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Burim N. Ametaj Editor
Periparturient
Diseases of Dairy
Cows
A Systems Biology Approach
Periparturient Diseases of Dairy Cows
Burim N. Ametaj
Editor
Periparturient Diseases of
Dairy Cows
A Systems Biology Approach
Editor
Burim N. Ametaj
Department of Agriculture
Food and Nutritional Science
University of Alberta
Edmonton, Alberta, Canada
ISBN 978-3-319-43031-7 ISBN 978-3-319-43033-1 (eBook)

DOI 10.1007/978-3-319-43033-1
Library of Congress Control Number: 2017959645
© Springer International Publishing Switzerland 2017

This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of
the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation,
broadcasting, reproduction on microfilms or in any other physical way, and transmission or information
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The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication
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protective laws and regulations and therefore free for general use.
The publisher, the authors and the editors are safe to assume that the advice and information in this book
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The registered company address is: Gewerbestrasse 11, 6330 Cham, Switzerland
Preface
There are several reasons for undertaking the editing and writing of this book. The
first reason is that there is a need to address the definition of metabolic diseases,
metabolic disorders, production diseases, or transition cow diseases. Which one to
choose and which one is more accurate? In fact, the definitions of those diseases
were developed during the last half century and given that there are new develop-
ments and contributions in this particular area of science it is imperative that we
discuss the drawbacks of those definitions. Based on new research reports of mul-
tiple labs around the world, we could say that the concepts of metabolic disease or
production disease are not accurately defined and we need to address several other
issues that influence our approach to the causality and pathogenesis of those dis-
eases. Defining them as simply metabolic or simply production diseases has affected
our efforts to identify the real causal agents and the development of new prevention
strategies. Second, the incidence rates of periparturient diseases have been increas-
ing steadily during the last two decades and the culling rate has reached more than
50%, shortening the productive life of dairy cows to less than 2 years. If we choose
to do nothing, then the health status of dairy cows will continue to decline and the
culling rates will further increase causing big losses to the dairy industry. The
increasing rates of culling indicate that there is something missing in our under-
standing of the cause(s) of these diseases and that the methodology and the philoso-
phy that we have been using to approach the etio-pathobiology deserve to be
revisited and redimensionalized. The title of this book has been intentionally
selected as “periparturient diseases of dairy cows.” The reason for this choice is to
include in the book not only those diseases that traditionally have been defined as
metabolic in nature like milk fever or ketosis but also those that have been defined
as bacterial in nature like metritis and mastitis. It should be noted that metabolic
alterations and bacterial involvement are present in all periparturient diseases
whether they have been defined as metabolic or infective in nature. The reason for
this is that they seem to be interrelated to each other and one cow might be affected
by more than one of these traditional diseases. The title of the book also has included
a “systems biology approach” to periparturient diseases. Most readers are aware
that a new group of sciences under the name of systems biology or systems veteri-
nary approach has emerged during the last decade. These new sciences include
genomics, proteomics, transcriptomics, and metabolomics. Although contribution
of omics sciences have been at the pioneering level and not very well-organized
v
vi Preface
contribution that they are giving to the understanding of periparturient diseases of

dairy cows is tremendous. In this book we bring forward the contribution of omics
sciences to the understanding of periparturient diseases of dairy cows. We hope that
this book will serve as a stimulus to further research in clarifying the pathomecha-
nisms and causality of periparturient diseases of dairy cows and in developing new
preventive strategies for lowering the incidence rate of those diseases in the future.
This book has been written with the intention to reach every undergraduate and
graduate students as well as instructors in animal science departments and faculties
of veterinary medicine that study or teach periparturient diseases of dairy cows.
Structure of the Book
The book is structured in such a way that the reader is first introduced into the con-
cept of omics sciences. Since this book is about the application of systems biology
in better understanding the etio-pathobiology of periparturient diseases of dairy
cows, the reader is introduced first to those concepts. The second chapter discusses
myths established during the last half century with regard to the definition of meta-
bolic and production diseases and presents the benefits of the new philosophy of
disease approach, the systems biology or veterinary approach as well as advantages
of the predictive, preventive, and individualized medicine versus traditional
approach of reactive medicine. Immunity around parturition is a very important
topic that has been indicated as key to multiple diseases. In the third chapter, new
concepts of potential effects of external factors on immunity around parturition are
discussed. The fourth chapter deals with ruminal acidosis. Rumen is very important
not only for digestion of feed material but also for generation of multiple bacterial
products that can harm the health of cows. The authors describe ruminal acidosis
from the systems biology approach perspective. The authors of the fifth chapter
discuss microbiota of the rumen and intestines and their contribution to diseases.
Also, all the new knowledge about utilization of omics sciences in approaching
microbiota in the GI tract is discussed. The sixth chapter deals with the number one
health problem, i.e., dairy cows’ infertility. This is the main reason for culling cows
in a dairy herd. The authors discuss both male and female fertility and the contribu-
tion of omics sciences in better understanding the reasons of infertility. Chapter 7
deals with retained placenta. Although retained placenta is not the second most
important disease of dairy cows, it is listed immediately after infertility because
retained placenta cows are affected significantly by infertility. Chapter 8 deals with
mastitis, the second most important disease of dairy cows from the culling perspec-
tive. It is a very difficult disease and there is much activity from various labs to
better understand the pathomechanism of the disease. Laminitis is discussed in
Chap. 9. The authors discuss the most recent knowledge about the application of
systems biology approach to laminitis in dairy cows. Ketosis is discussed in Chap.
10. Ketosis is a silent disease that affects more than 40% of dairy cows in a subclini-
cal way. Understanding ketosis from the omics perspective is the subject of that
chapter. Fatty liver also is a silent disease and requires a liver biopsy to be
Preface vii
diagnosed. Almost 50% of cows are affected by fatty liver. It has multiple implica-
tions and is associated with several other periparturient diseases, especially metritis
and mastitis. The authors bring the most up-to-date information about the applica-
tion of omics sciences in this area of research. Finally, the book concludes with one
of the most studied and most controversial diseases in the area of cow health, milk
fever, or periparturient hypocalcemia. Is hypocalcemia a deficiency or part of
immune response of the host during endotoxemias? The book discusses some of the
most known hypotheses on milk fever and brings forward the omics research work
in this field of study. We hope that the reader will find this book interesting and up-
to-date and will use the knowledge in their research and teaching to the new
generation.
Edmonton, AB, Canada Burim N. Ametaj

Contents
1 What Are Omics Sciences?�� 1

Mario Vailati-Riboni, Valentino Palombo, and Juan J. Loor
2 Demystifying the Myths: Switching Paradigms from
Reductionism to Systems Veterinary in Approaching
Transition Dairy Cow Diseases �� 9
Burim N. Ametaj
3 An Omics Approach to Transition Cow Immunity�� 31
Emily F. Eckel and Burim N. Ametaj
4 Systems Biology and Ruminal Acidosis�� 51
Morteza H. Ghaffari, Ehsan Khafipour, and Michael A. Steele
5 Cattle Gastrointestinal Tract Microbiota in Health
and Disease �� 71
André Luiz Garcia Dias and Burim N. Ametaj
6 A Systems Biology Approach to Dairy Cattle Subfertility
and Infertility �� 93
Fabrizio Ceciliani, Domenico Vecchio, Esterina De Carlo,
Alessandra Martucciello, and Cristina Lecchi
7 Retained Placenta: A Systems Veterinary Approach�� 121
Elda Dervishi and Burim N. Ametaj
8 Omic Approaches to a Better Understanding of Mastitis
in Dairy Cows �� 139
Manikhandan Mudaliar, Funmilola Clara Thomas,
and Peter David Eckersall
9 Laminitis: A Multisystems Veterinary Perspective with Omics
Technologies�� 185
Richard R.E. Uwiera, Ashley F. Egyedy, and Burim N. Ametaj
ix
x Contents
10 Ketosis Under a Systems Veterinary Medicine Perspective �� 201

Guanshi Zhang and Burim N. Ametaj
11 The Omics Side of Fatty Liver: A Holistic Approach
for a Commonly Occurring Peripartal Disease�� 223
12 Milk Fever: Reductionist Versus Systems Veterinary Approach �� 247
Elda Dervishi and Burim N. Ametaj
Index�� 267
Editor and Contributors
About the Editor
Burim N. Ametaj, D.V.M., Ph.D., Ph.D. is a Professor of Animal Physiology and

Bovine Periparturient Diseases and Immunology in the Department of Agricultural,
Food and Nutritional Science at the University of Alberta, Canada. He received his
veterinary degree (D.V.M.) at the Faculty of Veterinary Medicine, University of
Agriculture, Tirana, Albania. He worked there as a Professor of Animal Physiology
and conducted a Ph.D. on metabolic diseases of dairy cows. He served as Vice-Dean
for Research and Graduate studies between 1997 and 2002. In 2004 Dr. Ametaj
moved to Iowa State University and National Animal Disease Center, IA, USA,
where he did a 1 year Fulbright Scholarship. In 1995 he started a second Ph.D. on
immunobiology of dairy cows and graduated in 1999. Dr. Ametaj served three post-
doctoral fellow positions at Iowa State University, Ames, Iowa, Purdue University,
Lafayette, Indiana, and Cornel University, Ithaca, New York, USA. In 2004, Dr.
Ametaj moved as Assistant Professor to the University of Alberta, Edmonton,
Alberta, Canada. His research activities involve studying the pathomechanism of
periparturient diseases and development of new technologies for their prevention.
Dr. Ametaj’s lab has developed a new grain processing technology that prevents
ruminal acidosis, two oro-parenteral vaccines against bacterial endotoxins, one
intravaginal probiotic technology that lowers the incidence of uterine infections,
and has applied metabolomics and microbiome studies to develop biomarkers of six
periparturient diseases of dairy cows. His lab also has been involved in understand-
ing the role of bacterial endotoxins in the pathobiology of prion disease.
xi
Contributors
Burim N. Ametaj, D.V.M., Ph.D., Ph.D. Department of Agricultural, Food and

