after reacting with nitrite (Kikugawa and Kato
could regulate the endocrine function of the gut 1988). Hydrogen sulfide that is a bacterial metab-
(Fig. 1.5). The tryptophan bacterial catabolite olite produced from cysteine was reported to be
indole regulates the secretion of glucagon-like able to alter DNA integrity in intestinal colonic
peptide 1 (GLP-1) by enteroendocrine cells in epithelial cells (Attene-Ramos et al. 2010).
vitro (Chimerel et al. 2014). Similarly, hydrogen However, these results were not confirmed in fur-
sulfide stimulated GLP-1 secretion by L-cells ther experiments, likely because of different
(Pichette et al. 2017). If confirmed in vivo, these experimental design. Indeed, using both in vivo
results would indicate that amino acid derived colonic intraluminal instillation in rats and
bacterial metabolites represent new compounds longer-­term culture of human colonic epithelial
that could be targeted for the control of intestinal cells with millimolar concentrations of the H2S
hormones secretion. donor NaHS, no effect of this agent on DNA
Some bacterial metabolites produced from integrity was detected using the sensitive gamma
amino acids have been shown to alter DNA integ- H2AX genotoxicity test (Beaumont et al. 2016).
rity (Fig. 1.5). This topic is in our opinion of par-
ticular importance as long-term exposure of
colonic crypt stem cells to excessive DNA-­ 1.4.2  ffects of Amino Acid
E
damaging agents is likely to increase the risk of Supplementation
unrepaired DNA lesions in these cells (Gill and on Microbiota Composition
Rowland 2002). To make a long and complicated and Metabolic Activity
story short, the cancer stem cell hypothesis pro-
pose that crypt stem cells are the cells at the ori- Although the effects of dietary protein on the
gin of intestinal cancer (Vermeulen et al. 2008; gut microbiota composition are well described
Barker et al. 2009). However, whether a colorec- (Blachier et al. 2019), only few studies investi-
tal cancer stem cell is a transformed descendent gated the impact of individual amino acid sup-
of a normal intestinal stem cell, or whether dif- plementation on the microbiota composition
ferentiated cells can acquire a cancer stem cell and its metabolic activity. In weaned piglets,
phenotype upon transformation remains unknown dietary tryptophan supplementation increased
(Yousefi et al. 2017). The mechanisms for genetic large intestine microbiome α-diversity and the
changes in colorectal cancer and their interac- abundance of the SCFA producers Prevotella
tions with the environmental risk factors are dif- and Roseburia while it reduced the abundance
ficult to unravel. However, recent studies have of Clostrium species and Enterobacter (Liang
begun to better clarify how the intestinal micro- et al. 2018). Moreover, in this study tryptophan
biota can generate genomic changes in colorectal supplementation increased the colonic concen-
cancer, for instance through toxin production, tration of propionate, indole 3-acetate and
metabolite synthesis, reactive species production tryptamine (Liang et al. 2018). In a pilot study
etc. (Wang et al. 2017). Among the luminal com- with Humans, glutamine supplementation for
pounds that have been identified as able to alter 14 days decreased the abundance of the
DNA integrity in mitochondria and nuclei, sev- Actinobacteria, Firmicutes, Dialister and
eral of them appears to be bacterial metabolites Dorea (de Souza et al. 2015). In mice, gluta-
derived from amino acids. The bacterial metabo- mine supplementation reduced the abundance
lite p-cresol that is produced from tyrosine has of Firmicutes and increased Bifidobacterium
been shown to be genotoxic upon human colono- and Streptococcus in the jejunum while it
cytes in a dose-dependent manner without any decreased the abundance of Firmicutes,
14 M. Beaumont and F. Blachier

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 Amino Acid Metabolism
in the Liver: Nutritional 2
and Physiological Significance

Yongqing Hou, Shengdi Hu, Xinyu Li,

Wenliang He, and Guoyao Wu

Abstract of this pathway is limited in human infants

(particularly preterm infants) and is also low in
The liver plays a central role in amino acid adult humans as compared with rats, birds and
(AA) metabolism in humans and other ani- livestock species (e.g., pigs, cattle and sheep).
mals. In all mammals, this organ synthesizes The liver exhibits metabolic zonation and
many AAs (including glutamate, glutamine, intracellular compartmentation for ureagene-
alanine, aspartate, asparagine, glycine, serine, sis, uric acid synthesis, and gluconeogenesis,
and homoarginine), glucose, and glutathione (a as well as AA degradation and syntheses.
major antioxidant). Similar biochemical reac- Capitalizing on these extensive bases of knowl-
tions occur in the liver of birds except for those edge, dietary supplementation with functional
for arginine and glutamine hydrolysis, proline AAs (e.g., methionine, N-acetylcysteine, and
oxidation, and gluconeogenesis from AAs. In glycine) to humans and other animals can alle-
contrast to mammals and birds, the liver of fish viate or prevent oxidative stress and damage in
has high rates of glutamate and glutamine oxi- the liver. Because liver diseases are common
dation for ATP production. In most animals problems in humans and farm animals (includ-
(except for cats and possibly some of the other ing fish), much research is warranted to further
carnivores), the liver produces taurine from both basic and applied research on hepatic AA
methionine or cysteine. However, the activity metabolism and functions.