Nutritional Science, University of Alberta, Edmonton, AB, Canada
The Faculty of Veterinary Medicine, University of Agriculture, Tirana, Albania
Fabrizio Ceciliani, D.V.M., Ph.D. Department of Veterinary Medicine, Università
degli Studi di Milano, Milano, Italy
Esterina De Carlo, Ph.D. Istituto Zooprofilattico Sperimentale del Mezzogiorno—
Centro di Referenza Nazionale sull’Igiene e le Tecnologie dell’Allevamento e delle
Produzioni Bufaline—Sezione di Salerno, Salerno, Italy
Elda Dervishi, Ph.D. Department of Agricultural, Food and Nutritional Science,
University of Alberta, Edmonton, AB, Canada
André Luiz Garcia Dias, Ph.D. Department of Agricultural, Food and Nutritional
Science, University of Alberta, Edmonton, AB, Canada
Emily F. Eckel, Ph.D. Department of Agricultural, Food and Nutritional Science,
Peter David Eckersall, Ph.D. College of Medical, Veterinary and Life Science,
Institute of Biodiversity Animal Health and Comparative Medicine, University of
Glasgow, Glasgow, UK
Ashley F. Egyedy, M.Sc. Department of Agricultural, Food and Nutritional
Morteza H. Ghaffari Department of Agricultural, Food and Nutritional Science,
Ehsan Khafipour, Ph.D. Departments of Animal Science and Medical
Microbiology, University of Manitoba, Winnipeg, MB, Canada
Cristina Lecchi, D.V.M., Ph.D. Department of Veterinary Medicine, Università
degli Studi di Milano, Milano, Italy
Juan J. Loor, Ph.D. Department of Animal Sciences, University of Illinois,
Urbana-Champaign, IL, USA
Alessandra Martucciello, Ph.D. Istituto Zooprofilattico Sperimentale del
Mezzogiorno—Centro di Referenza Nazionale sull’Igiene e le Tecnologie
dell’Allevamento e delle Produzioni Bufaline—Sezione di Salerno, Salerno, Italy
Manikhandan Mudaliar, Ph.D. Glasgow Molecular Pathology Node, College of
Medical, Veterinary and Life Science, University of Glasgow, Glasgow, UK
Valentino Palombo, Ph.D. Department of Animal Sciences, University of Illinois,
Urbana-Champaign, IL, USA
xiii
xiv Editor and Contributors
Michael A. Steele, Ph.D. Department of Agricultural, Food and Nutritional

Funmilola Clara Thomas, Ph.D. Biochemistry Unit, Department of Veterinary
Physiology and Pharmacology, College of Veterinary Medicine, Federal University
of Agriculture, Abeokuta, Nigeria
Richard R.E. Uwiera, D.V.M., Ph.D. Department of Agricultural, Food and
Nutritional Science, University of Alberta, Edmonton, AB, Canada
Mario Vailati-Riboni, Ph.D. Department of Animal Sciences, University of
Illinois, Urbana-Champaign, IL, USA
Domenico Vecchio, Ph.D. Istituto Zooprofilattico Sperimentale del Mezzogiorno—
Centro di Referenza Nazionale sull’Igiene e le Tecnologie dell’Allevamento e delle
Produzioni Bufaline—Sezione di Salerno, Salerno, Italy
Guanshi Zhang, D.V.M., Ph.D. Institute of Metabolomic Medicine, Center for
Renal Translational Medicine, School of Medicine, University of California San
Diego, La Jolla, CA, USA
What Are Omics Sciences?
1
Abstract
The word omics refers to a field of study in biological sciences that ends with
-omics, such as genomics, transcriptomics, proteomics, or metabolomics. The
ending -ome is used to address the objects of study of such fields, such as the
genome, proteome, transcriptome, or metabolome, respectively. More specifi-
cally genomics is the science that studies the structure, function, evolution, and
mapping of genomes and aims at characterization and quantification of genes,
which direct the production of proteins with the assistance of enzymes and mes-
senger molecules. Transcriptome is the set of all messenger RNA molecules in
one cell, tissue, or organism. It includes the amount or concentration of each
RNA molecule in addition to the molecular identities. The term proteome refers
to the sum of all the proteins in a cell, tissue, or organism. Proteomics is the sci-
ence that studies those proteins as related to their biochemical properties and
functional roles, and how their quantities, modifications, and structures change
during growth and in response to internal and external stimuli. The metabolome
represents the collection of all metabolites in a biological cell, tissue, organ, or
organism, which are the end products of cellular processes. Metabolomics is the
science that studies all chemical processes involving metabolites. More specifi-
cally, metabolomics is the study of chemical fingerprints that specific cellular
processes establish during their activity; it is the study of all small-molecule
metabolite profiles. Overall, the objective of omics sciences is to identify, char-
acterize, and quantify all biological molecules that are involved in the structure,
function, and dynamics of a cell, tissue, or organism.
M. Vailati-Riboni, Ph.D. • V. Palombo, Ph.D. • J.J. Loor, Ph.D. (*)

Division of Nutritional Sciences, Department of Animal Sciences, University of Illinois at
Urbana-Champaign, Urbana, IL 61801, USA
e-mail: [email protected]; [email protected]; [email protected]
© Springer International Publishing Switzerland 2017 1

B.N. Ametaj (ed.), Periparturient Diseases of Dairy Cows,
DOI 10.1007/978-3-319-43033-1_1
2 M. Vailati-Riboni et al.
1.1 Introduction
The trademark characteristic of omics technologies is their holistic capability in the

context of the cell, tissue, or organism. They are aimed primarily at the universal
detection of genes (genomics), mRNA (transcriptomics), proteins (proteomics), and
metabolites (metabolomics) in a specific biologic sample in a non-targeted and non-
biased manner. The basic aspect of these approaches is that a complex system can
be understood more thoroughly if considered as a whole. The omics approach is
suitable for hypothesis-generating experiments, as holistic approaches acquire and
analyze all available data to define a hypothesis, which can be further tested, in situ-
ations when no hypothesis is known or prescribed due to lack of data. When applied
to well-studied scenarios, omics are still applicable to test and prove the connec-
tions and interrelationships among the many faces of a complex physiologic state,
and to discover missing pieces in the current knowledge.
The first omics technologies were the automated DNA sequencer and the ink-jet
DNA synthesizer developed in the early 1990s by Leroy Hood and colleagues as a
tool for global gene expression analysis (e.g., transcriptomics) (Hood 2002). Around
the same time, Hood’s group also introduced the protein sequencer and the protein
synthesizer to study protein expression at the cellular level, a process known as
“proteomics.” Furthermore, the concomitant emergence of metabolomics studies
started by Frank Baganz and his group (Oliver et al. 1998) completed the physio-
logic flow of biological information processing and synthesis, from gene expres-
sion, to protein synthesis, and metabolites changes.
1.2 Genomics
Genomics pertains to the study of the complete set of DNA in an organism, includ-
ing all of its genes, i.e., the “genome.” With the advent of next-generation sequenc-
ing (NGS) technology the acquisition of genome-scale data has never been easier,
expanding our ability to analyze and understand whole genomes and decreasing the
existing gap between genotype and phenotype. Genetics and genomics sound alike
but they have specific distinctions. Genetics is the study of heredity, or how the
characteristics of living organisms are transmitted from one generation to the next
via DNA. It involves studies focusing on specific and limited numbers of genes, or
part of genes with known function, to understand how these influence particular
traits of interest. At present, high-throughput technology and advances in computa-
tional biology have changed this paradigm enabling the study of organisms in terms
of genome structure, addressing biological questions at a genome-wide scale, i.e.,
genetics is being progressively “contaminated” with genomics.
The advent of genomics turned genome-wide association studies (GWAS) into
the gold standard method to identify candidate regions associated with complex
traits of interest (quantitative trait loci—QTL), both in humans and other species
(Gondro et al. 2013). Probe-based chips developed by various commercial compa-
nies and with a large number of single nucleotide polymorphism (SNP) markers
1 What Are Omics Sciences? 3
spread across the genome are currently being used to help uncover associations
between genes and traits of interest. Species-specific arrays encompassing 10,000
up to 800,000 SNP are currently available. Such coverage ensures that any QTL will
be closely linked with at least one marker. For this reason, GWAS became powerful
enough to map causal genes with modest effects, i.e., disease-related quantitative
traits. With the large number of genes studied simultaneously, genomic studies, in
fact, can overcome the limitations of traditional genetic association approaches,
enhancing our understanding of peripartal diseases (Loor 2010).
The interpretation of GWAS results still represents an important challenge. For
instance, if a robust association between a phenotype and a list of genes is uncov-
ered, one can have more confidence about the possibility for discovery of novel
candidate genes. Despite the power of GWAS for discovery, studies to confirm the
role of genes associated with the trait of interest should be performed to confirm
functional relationships. To address this issue, gene-based software offers an effec-
tive solution in post-GWAS analysis (Capomaccio et al. 2015). Several SNP array
data management tools have been developed in recent years and among these
PLINK (Purcell et al. 2007), due to its speed and stability, is standard for data man-
agement. Currently, the entire GWAS pipeline can be easily executable by ad hoc
computer programs, which, in the majority of cases, are open-source multiplatform
software packages often developed in the R environment (Nicolazzi et al. 2015).
In the context of animal breeding for a given trait or traits, “genomic selection”
deserves special mention (Meuwissen et al. 2001). This approach is a form of
“marker-assisted selection” in which a large number of genetic markers, covering
the whole genome, are used to estimate animal breeding values (EBV), i.e., the
genetic value of young animals based on their genotype. This can lower the genera-
tion interval and increase the rate of genetic progress in different animal popula-
tions, traditionally based on progeny testing (Goddard and Hayes 2007). The
continued progress in DNA sequencing efficiency in the near future will allow for
sequencing complete genomes of individual animals, hence allowing the selection
of animals with favorable QTL’s alleles. Clearly, we are at the beginning of an era
where individual genome sequencing will allow not only the study of domestication
and selection of breeds, but also the understanding of quantitative differences asso-
ciated with environmental factors, all of which will help guide experimental design
for more effective animal disease control (Bai et al. 2012).
1.3 Transcriptomics
The transcriptome is the total RNA (i.e., mRNA, noncoding RNA, rRNA, and
tRNA) expressed by a cell or tissue, thus representing a snapshot of cellular metabo-
lism. The transcriptome era started when Schena et al. (1995) developed the “micro-
array” technology using the ink-jet DNA synthesizer, allowing for the analysis of a
predetermined set (from hundreds to thousands) of cellular mRNA on a large scale.
However, the recent introduction of high-throughput next-generation DNA sequenc-
ing (NGS) technology has revolutionized transcriptomics by allowing RNA
analysis through cDNA sequencing on a massive scale (RNAseq) (Voelkerding

et al. 2009). This technology eliminated several challenges posed by microarray
technologies, including the limited dynamic range of detection, while providing
further knowledge of the qualitative, and not only quantitative, aspects of transcrip-
tome: (1) transcription initiation sites, (2) sense and antisense transcripts, (3) alter-
native splicing events, and (4) gene fusion.
As it also provides detailed information on the noncoding RNA portion of the
total RNA, RNAseq has enabled the understanding of complex regulatory mecha-
nisms (e.g., epigenetics). Since the early twenty-first century, among the various
epigenetic mechanisms, microRNA (miRNA), a class of small noncoding RNA
(18-25 nucleotides), have received the greatest notoriety. Such attention is well
founded because miRNA play a major role in controlling posttranscriptional regula-
tion by preventing translation of mRNA (Romao et al. 2011). Furthermore, miRNA
are not only part of the epigenetic machinery, but also are involved in its regulation,
underscoring their pivotal role as epigenetic mediators (Poddar et al. 2017). In addi-
tion, through RNAseq or miRNA-designed microarrays, the miRNome (the total
mRNA expressed by a cell at a given time) also can be analyzed.
1.4 Proteomics
The term “proteome” was defined as the characterization and quantification of all
sets of proteins in a cell, organ, or organism at a specific time and was coined by
Wasinger et al. (1995). Thus, a proteomic analysis provides the protein inventory of
a cell or tissue at a defined time point, facilitating discovery of novel biomarkers,
identification and localization of post-translational modifications, and study of pro-
tein–protein interactions (Chandramouli and Qian 2009). Powerful techniques have
been established to identify and differentially quantify protein species of complex
biological samples, and proteomic is being adopted by livestock researchers
(Lippolis and Reinhardt 2008; Sauerwein et al. 2014).
The core of modern proteomics is mass spectrometry (MS) (Aebersold and
Mann 2003), a technique in which all chemical compounds in a sample are ionized
and the resulting charged molecules (ions) are analyzed according to their mass-to-
charge (m/z) ratios. For a simple pre-separation of complex protein mixtures before
MS analysis one- or two-dimensional polyacrylamide gel electrophoresis
(1D-PAGE, 2D-PAGE) is often used. But to further enhance automation in the pro-
cess and create a streamed pipeline analyses, different types of liquid chromatogra-
phy (LC or HPLC) are used to complement or substitute gel-based separation
techniques.
Identification of the proteins among treatments or conditions is performed by
comparison against a database of proteins “digested in silico,” meaning that the raw
data are directly compared with theoretically generated data from protein databases.
Reliable quantification of the identified protein also is possible with several
MS-based quantification methods including chemical, metabolic, enzymatic label-
ing, and label-free (May et al. 2011). Proteomic advances made absolute
quantification of proteins possible through the AQUA (Absolute quantification of

proteins), QConCat (artificial proteins comprised of concatenated peptides), and
protein standard for absolute quantification (PSAQ) approaches (Rivers et al. 2007;
Brun et al. 2007).
1.5 Metabolomics
The metabolome consists of the global profiling of metabolites in a biological

sample. A metabolomics analysis may be conducted on a variety of biological
fluids and tissue types and may utilize a number of different technology plat-
forms. Metabolomics typically uses high-resolution analysis together with statis-
tical tools such as principal component analysis (PCA) and partial least squares
(PLS) to derive an integrated picture of the metabolome (Zhang et al. 2012). As
one of the most-common spectroscopic analytical techniques, nuclear magnetic
resonance (NMR) can uniquely identify and simultaneously quantify a wide range
of organic compounds in the micro-molar range, providing unbiased information
about metabolite profiles. The wide spectrum of molecules detectable by this
approach includes peptides, amino acids, nucleic acids, carbohydrates, organic
acids, vitamins, polyphenols, alkaloids, and inorganic species. Application of MS
is gaining increased interest in high-throughput metabolomics, often coupled with
other techniques such as chromatography (GE-MS, LC-MS, UPLS-MS) or elec-
trophoretic techniques (CE-MS). Due to its high sensitivity and wide range of
covered metabolites, MS has become the technique of choice in many metabolo-
mics studies (Zhang et al. 2012).
1.6 Perspectives
Omics technologies have contributed widely to the understanding of the delicate

physiologic equilibrium that allows for a successful transition into lactation (Vailati-
Riboni et al. 2016). Their application to the study of peripartal disease pathophysi-
ology is spreading across research groups worldwide. Despite this, a reductionist
approach focusing on parts and sections of the physiology (rather than considering
it as a whole) is still the main approach used by scientists when handling this holis-
tic output. We are still considering single organs as the “system” to study, subse-
quently inferring the connection with the rest of the organism based on the existing
literature. The physiologic and metabolic complexity of these diseases unavoidably
requires a systems biology approach, i.e., a way to systematically study the complex
interactions in the cow using a method of integration instead of reduction. Only in
this way researchers will be able to uncover the underlying links (pathways, regula-
tory networks, and structural organization) within and between tissues (e.g., adipose
and liver; skeletal muscle and adipose; gut microorganisms and epithelia), and to
detect new emergent properties that may arise from examining the interactions
between all components of a system.
The systems approach in its purest connotation has not yet been applied to the
field of dairy science. This is largely due to the fact that when integrating multiple
datasets, one tends to generate bare numerical relationships rather than meaningful
biological connections among organs. Therefore, as a future frontier, the dairy sci-
ence community must address the need for “useful” approaches (e.g., modeling,
bioinformatics) to integrate knowledge derived from multiple “omics” analyses
within and between tissues, focusing both on the classical flow of genetic informa-
tion (transcriptome, proteome, metabolome), and what lies above it (epigenetic).
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Demystifying the Myths: Switching
Paradigms from Reductionism 2
to Systems Veterinary in Approaching
Transition Dairy Cow Diseases
Burim N. Ametaj
Abstract
Animal scientists have made tremendous progress and put their best efforts, dur-
ing the last 50 years, in regard to selecting dairy cows for high milk yield and in
designing the best rations for high milk production. Moreover, dairy cow health
scientists have persistently studied health issues and offered the best solutions to
numerous transition cow diseases. Indeed, one dairy cow today produces an
amount of milk that is equal to six cows 50 years ago. This is an accomplishment
of both geneticists and animal nutritionist that deserve to be credited. However,
there is still one grey area that both animal and health scientists have not been
able to solve, the reason for high incidence of periparturient diseases and the
high cull rates. Indeed, despite much research work and progress made with
regard to cow health there are still various health concerns that continue to affect
dairy cows, which cost dairy industry billions of dollars in economic losses on a
yearly basis. The number of cull cows is increasing and so has the incidence of
several diseases including uterine infections and infertility, mastitis, laminitis,
ketosis, and retained placenta. This has raised questions whether the approach,
the philosophy, or the scientific methodology that we have been using to address
diagnosis, treatment, and prevention of transition cow diseases is appropriate.
There is broad discussion among scientists in biological and medical sciences
that suggests that the reductionist philosophy that has led biological sciences and
medicine for centuries has failed to find optimal solutions to the many unre-
solved health issues of humans and animals. A new philosophy, known as sys-
tems biology approach, is emerging that has been embraced by various leading
groups in the world that seems very promising and that proposes to look at the
animal as a whole and the disease as a complex interaction among genotype,
B.N. Ametaj, D.V.M., Ph.D., Ph.D.

Department of Agricultural, Food and Nutritional Science, 4-10G, Agriculture/Forestry
Centre, University of Alberta, Edmonton, Alberta T6G 2P5, Canada
e-mail: [email protected]
© Springer International Publishing Switzerland 2017 9

B.N. Ametaj (ed.), Periparturient Diseases of Dairy Cows,
DOI 10.1007/978-3-319-43033-1_2
10 B.N. Ametaj
phenotype, and environment. This discussion, recently, has involved animal and
veterinary scientists and we are bringing those debates to the readers of this
book. In this chapter, we examine some of the concepts that have dominated the
animal and veterinary sciences during the last century and have become myths
and suggest that it is time to revisit and redefine those concepts in order to
improve cows’ health, their welfare and well-being as well as the profitability of
dairy industry. In the last section of the chapter a comparison between the reduc-
tionist approach and the systems biology or veterinary approach is made and a
discussion of the advantages and the drawbacks are presented so that the readers
better understand the philosophy of veterinary medicine and adopt the best
approach in their research activities.
2.1 Introduction
According to CanWest DHI Canada (2015) the incidence rate of periparturient dis-
eases of dairy cows has been increasing during the last 14 years (2001–2014). Based
on their records and other surveys conducted by various research labs worldwide the
three most predominant periparturient diseases of transition dairy cows are metritis
(inflammation of the uterus), mastitis (inflammation of the udder), and laminitis
(inflammation of the hoof laminae). Other major periparturient diseases reported
include ketosis, milk fever, retained placenta, fatty liver, displaced abomasum, and
ruminal acidosis.
The culling rates (for different reasons) also have been increasing from around
24% during 2011 to almost 51% during 2014. This has shortened the productive life
of dairy cows to less than 2 years. Increasing trends of disease incidence and culling
rates have been reported in the US, European countries, and beyond (USDA 2007a,
b; Maher et al. 2008; Rushen 2013). The increasing number of cull cows is a major
setback for the dairy industry and if this trend will continue during the next decade,
then, the productive life of a cow might even shorten to 1 year. Occurrence of dis-
ease is associated with lower milk production, lower pregnancy rate and infertility,
and lower profitability for dairy producers. This state of cows’ health influences
greatly the profitability and the future of dairy industry. Moreover, sickness is asso-
ciated with poor welfare and well-being of dairy cattle and certainly poor
products.
It should be noted that almost 30–50% of cows in a herd are affected by one or
more periparturient disease at the same time (Ametaj et al. 2010; LeBlanc 2010;
CanWest DHI Canada 2015). The unsolved question is to why this high incidence
of disease and what is/are the cause(s) or the etiological factors of the disease state?
This question has been raised and addressed by cow health researchers during the
last 100 years and although the knowledge about pathobiology of diseases in transi-
tion dairy cows is increased tremendously we still do not have a complete under-
standing of the causes and etiopathogenesis of transition cow diseases. Lack of full
knowledge of disease process and causative agents has affected the appropriate
2 Demystifying the Myths 11
treatment of disease and development of prevention strategies. Some of the reasons