Keywords
Y. Hou
Hubei International Scientific and Technological Liver · Amino acids · Metabolism · Nutrition ·
Cooperation Base of Animal Nutrition and Gut
Health, Wuhan Polytechnic University, Wuhan, China Humans · Animals
S. Hu
Feed Research Institute, Newhope Liuhe Feeds Inc.,
Chengdu, Sichuan, China
Key Laboratory of Feed and Livestock and Poultry 2.1 Introduction
Products Quality & Safety Control, Ministry of
Agriculture, Chengdu, Sichuan, China The liver plays a central role in the digestion,
X. Li · W. He · G. Wu (*) metabolism, transport, and storage of nutrients,
Department of Animal Science, Texas A&M as well as detoxification, immunity and health
University, College Station, TX, USA
(Treyer and Müsch 2013). In this organ, amino
e-mail: g-wu@tamu.edu

© Springer Nature Switzerland AG 2020 21

G. Wu (ed.), Amino Acids in Nutrition and Health, Advances in Experimental Medicine
and Biology 1265, https://doi.org/10.1007/978-3-030-45328-2_2
22 Y. Hou et al.

acids (AAs) serve as the building blocks of pro- dogs, geese, goats, guinea pigs, hawks, humans,
teins (including such transport proteins as albu- mice, monkeys, owls, pigs, rabbits, sheep, and
min, lipoproteins, transferrin, and retinol-binding zebrafish) that have a gallbladder, the liver is
protein); the regulators of intracellular protein closely connected with the gallbladder (Oldham-­
turnover (protein synthesis and proteolysis); con- Ott and Gilloteaux 1997). The latter stores bile (a
jugators with bile acids; substrates for the synthe- mixture of water, bile salts, cholesterol and bili-
ses of glutathione (the most abundant rubin) produced by the liver, and then releases the
low-molecular-weight antioxidant in cells), tau- bile into the duodenum in response to a feeding-­
rine (essential for retinal, cardiac and skeletal induced surge of cholecystokinin (a peptide
muscle functions), glucose, lipids, and anti-­ secreted by enteroendocrine cells in the small
inflammatory molecules; and protectors against intestine) in plasma (Liddle 1995). In contrast,
toxic xenobiotics and pathogenic microorgan- some mammals (i.e., horses, deer, rats, seals, and
isms (Hou et al. 2015a; Wu 2018). For example, laminoids), birds (e.g., pigeons, parrots and
the liver of a healthy human adult releases about doves), certain fish (e.g., lampreys), and all inver-
20 g albumin per day (Maxwell et al. 1990). tebrates lack a gallbladder (Oldham-Ott and
Moreover, the liver is a major site for the metabo- Gilloteaux 1997). In animals without a gallblad-
lism of lipoproteins, such as very low-density der, bile flows directly from the liver into the
lipoprotein (VLDL), low-density lipoprotein lumen of the duodenum through the bile duct. As
(LDL), and high-density lipoprotein (HDL; the bile flows through the bile ducts, its composi-
Perez-Matos et al. 2019). Thus, in humans and tion is modified by the addition of a bicarbonate
other animals, abnormal metabolism of AAs in secretion from ductal epithelial cells in response
the liver results in many diseases [including to a surge of the duodenum-derived secretin.
edema, hepatic encephalopathy, fatty liver, The liver has a high rate of oxidative metabo-
hepatic injury, hepatic cirrhosis (scarring), and lism and, therefore, needs a large amount of oxy-
liver failure (a life-threatening condition)] and gen. This is met by a high rate of blood flow into
increases risk for liver cancer (Holm et al. 1999; this organ. The liver accounts for only 2.5% of
Lee and Kim 2019). In all animals (including body weight (BW) but receives 20–25% of the
mammals, birds, fish, and shrimp), liver dysfunc- cardiac blood output (Lautt 2010). In a healthy
tion also reduces their food intake, growth, and 70-kg human with a 1.75 kg liver, the total blood
development (Wu 2020a). This issue is critical flow into the liver is 30 ml/min per kg BW or
for the production of farm animals worldwide, 120 ml/min per 100 g liver, with ~70–75% and
because feed efficiency is a major factor affecting 25–30% of the blood being supplied by the portal
economic returns and sustainability. Furthermore, veil and the hepatic artery, respectively. Water-
in mammalian fetuses and avian embryos, where and lipid-soluble nutrients that are carried within
the production of erythrocytes occurs in their liv- the portal vein and the hepatic artery enter the
ers, spleens and bone marrows, this physiological liver for extraction by hepatocytes and other
process is stimulated by fetal/embryonic liver-­ types of cells (Wu 2018). The nutrients that
derived erythropoietin (Palis 2014). Therefore, bypass the liver without uptake and metabolites
research on hepatic AA metabolism has both released from the liver enter the inferior vena
medical and agricultural significance, and is the cava for utilization in extrahepatic tissues or for
focus of the current work. excretion (Lautt and Greenway 1987).
The functional unit of the liver is the hepatic
acinus, which contains the terminal branches of
2.2 Anatomy of the Liver the portal vein, hepatic arteries, and bile ducts.
There are about 100,000 acini in the human liver
Based on gross anatomy, the liver has four lobes: (Lautt and Greenway 1987). Blood from the portal
left, right, caudate, and quadrate. In animals venule and blood from the hepatic arteriole enter
(bears, cats, cattle, channel catfish, chickens, hepatic sinusoids (the capillaries in the liver with
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