for this state of knowledge are discussed below.
An important reason for the present state of cow’s health status is the philosophy
that the scientists have used to diagnose disease, treat the sick cows, or develop
prevention interventions. The dominant philosophy of science in the last few centu-
ries has been the “Reductionist” approach. The basis of reductionist philosophy of
disease has been to theoretically split the whole organism of the animal into smaller
and smaller parts and analyze and study the details of those parts in order to better
understand the components of the whole. This approach has generated a tremendous
amount of knowledge about the structure and functions of various body units includ-
ing various organs, tissues as well as cells, enzymes, proteins, carbohydrates, lipids,
minerals, vitamins, or other components of the body. However, it is obvious that the
reductionist approach has not been successful in addressing complex health issues
of dairy cows and the issues of the organism as a whole.
Other important reasons for this state of health status in dairy cows are the feed-
ing (i.e., environment) systems used and the genotype of the cows. During the last
century there was not very much knowledge about how to properly feed dairy cows
to keep them healthy and productive. Currently the science of nutrition is advanc-
ing; however, it is not yet at the level of individual feeding and feeding for both
health and productivity. Developing a diet that will support both productivity and
health would be the future challenge of animal nutritionists.
Also, not very much knowledge exists with regard to selection of dairy cows for
health traits (i.e., healthy genotype). The only focus of cow geneticists in the past
few decades has been selecting cows for high milk yield. Presently there is a great
interest from scientists and dairy industry to select dairy cows for health traits.
Another area that deserves more efforts from research scientists is the etiopathol-
ogy of disease process around parturition. There are opportunities in the area of
early diagnosis of disease, better prognosis of disease outcome as well as develop-
ment of new preventive interventions. However, these efforts are at their pioneering
stage.
It should be noted that a new philosophy has emerged in relation to how we study
periparturient diseases of dairy cows: the philosophy of systems biology or veteri-
nary approach. This new philosophy proposes a new methodology of how we diag-
nose disease, how we treat sick animals, and how we prevent disease from occurring.
Indeed, presently we are able to use multiple sophisticated instruments that the sci-
entists of the past did not have. These instruments are helping us to better approach
sick animals and better understand the disease processes and causality. Instruments
like NMR (nuclear magnetic resonance), DI-MS (Desorption Ionization Mass
Spectrometry), GC-MS (Gas Chromatography Mass Spectrometry), ICP-MS
(Inductively Coupled Plasma Mass Spectrometry), and many other modern instru-
ments related to RNA, DNA, proteomics, and microbiome research make the basis
for a higher level of approach to disease state.
Another advantage of systems biology approach is the current evolvement of
computers, bioinformatics, and the means of communication. Scientists of the past
had to use mostly hand writing, book writing, letter writing, telephoning (if that was
12 B.N. Ametaj
available), library loans, and borrowing of information from one another or from
libraries of other countries. Presently, scientists can obtain information and learn
about research conducted in any part of the globe in a matter of seconds or minutes
and not days or months as during the last century. They can process large amounts
of data in a matter of minutes with more advanced bioinformatics tools. Indeed, this
is the century of electronics and vast and fast information and communication. This
facilitates interaction among scientists and expedites the process of innovation.
In this chapter, issues related to drawbacks of reductionist approach will be dis-
cussed in more detail later. Moreover, the novel philosophy of “systems veterinary
approach” will be presented. Although the original terminology for this new phi-
losophy is “systems biology approach,” it would be more appropriate to use the term
“systems veterinary approach” for veterinary medicine. The reason for that is that
the whole science of veterinary as related to monitoring of animal health, diagnosis
of disease, treatment of disease as well as prevention strategies and prediction of
risk for diseases needs to embrace the systems approach in order to improve the
health status of animals in general and more specifically the health of dairy cows.
Multiple hypotheses have been proposed during the years for each periparturient
disease of dairy cows with milk fever championing all other diseases with more than
30 different hypotheses during the last century. Although hypotheses put forward
about the etiology of various diseases have their merits, they still have not been able
to solve the multiple issues related to cow’s health. Cows still continue to be sick in
large numbers and culled in high rates and unfortunately we are at a standstill situ-
ation that requires solutions. Because many scientists of the last century have based
their approaches to disease diagnosis, treatment, and prevention based on the meth-
odology of reductionism or reactive veterinary medicine, it would be of great inter-
est to discuss some of the myths created during the last century and the need for
their demystification in order to open the way to new approaches and new
solutions.
2.2 yth Number 1: A Metabolic Disease Is a Disturbance

M
of the Internal Homeostasis of a Metabolite or Several
Metabolic Processes
According to Jack Payne (1977) “a metabolic disease is an abnormal change in the

internal homeostasis of a metabolite or several metabolic processes.”
Payne made this statement almost half a century ago when there was not very
much knowledge about metabolic diseases. The scientific study of metabolic dis-
eases was at its early stages. The definition given by Payne on metabolic diseases
was correct, based on the knowledge of that time. However, since that time there has
been major developments in the understanding of metabolic and periparturient dis-
eases of dairy cows. For example, for several decades it was thought that lower iron
in the blood (i.e., hypoferremia) was an indication of iron deficiency. However, dur-
ing the last decade scientific research has proven that during bacterial infections
iron is withdrawn from blood systemic circulation, also known as anemia of
inflammation, in order to make it difficult for pathogenic bacteria to freely access

iron, which is essential for their growth and proliferation (Ganz 2009; Wander et al.
2009). Mounting evidence also suggests that the same might be true in regard to
calcium (Ca) concentration in the systemic circulation or other body fluids or cells.
Several recent review articles suggest that lowering of calcium in the blood, during
bacterial infections or endotoxemia, might be part of the immune response for
safely removing bacterial endotoxins from blood circulation (Waldron et al. 2003;
Ametaj et al. 2010; Eckel and Ametaj 2016). Moreover, sensing an increase in the
concentration of Ca inside the pathogenic bacterial cells of the lungs may play a role
in the activation of virulence genes, particularly for expression of pili and neur-
aminidase. Pili are involved in infection of the lungs, and elevated intracellular Ca
is one of the most important signals for activating expression of pili, a condition that
could begin as bacteria transition into the particularly high Ca environment of the
lung (Rosch et al. 2008). Therefore, high extracellular (i.e., blood) Ca might help
pathogenic bacteria to activate their virulence genes and withdrawal of Ca might be
a protective response of the host against bacterial infection.
During the last decade there has been a boom in application of omics technolo-
gies in the study of transition cow diseases. Exciting results have been reported by
multiple labs around the globe. An important lesson learned from metabolomics
studies is identification of multiple metabolite alterations in the body fluids (blood,
urine, or milk) during various periparturient diseases of transition dairy cows. This
has raised the question, whether we can define or associate one metabolic disease
with perturbation of one single metabolite or even a few metabolites in the body
fluids of the host? Recently our group has been able to identify and measure hun-
dreds of metabolites and multiple metabolic pathways that are altered before, dur-
ing, and after clinical appearance of six important periparturient diseases of dairy
cows including uterine infections, mastitis, laminitis, ketosis, milk fever, and
retained placenta (Dervishi et al. 2016a, b; Zhang et al. 2017). These data suggest
that each periparturient disease whether typically infectious (metritis or mastitis) or
metabolic in nature (ketosis or milk fever) is characterized by multiple changes in
the concentrations of multiple metabolites and mineral elements. Therefore, identi-
fying one metabolic disease (e.g., ketosis, fatty liver, or milk fever) with one per-
turbed metabolite (BHBA, NEFA, or Ca, respectively) doesn’t seem to be any
longer acceptable scientifically. By the same token, it would not be scientifically
accurate to identify a few perturbed metabolites with one metabolic disease because
in most of the major periparturient diseases there are tens of metabolites and mul-
tiple metabolic pathways that are perturbed.
Another interesting development in life sciences is that in most human modern
metabolic diseases including type 2 diabetes, obesity, and metabolic syndrome there
is always present a chronic inflammatory state (Monteiro and Azevedo 2010).
Recently, data from our laboratory also show that all six major periparturient dis-
eases of dairy cows, including metritis, mastitis, laminitis, ketosis, milk fever, and
retained placenta (Dervishi et al. 2015, Dervishi et al. 2016a, b; Zhang et al. 2015,
2016), are preceded and associated by chronic inflammation. These data suggest
that there are no simply metabolic or inflammatory states but more combined host
14 B.N. Ametaj
metabolic and immune responses to the pathological state. This also suggests that
the etiology, pathobiology, and definition of a metabolic disease should be revisited
and redefined.
Since the time Payne presented his definition of a metabolic disease various
research groups have demonstrated that numerous inflammatory intermediates
stimulate or inhibit various metabolic responses. For example, tumor necrosis factor
(TNF) and interleukin (IL)-1β have been shown to have lipolytic activities and
inhibitory effects on gluconeogenesis, whereas IL-6 influences hepatic protein syn-
thesis (Raj et al. 2008). Additionally, TNF was demonstrated to lower insulin sensi-
tivity of the liver, adipose tissue, and skeletal muscles (Hotamisligil et al. 1993;
Weisberg et al. 2003). Furthermore, TNF and IL-1β suppress expression of GLUT2
(glucose receptor) and glucokinase in pancreatic β-cells, thus making them less
sensitive to the blood glucose level (Park et al. 1999). TNF also was demonstrated
to cause fatty liver in dairy cows (Bradford et al. 2009) and administration of endo-
toxin lowered plasma Ca (Waldron et al. 2003). These examples indicate that there
is no clear separation between metabolic and inflammatory responses and that dis-
eases are far more complex than previously thought and cannot be classified any
longer as solely metabolic or merely inflammatory.
Another issue that deserves more discussion from the dairy cow health commu-
nity is related to definition of what is and what is not a metabolic disease. As a start-
ing point for a discussion is the recent reported findings of the number of metabolites
present in the body fluids of humans. For example, Psychogios et al. (2011) reported
a total of 4229 various metabolites in the serum of human subjects. It is anticipated
that the same number of metabolites will be identified and quantified in the blood of
different livestock animals, including cattle. There are several challenging questions
for the human and animal health scientists that need to be addressed with regard to
definition of a metabolic disease. For example, does the host have >4000 homeo-
static control mechanisms to regulate concentrations of all metabolites present in
the body fluids or some or most of them are just passing by through the host because
they are part of the food products consumed? Are there essential metabolites that are
strictly regulated, and others that are not so important? Moreover, if homeostasis of
one or a few or all of those metabolites are disturbed (increased or decreased) at a
certain time point, then, should we define a total of 4229 metabolic diseases in
humans or animals (based on reductionist concept of one perturbed metabolite one
disease)?
Another issue worth to be discussed is what is called “an abnormal change in the
internal homeostasis” as suggested by Payne? Can we call fluctuations (i.e.,
increases or decreases) of blood metabolites in the body fluids “abnormal changes
of the internal homeostasis”? It should be emphasized that most metabolites that
circulate in the blood or other body fluids during disease process flow to various
organs, tissues, and cells to participate in numerous activities like synthesis of larger
molecules such as glycogen, phospholipids, triglycerides, enzymes, proteins, immu-
noglobulins, acute phase proteins, antimicrobial compounds, and many others.
Some of the metabolites participate in energy production, others become part of cell
membranes, some others serve as building blocks for enzymes or fuel for the cells,
several metabolites participate as components of the immune response and many

other functions. Moreover, metabolites are increased or decreased in the body fluids
based on the needs of specific sites, tissues, or organs for these compounds at certain
time points or activities. They are absorbed from the GI tract or released from body
storage sites into the systemic circulation and are transported from one part of the
body to another organ, tissue, or cell. Therefore, the challenging question is how do
we distinguish the normal flow of metabolites from an abnormal one? It might be
that metabolites are flowing to the mammary gland to provide nutrients for milk
synthesis, or they might be flowing to the rumen to support development of an
immune response. So, what is an abnormal and what is a physiological flow of
metabolites and nutrients?
Another important question is what is considered a normal concentration of a
blood metabolite? This is a very complex question and very difficult to be answered.
There are multiple variables that need to be controlled in order to determine the
normal concentration of a blood metabolite. Here are some of them: (1) The animal
has to be absolutely free of any disease process. The animal should be free of para-
sites, infectious diseases, viral diseases, clinical metabolic diseases, subclinical dis-
eases including subclinical ketosis, subclinical hypocalcemia, subclinical mastitis,
or any other ailment, which is very difficult to be achieved; (2) The animal should
have absolutely no deficiencies or sufficiency of any nutrient(s) in the diet. Feeding
lower amounts of nutrients than the NRC recommended amounts or more than the
recommended amounts would affect their blood concentrations and therefore the
definition of normality; (3) Environmental conditions should be such that they will
not influence in any way the health or metabolic processes of the host. Temperature,
humidity, barn and stall space, and season of the year; (4) The animals should be
free of stress (i.e., optimal well-being and welfare) like stress of being tied in stalls,
stress of management, stress of hierarchy, stress of accessing foodstuff or water and
other potential influential variables; (5) The source of water and mineral mix also is
important because they vary from one dairy farm to the other and from one location
to the other and contain different amounts of minerals or other compounds; (6)
Physiological stage and age of the animals also are major factors that influence
concentration of various metabolites in the body fluids. For instance, cows during
the dry off have a different diet, a different physiological stage compared to cows in
early lactation or mid- or late-lactation and have completely different nutrient
requirements. Moreover, young animals as well as heifers versus cows have differ-
ent physiologies and certainly different concentrations of blood variables; (7)
Feedstuff used for the animals should be absolutely free of mycotoxins, endotoxins,
heavy metals, or other toxic compounds. It is known that various fungi and bacteria
grow under humid and optimal temperatures in the feedstuff used for dairy cattle or
other livestock animals. Metabolic and immunity effects of some of those toxic
compounds have been reported in the scientific journals. Presence of those com-
pounds certainly will affect the normality or abnormality of metabolites in the body
fluids of cattle. Overall, defining what is normal and what is abnormal with regard
to the concentration of a metabolite or multiple metabolites in various body fluids
of a dairy cow or other animals is a very challenging task.
16 B.N. Ametaj
The methodology that the scientists have used to determine whether an abnormal
change has occurred in the internal homeostasis of a metabolite in a cow or a group
of cows has been mainly by comparing clinically healthy cows versus those display-
ing clinical or subclinical signs of a disease and under comparable parities, physi-
ological stages as well as similar feeding and management systems. However,
generally, no specific evaluations of control animals are conducted to rule out that
they did not have subclinical health issues. It might take some time until studies that
will control all the variables described above could be conducted and advanced
instrumentation will be used to determine normal concentrations and fluctuations of
thousands of metabolites present in the body fluids of dairy cows.
It should be noted that the concept of a metabolic disease in dairy cows is quite
different from that of humans, which defines metabolic disease as “any of the dis-
eases or disorders that disrupt normal metabolism, the process of converting food to
energy on a cellular level (Enns 2016).” In human medicine metabolic diseases are
defined mainly as hereditary or inborn errors of metabolism (Enns 2016). It is inter-
esting also to point out that except for diabetes, a disease related to alteration of
glucose and insulin metabolism, and metabolic syndrome there are no other defined
metabolic diseases of humans. In contrast in veterinary medicine there are several
diseases that have been defined as metabolic disorders including milk fever, ketosis,
fatty liver, and several others less important diseases like hypophosphatemia, grass
tetany or hypomagnesemic tetany, and pregnancy toxemia.
Finally, given the most recent developments in systems biology, metabolic dis-
eases should be viewed more as perturbations of multidimensional and integrated
cellular and organ level genomics, transcriptomics, proteomics, and metabolomics
networks in interaction with the environmental factors. These interactions should be
viewed as multilayered and different in individual animals with the same disease.
This complexity requires a new methodology of handling the challenges associated
with the disease process. It also requires development of a new philosophy on how
to prevent occurrence of disease in livestock animals.
Overall the concept of metabolic diseases or disorders for livestock animals in
general and dairy cattle in particular needs to be revisited and redefined. This is a
necessity deriving from new developments in the area of dairy cow health. This is
also an obligation of the current research community to the dairy industry, the future
generations of students and researchers, and to the dairy cattle well-being and
welfare.
2.3 Myth Number 2: The Concept of Production Diseases
The term production disease has been coined and widely accepted by the scientific
community since its first introduction by Jack Payne in the early 1970s. Sixteen
international conferences have been organized so far starting from 1972 until the
most recent one on 2016, under the name of “International Conference on Production
Diseases of Farm Animals.” However, since the introduction of this concept there
has been many new developments in the science of biology and veterinary medicine
and the philosophy of approaching a disease state. Therefore, it is time to revisit this
concept and adjust the concept of production disease to the new era of systems
biology approach.
What was the original definition of production diseases? The concept of produc-
tion diseases was introduced by Jack Payne (1977). He indicated that: “as intensifi-
cation and production levels increase so too do the problems of metabolic disorders.”
He further continues to elaborate the concept indicating that: “The modern view is
that metabolic diseases of farm ruminants are not primarily due to inherent defects
in the animal’s biochemistry. Rather they result from a breakdown in the animal’s
ability to cope with the metabolic demands of high production, coupled with the
strains of modern intensive husbandry and feeding. In other words, metabolic dis-
ease is a failure to compensate for imposed and man-made demands on farm live-
stock. This idea has led to the introduction of a new collective name for metabolic
disorders of farm ruminants—production disease.”
Payne proposed that metabolic diseases are related to the inability of the cows to
cope with the high nutrient demands of milk production. However, dairy cows that
produce high amounts of milk have inherited the trait of high milk production from
their parents. Therefore, they have or own the capacity to produce high amounts of
milk. If we offer cows all the necessary nutrients required for the level of milk pro-
duction that they are capable off, then, the cows must reach that potential. This is
supported by the fact that around half of high producing dairy cows in a herd are
affected by metabolic or periparturient diseases during the transition period. The
other half remains healthy and productive. They can reach their production capacity
with no health issues. This is an important indication that the environment is not the
only or the main actor in the development of most metabolic or periparturient dis-
eases of dairy cows, as indicated by Payne (1977). Moreover, if half of the cows in
a herd consume the same amount of feed and similar ingredients and are not affected
by metabolic diseases, this means that the genotype is also a very significant factor
that should be taken into consideration when studying metabolic diseases. However,
Payne in his book (Payne 1977) indicates that “metabolic disease is not an inherent
defect in the animal’s biochemistry.” Therefore, Payne excludes the possibility that
metabolic diseases in dairy cows are related to inborn errors of metabolism or geno-
type of the cow.
Let’s take another example to better understand the role of genotype in the patho-
biology of metabolic diseases. Feeding high amounts of grain immediately after
calving, to provide cows the necessary energy and nutrients required for milk pro-
duction, is associated with low rumen fluid pH. This low pH affects microbiome
composition and the bacterial toxic compounds released in the rumen. For example,
the amount of endotoxin in the rumen fluid of cows fed high amounts of grain is
increased almost 14-fold (Emmanuel et al. 2008). Endotoxin is able to translocate
through rumen and colon tissues and to enter into systemic circulation triggering a
whole variety of metabolic and immune responses, even diseases like fatty liver,
laminitis or retained placenta (Emmanuel et al. 2007). There is increasing evidence
that mammals and cows respond differently to endotoxin (Jacobsen et al. 2007,
2008). Some individuals are more susceptible to endotoxin and succumb to sickness
18 B.N. Ametaj
or even death. Other individuals are more resistant to the same dose of endotoxin
and overcome the challenge of endotoxin with a slight fever. There is also mounting
evidence that endotoxins are involved in multiple periparturient diseases of dairy
cows including fatty liver, milk fever, ketosis, retained placenta, displaced aboma-
sum, laminitis, and several others diseases (Ametaj et al. 2010, 2015). In this case it
is obvious that the susceptibility or resistance of some of the cows to endotoxin-
related diseases is strongly related to the genotype of the animal.
Payne (1977) and other scientists also believed that “metabolic disease is a fail-
ure to compensate for imposed and man-made demands on farm livestock.” Based
on this definition it seems like men have created metabolic diseases by demanding
or selecting cows for greater milk production. However, there is no solid evidence
to indicate that selection of cows for high milk production is associated with greater
incidence of periparturient diseases (including those called metabolic diseases).
One clear example that increased milk production is not associated with increased
incidence of periparturient diseases is milk fever. Milk fever was reported for the
first time during the eighteenth century. It’s been almost one century that we study
milk fever, however, the incidence of this disease in North America, Europe, or
elsewhere has fluctuated around 5–10%. This clearly shows that milk fever is not a
man-made disease, not related to selection of cows for high milk production. On the
other hand, some breeds of cows like Jerseys are more prone to milk fever than
Holsteins. This also supports the idea that genotype of the cows is very important in
disease development.
Payne (1977) further explains definition of a production disease: “Firstly, it
implies that the disease is likely to occur when the demand for production exceeds
the animal’s metabolic capacity. Secondly, it draws attention to the fact that, in the
interests of high production, animals are exposed to metabolic hazard because they
are not always fed or managed appropriately for their specialized physiology and
metabolic needs.”
If Payne’s statement would be true, then 100% of the cows in a herd should suc-
cumb to metabolic or periparturient disease around calving. However, this does not
happen although cows are fed a similar ration. In fact, only up to 30–50% of the
cows are affected by one or multiple periparturient diseases concurrently. This again
suggests that genotype is very important in the susceptibility of the cows to peripar-
turient disease.
Another aspect of Payne statement (Payne 1977) that deserves to be discussed is
that he is defining metabolic disease in a mechanical way. He states: “All production
systems have three basic components. All have inputs of raw materials, a central
processing system and an output of the finished product. This is the basic pattern of
production not only for the dairy cow but also for manufacturing systems of all
kinds. All are prone to similar ‘diseases’.” It is obvious that Payne is considering the
animal a machine ignoring that biology is quite different from a human or electri-
cally or electronically controlled machine. A cow is far more complex being than a
human made machine. Another aspect that was ignored by Payne’s definition is that
there are tenfold or more bacteria in the GI tract of a cow than her own body cells.
Those bacteria and their products have been reported to be involved in various
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VII.
Décadence des contrées du Dniéper.
Le nouveau monde russe et ses
prétentions.
Cependant, depuis le XIe siècle, cette suprématie de Kiev

commençait à décliner. Le règne de Iaroslav fut une brillante époque
qui ne devait plus revenir. Ses terres réparties entre ses fils, puis
entre ses petits-fils, s’émiettaient en états distincts, très peu liés
entre eux et échappant à la suzeraineté du prince de Kiev. Seuls
quelques princes comme le fils de Iaroslav, Vsevolod (décédé en
1093), son petit-fils, Vladimir Monomaque (1125) et son arrière petit-
fils Mstislav (1132), réussirent à réunir sous leur sceptre un nombre
de pays plus ou moins considérable et à s’assurer une situation
prépondérante parmi les autres princes. Mais ces périodes d’éclat
ne furent que de courte durée.
Les autres princes, dépossédés de leurs patrimoines,
entreprirent une longue série de guerres acharnées et appelèrent à
leur secours les hordes des Coumanes qui vivaient dans les
steppes. Les boïards et les populations autochtones, croyant plus
avantageux d’être gouvernés par un prince de la dynastie vivant au
milieu d’eux, que d’obéir au gouvernement de Kiev, soutenaient
leurs « maîtres patrimoniaux ». Au congrès de Lubtché, en 1097, on
adopta le principe, que chaque prince apanagé resterait maître dans
son patrimoine. C’était sanctionner le démembrement du royaume
de Kiev et revenir à peu près à l’ancien régime des tribus. Il s’en
suivit une division générale : sur le territoire ukrainien : la Galicie, la
Volhynie, les pays de Tchernyhiv et de Pereïaslav ; sur le territoire
des Ruthènes blancs, outre le pays mixte de Tourov-Pinsk, ceux de
Polotsk et de Smolensk ; sur le territoire des Grands Russes, les
pays de Novogorod, de Rostov-Souzdal et de Mourom-Riasan. Et
encore à l’intérieur ces principautés se divisaient-elles en domaine
de l’aîné et en parts des cadets.
Ainsi en faisant valoir leurs droits dynastiques et en s’attachant la
population locale, les princes deviennent de plus en plus
indépendants de la suzeraineté de Kiev. La morale chrétienne et la
théorie de l’amour fraternel ont fait des progrès dans l’opinion : les
princes n’osent plus s’entretuer sans scrupules, comme l’avaient fait
les fils de Sviatoslav et de Vladimir. « La descendance de Vladimir »
s’accroissant toujours, les terres se divisent et se subdivisent, les
règlements de compte deviennent de plus en plus compliqués, et le
pouvoir du prince de Kiev se réduit à l’étendue de ses domaines
réels, et à leur voisinage immédiat. Il doit se contenter d’une
suzeraineté nominale, il ne joue plus que le rôle de primus inter
pares.
Cela ne fut pas sans porter atteinte à l’influence civilisatrice de
Kiev qui, d’ailleurs, vivait depuis longtemps non seulement sur ses
propres ressources, mais encore sur ce que lui fournissaient les
autres contrées en qualité de tribut, de butin et autres contributions.
En outre, la colonisation, le commerce et la vie économique des
pays situés sur les confins de son territoire, notamment de toute la
partie ukrainienne du bassin du Dniéper, se trouvèrent ruinés, par de
nouvelles invasions. La formation du royaume de Kiev n’avait pu
arrêter, encore moins anéantir la pression des hordes turques
venant d’Asie, sous laquelle avait succombé l’état des Khozares.
Les Petchenègues, après s’être étendus, au Xe siècle, du Don
jusqu’au Danube, avaient détruit les établissements slaves
(ukrainiens) de la steppe, en avaient chassé la population vers les
contrées moins accessibles du Nord et de l’Ouest et commençaient
à ruiner par leurs incursions les parties moins exposées du bassin
du Dniéper. Ils avaient même menacé Kiev dans la seconde moitié
du Xe siècle et au commencement du XIe. Souvent ils s’en
approchaient, la tenaient bloquée et ravageaient la contrée
environnante. L’époque de Vladimir, qui a laissé dans l’imagination
de la postérité le souvenir d’un âge d’or, ne fut, en réalité, qu’une
longue guerre défensive, d’ailleurs pas toujours heureuse, contre
ces nouveaux intrus. La population fuyait devant eux, elle se
réfugiait dans les régions boisées et marécageuses de la contrée de
Kiev et de Tchernihiv ou même plus loin vers l’Ouest et le Nord.
Vladimir avait été obligé de ramener de force la population sur une
ligne de défense qu’il avait fait établir pour sauvegarder sa capitale,
entassant à cet effet remparts, fossés et forteresses.
Après sa mort, les Petchenègues s’affaiblirent, de nouvelles
hordes turques sorties de l’orient apparurent : d’abord les Torques,
plus tard les Kiptchaks ou Coumanes, que les chroniqueurs
ukrainiens appellent Polovtses. Iaroslav profita de cette conjoncture
pour attaquer ses anciens ennemis par le nord, il les repoussa vers
le sud, où il édifia une nouvelle ligne de défense sur la rivière de
Ross et la horde des Petchenègues porta son camp au delà du
Danube. Une accalmie se produisit dans le bassin du Dniéper, mais
la situation s’aggrava de nouveau lors des discordes qui éclatèrent
vers 1070, entre les fils et les petits-fils de Iaroslav au sujet de la
répartition des domaines. Dès lors ce ne fut plus pendant plus d’un
siècle qu’une longue série de calmes et de tempêtes. Dès que les
attaques des Kiptchaks cessent, les relations commerciales
reprennent, les colonies se multiplient sur la lisière de la steppe ;
l’activité des hordes se fait-elle de nouveau sentir, les colons se
réfugient dans la zone boisée, les caravanes ne peuvent plus se
faire jour vers le Dniéper que sous le couvert des troupes et les
princes de Kiev, de Pereïaslav et de Tchernihiv sont obligés
d’employer toutes leurs forces à la défense des frontières.
Tout l’intérêt du pays est donc concentré dans une question : se
défendre contre les « infidèles ». Cette question vitale domine toute
la politique, elle inspire la littérature, dont Kiev reste toujours le
centre. Les classes dirigeantes, les écrivains, la population même
réclament que les princes s’unissent pour être mieux en état de
repousser les infidèles. Un prince s’attache-t-il à cette politique, il est
sûr de gagner en popularité. Au contraire on est plein de mépris pour
ceux qui demandent secours aux Kiptchaks pour régler leurs
discordes intestines et amènent ainsi les païens en terre russe. En
effet, après avoir été appelés par les princes, les chefs de hordes ne
se faisaient pas faute de revenir faire quelques incursions à leurs
frais. Du reste les guerres intestines, grâce à un système compliqué
de succession, étaient devenues un mal chronique. A la succession
en ligne directe, qui avait l’appui du peuple parce qu’elle causait
moins de perturbations, s’ajoutait le principe de l’héritage familial qui
voulait que toute la famille princière régnât en commun. De là des
conflits de droits et d’intérêts vraiment insolubles. La population était
bien forcée de prendre parti dans ces querelles dynastiques, aussi
en supportait-elle les conséquences. Les prétendants persécutaient
les adhérents du parti adverse, ruinaient leurs villes, leur imposaient
des contributions.
Tout cela devait être funeste à la civilisation et à la vie
économique du bassin ukrainien du Dniéper, à ce célèbre triangle de
capitales qui avait été le foyer intellectuel non seulement de
l’Ukraine, mais de toute l’Europe orientale, dans le siècle précédent.
Les princes, la caste militaire, le patriciat, le clergé commencent à se
désintéresser du « trône d’or de Kiev », de la « mère des villes
russes » ; ils préfèrent des positions moins brillantes mais plus sûres
au nord-est, dans les nouvelles colonies slaves, au milieu des
peuplades finnoises du bassin de la Volga.
Ces populations étaient plus faciles à gouverner, moins
turbulentes que celles du bassin du Dniéper, qui s’étaient toujours
montrées plus sensibles aux empiètements des autorités. A cause
de cela, non seulement des paysans et des artisans slaves, mais
aussi des personnes appartenant aux classes élevées s’y étaient
fixés. C’était dans ces régions qu’étaient déjà venus se réfugier des
émigrants des contrées de Novogorod, de celles des Krivitches et
des Sévérianes : maintenant des contingents partis du midi les
rejoignirent. Au cours du XIIe siècle, les pays finnois des bassins de
la Volga et de l’Oka changent complètement d’aspect. Des villes
nouvelles fondées par des « Russes », des monastères, des églises
sortent du sol. C’est un nouveau monde russe, qui jette là ses
racines, qui se développe rapidement, s’accroît non seulement des
flots des nouvelles immigrations slaves, mais en s’assimilant la
population finnoise autochtone. Cette dernière s’accommode à la
civilisation slave, en adopte la langue et par ce procédé se forme
cette branche de la famille slave, la plus jeune et la plus nombreuse,
qui sera la Grande-Russienne, ou, à proprement parler, le rameau
méridional des Grands-Russes, cette partie qui jouera le rôle le plus
actif dans leur histoire.
Princes et clergé s’évertuent à rebâtir sur ce nouveau sol une
imitation des vieux pays, comme le firent plus tard les colons
européens en Amérique. Ils donnent à leurs villes les noms des cités
ukrainiennes du sud, dont ils essayent de copier l’aspect et
l’organisation politique : les Pereïaslav, les Zvenihorod, les Halitch,
les Vladimir réapparaissent ici. On y porte de l’Ukraine les objets du
culte, les œuvres d’art, on y transplante la littérature. Dans la
seconde moitié du XIIe siècle, cette Russie nouvelle est déjà si
peuplée et si riche que ses princes ne veulent plus échanger leurs
domaines pour ceux de l’Ukraine. Bien plus, ils aspirent à
l’hégémonie, ils prétendent pouvoir porter le titre « d’anciens » dans
les pays russes et dans la famille de Vladimir, sans avoir pour cela à
quitter leurs trônes de la Volga.
Le principe de succession patrimoniale leur fournissait des
arguments juridiques. Comme il a été dit plus haut, ce principe avait
été admis conjointement à celui de succession en ligne directe. Un
prince de Kiev mourait-il, ses frères puînés, aussi bien que le fils
aîné, prétendaient à la couronne et l’opinion publique était toujours
là pour soutenir les droits de la famille. Ainsi les princes de la
branche cadette de Rostov-Souzdal, survivant à leurs frères aînés,
devenaient eux-mêmes les aînés de la famille, réclamaient le trône
de Kiev et la suzeraineté sur les descendants en ligne directe qui
gouvernaient à Kiev, à Tchernihiv et à Pereïaslav et qui, pour eux,
n’étaient que des petits neveux sans précédence au trône. Ces
prétentions furent évidemment soutenues par le clergé et les boïards
des contrées placées sous leur domination, mais les milieux
ecclésiastiques et littéraires de Kiev eux-mêmes furent bien forcés
d’en reconnaître le bien-fondé, puisqu’elles découlaient logiquement
de cette conception de l’unité des pays russes et du règne en
commun de la famille de Vladimir qu’ils avaient toujours choyée et
soutenue.
Frontières politiques aux XIIe–XIIIe siècles — les principautés de

Halitch, de Volhynie, de Tourov-Pinsk, de Kiev, de Tchernyhiv, de
Péreïaslav.
Cependant, une fois leurs prétentions reconnues, ces princes du
Nord (de Souzdal et de Vladimir du Nord) ne voulurent pas se
transporter à Kiev, mais ils y envoyèrent leurs parents non nantis, ce
que les princes ukrainiens ne pouvaient tolérer. De là des guerres et
les souverains du nord firent tout leur possible pour détruire
définitivement le pouvoir et le prestige national de Kiev et du midi.
En 1169 cette ville fut mise à sac par les troupes du prince André de
Souzdal ; tout ce qu’on put enlever fut transporté dans les pays du
nord. Trente ans après, son frère Vsevolod, ayant réussi par une
politique habile à diviser les princes ukrainiens, amena de nouveau
la ruine de la malheureuse ville.
De cette façon, par suite de circonstances défavorables, mais
aussi grâce aux calculs de la Russie du nord, les contrées
ukrainiennes du bassin du Dniéper se virent, dans la première moitié
du XIIIe siècle, vouées à une ruine certaine, que l’invasion de Batou
vint achever.
VIII.
L’Ukraine Occidentale.
Ce n’est pas seulement dans le nord que les populations

ukrainiennes du bassin du Dniéper avaient cherché un refuge.
Fuyant devant les nomades de la steppe, elles s’étaient aussi
retirées, et en plus grande quantité, vers le nord-ouest et vers
l’ouest. Là, dans les contrées boisées de la Polissie, de la Volhynie,
dans le bassin du Bug, sur les pentes escarpées des Carpathes,
elles s’étaient établies durant cette même période, y avaient
progressé matériellement et intellectuellement. Cela devient
manifeste lorsque tout à coup, vers la fin du XIIe siècle, on entend
parler d’Ovroutche, comme d’une ville résidence des plus
importantes après Kiev, tandis qu’auparavant ce nom était presque
inconnu. A la même époque, la classe des boïards se multiplie dans
la Polissie. La Galicie, la Volhynie surgissent aussi : Vladimir de
Volhynie, la capitale construite par le prince de ce nom, pour faire
concurrence aux vieux centres de Doulibs, de Tcherven et de
Bouzsk, prend alors une importance commerciale et intellectuelle,
qui attire les étrangers. Halitch, sur le Dniester, dans la contrée
même où refluent les émigrants sortis des vieux pays de Tyverts,
s’assure une situation proéminente, bien au-dessus des vieilles
résidences de Peremychl, de Zvenyhorod, de Terebovl et donne son
nom à tout le pays.
Cet afflux de population en Ukraine occidentale, permet à cette
dernière de faire face à ses voisins de l’ouest : les Polonais et les
Hongrois. Cette contrée occidentale servait déjà depuis longtemps
de brandon de discorde entre les princes russes et la Pologne.
Probablement les migrations ethniques, le mélange de la population
de ces pays frontières avaient fourni de nombreux prétextes à ces
luttes. Les trois courants colonisateurs, celui des Slaves orientaux
(Ukrainiens), celui des Polonais et celui des Slovaques s’y
rencontraient, aussi chacun des trois États : Russie, Pologne et
Bohême, aux heures où leur puissance expansive se manifestait, ont
toujours voulu s’en rendre maîtres. Les Tchèques s’emparèrent de la
contrée de Cracovie, les Polonais de Peremychl et de Tcherven. La
première mention qu’on en trouve dans la chronique de Kiev, se
rapporte à une expédition faite par Vladimir dans ces contrées et au
cours de laquelle il reprit aux Polonais Peremychl, Tcherven et
d’autres villes. Les frontières qu’il établit alors devaient s’étendre
assez loin vers l’ouest, probablement jusqu’à Cracovie même, ainsi
qu’en témoigne le document de la curie pontificale ci-dessus
mentionné. Après sa mort, profitant des discordes qui avaient éclaté
entre ses fils, le roi de Pologne Boleslav s’empara de nouveau des
marches ukrainiennes. Mais la mort de ce dernier ayant donné lieu
en Pologne à des dissensions encore plus graves, Iaroslav put non
seulement reprendre les territoires en question, mais il assuma la
tutelle du prince polonais, à qui il donna sa fille. Les siècles
postérieurs virent tantôt les Russes, tantôt les Polonais y prendre la
haute main.
Iaroslav avait donné la Galicie à un de ses premiers fils, qui
d’ailleurs mourut bientôt. Les frères de ce dernier tentèrent de
s’approprier ce domaine et de le réunir à la Volhynie. Ce ne furent
que les petits-fils de ce premier prince de Galicie qui parvinrent à
reprendre ce pays et, instruits par l’expérience, ils prirent bien soin
de ne laisser aucun prince de la dynastie Kiévienne se consolider en
Volhynie.
Ayant à se défendre, d’un côté contre les Polonais, de l’autre
contre les Magyares qui, maîtres du versant méridional des
Carpathes, manifestèrent l’intention, vers la fin du XIe siècle, de
mettre aussi la main sur le versant septentrional, les princes de
Galicie cherchèrent des alliances dans les contrées éloignées, chez
les princes grands russiens de Souzdal et Vladimir, à Byzance et
même plus tard auprès du pape, alors qu’il s’agissait de se tenir en
garde contre les princes de Volhynie, leurs plus proches voisins.
Comme la dynastie n’était pas nombreuse, le pays ne connut
guère les querelles intestines, il jouit longtemps de la tranquillité, se
peupla, s’enrichit, ce qui donna à ses princes, vers le XIIe siècle, une
importance assez considérable et leur permit d’étendre leur
influence. Mais, vers la fin de ce siècle, la dynastie s’éteignit.
Roman, prince de Volhynie, homme très énergique, resté célèbre
par ses guerres contre les Kyptchaks et la façon dont il mata ses
boïards, réunit sous son sceptre la Galicie et la majeure partie de la
Volhynie. Mais il périt bientôt (en 1205) dans une de ses expéditions
contre la Pologne. Les boïards galiciens, qui n’avaient subi qu’avec
peine son autorité, voulurent secouer le joug de sa dynastie, soit en
soutenant d’autres prétendants, soit en se mettant sous la protection
des rois de Hongrie. Il y eut un moment où l’on crut réalisé le
partage des pays ukrainiens, qui ne devait s’effectuer que plus tard,
entre la Pologne et la Hongrie : le fils d’André, roi de Hongrie,
épousa la fille du prince polonais et fut couronné roi de Galicie à
Halitch, tandis que les contrées situées dans le bassin du Bog
étaient réunies à la Pologne. Les fils de Roman durent se contenter
du pays de Vladimir en Volhynie. Mais cette combinaison ne tarda
pas à s’écrouler : les fils de Roman, Danilo et Vassilko, dès qu’ils
eurent atteint leur majorité, reprirent possession de la Galicie et de la
Volhynie. De cette façon se forma en Ukraine occidentale, vers
1240, un puissant état, qui s’étendait de Sloutche jusqu’à Vislolka
vers l’ouest et jusqu’à Dorohitchine et Bilsk dans le nord. Le partage
entre Danilo et Vassilko ne porta aucun préjudice à l’état, parce que
les deux frères restèrent étroitement unis.
Dans le même temps, les pays de Kiev étaient ruinés par les
guerres incessantes que se faisaient les prétendants, les pays de
Tchernihiv s’émiettaient en une foule de petites principautés, et les
pays de Pereïaslav s’épuisaient sous les dévastations des
Kiptchaks. Aussi les contrées tranquilles de la Galicie offraient-elles
un refuge tout indiqué aux autres ukrainiens ayant besoin de sûreté
ou de protection ou tout simplement en quête de gain :
ecclésiastiques, hommes de lettres, artistes et artisans, marchands,
tous y affluèrent, y apportant les lettres et les arts, ou vinrent y
mettre leur fortune en sûreté, pour le plus grand bien du pays, qui
s’enrichit ainsi sous les princes de Galicie et de Volhynie, patrons
éclairés des lettres et des arts, qui ne manquaient aucune occasion
de s’approprier les monuments de l’ancienne littérature et de l’art
des provinces orientales. Surtout Vladimir, fils de Vassilko, acquit le
renom « de grand lettré et de philosophe, tel qu’on n’en a jamais vu
dans tous les pays russes et tel qu’on n’en verra plus après lui »
d’après l’expression du chroniqueur écrivant à sa cour. Malade et
infirme, il s’appliqua avec passion à collectionner des livres, il les
recopia, il fit construire des églises, les dota, les orna d’œuvres d’art
et y entassa les livres.
Les traditions littéraires et artistiques de Kiev s’implantèrent dans
le royaume de Galicie et de Volhynie, où elles se continuèrent, s’y
combinèrent de plus en plus avec les courants intellectuels venus de
l’Occident. Ce qui caractérisera au cours de l’histoire la vie
intellectuelle de ce royaume, c’est qu’ici les relations avec
l’Allemagne, et par son intermédiaire, avec l’Italie, seront beaucoup
plus actives ; l’influence de l’occident catholique, qu’elle lui vienne
par la Pologne ou par la Hongrie, se fera beaucoup plus sentir que
dans l’Ukraine orientale, plus éloignée et plus profondément
pénétrée des traditions byzantines et orientales. Ici l’intelligence
ukrainienne s’enrichira au contact de l’occident. Malheureusement
l’invasion mongole va se déverser sur l’Ukraine, empêchera cette
civilisation nouvelle de se répandre vers l’est et retardera ainsi la
formation de l’unité ukrainienne.
IX.
L’invasion mongole et ses
conséquences.
Le flot mongol poussé par Temoudjine atteignit l’Ukraine vers

1235. C’était une invasion de nomades analogue aux précédentes
qui, à maintes reprises, avaient désolé le pays. Mais celle-ci était
mieux organisée et ses péripéties nous sont mieux connues. Cela
commença par une irruption, qui se termina par la défaite des
Kiptchaks, en 1223, près de la rivière de Kalka, après une sanglante
bataille, où périrent beaucoup de princes ukrainiens qui avaient
consenti à soutenir leurs voisins contre les nouvelles hordes. Dix ans
plus tard, se produisit la véritable invasion des Asiates. Leur chef,
Batou, avait la ferme intention de s’emparer des steppes de la Mer
Noire et des contrées avoisinantes. Le mouvement commença dans
le bassin de la Volga, puis les pays situés sur la rive gauche du
Dniéper furent ravagés, Péreïaslav et Tchernihiv conquis et pillés. En
1240, la marche en avant se continua sur Kiev, puis à travers la
Volhynie et la Galicie, l’invasion atteignit la Hongrie, la Silésie et la
Moravie. Batou avait d’abord voulu se fixer en Hongrie, mais il
retourna sur ses pas et vint établir sa résidence sur le cours inférieur
de la Volga. Alors commença pour l’Europe orientale cette triste
période de sujétion aux hordes mongoles que les Ukrainiens et les
Russes ont appelée la domination tartare.
Naturellement les principautés du bassin de la Volga et celles de
l’Ukraine orientale eurent à subir les premières le joug des Tartares :
les populations durent payer tribut et les princes furent obligés de se
rendre à la résidence du Khan, pour faire hommage de leurs terres
entre ses mains et en recevoir confirmation. Il naquit de là bien des
intrigues et maintes compétitions, de sorte que les princes
intéressés se virent souvent obligés de séjourner à la cour du Khan
pour écarter tous compétiteurs possibles. C’est ainsi que Danilo dut
s’y rendre lui aussi, parce qu’un prince quelconque avait réussi à se
faire octroyer la suzeraineté sur la principauté de Galicie. Il
n’accepta pas cependant de bon gré la domination mongole, non
parce que son ambition fût lésée comme nous l’a représenté le
chroniqueur, car sa situation de vassal du Khan raffermissait sa
position vis-à-vis de ses voisins de l’occident, mais parce que la
conquête mongole fit surgir des forces dangereuses pour l’autorité
des princes.
Sous l’impression de la défaite, les populations ukrainiennes,
convaincues de l’incapacité de leurs souverains et de l’insuffisance
de leurs troupes, se soumirent en grand nombre à la suzeraineté
immédiate des Mongols, et cela probablement depuis la première
expédition de Batou (1240–1241). Les communautés s’engageaient
à rester fidèles et à payer un certain tribut en céréales. En revanche
elles obtenaient de pouvoir se gouverner librement sous la conduite
de leurs anciens et retournaient ainsi au morcellement politique, qui
avait précédé le régime des princes. Ce mouvement, qui affaiblissait
la force de résistance du pays et assurait aux envahisseurs une
domination paisible, était trop favorable à ces derniers pour qu’ils ne
s’appliquassent à le favoriser et à le fomenter. Quelques
renseignements accidentels et même certains épisodes, qui nous
ont été conservés, nous montrent que cette suzeraineté directe des
Tartares existait dans les contrées voisines de Kiev et de la Volhynie,
sur les bords de la Sloutche, de la Horine, du Bog et du Teterev. Les
conquérants essayèrent non sans succès d’introduire ce nouveau
régime en Galicie et en Volhynie. Ce fut un avertissement évident
pour Danilo et Vassilko, qui trouvèrent une raison de plus d’abattre la
puissance des Tartares dans la nécessité de mettre un terme à ce
mouvement dangereux pour leur propre autorité et qui ressemblait
beaucoup à celui qui se manifestera plus tard dans les
communautés ukrainiennes, lorsque se formeront les organisations
cosaques.
Ayant été mis au courant par des messagers, envoyés chez les
Tartares par le Saint Siège, des intentions de la papauté d’organiser
contre ces derniers une croisade des puissances catholiques
occidentales, Danilo entra en relation avec le pape, sans que ce
rapprochement aboutît à aucun résultat appréciable. Certes on lui
offrit la couronne et on l’engagea vivement à rentrer dans le sein de
l’église catholique. Mais il était trop prudent politique pour cela.
Néanmoins, sur les instances de sa famille, il consentit à se faire
couronner. Cette cérémonie eut lieu à Dorohitchine, sur la frontière
septentrionale du pays, en 1253, et tout se passa sans pompe, peut-
être intentionnellement, de peur d’éveiller les soupçons des Tartares.
Du reste, après s’être convaincu qu’il ne pouvait attendre de ce côté
aucun secours réel et que, d’autre part, les pourparlers relatifs à
l’union des églises soulevaient du mécontentement dans la
population, Danilo rompit avec la papauté.
Entre temps ses relations avec les Tartares s’étaient tendues de
telle sorte que, quoiqu’il eût perdu tout espoir d’être secouru par les
princes catholiques, il n’en dut pas moins se résoudre à engager la
lutte contre ses oppresseurs et attaquer les communautés qui
reconnaissaient leur suzeraineté. Il s’attira ainsi la colère des
Tartares, qui, ayant organisé contre lui une grosse expédition, le
surprirent et le forcèrent à capituler. On l’obligea à raser ses
principales forteresses ; seule la ville de Kholm, résidence préférée
de Danilo, qu’il avait ornée de beaux monuments et pourvue de
solides fortifications, put rester intacte au milieu des ruines qui
affligeaient le pays.
Le prince fut vivement frappé de ce malheur ; il ne sut pas se
résigner et ne put jamais se faire à l’idée de s’assujettir au
vainqueur. Aussi, tout à l’opposé des princes moscovites, qui
tournaient leur asservissement à profit, consolidant leur autorité sous
la couleur du joug tartare, soumettant les principautés voisines et
étendant leur puissance, nous voyons Danilo et Vassilko s’évertuant
à étendre et à raffermir leur pouvoir vers l’ouest, vers les pays
lithuaniens et polonais pour pouvoir plus efficacement s’opposer aux
Asiates. Leurs efforts échouèrent et ne firent qu’attiser le
ressentiment des envahisseurs.
Danilo mourut bientôt après son désastre (1264). Ses
successeurs : son frère Vassilko, son fils Léon et son petit-fils
Georges continuèrent sa politique. A partir de l’invasion tartare, l’état
de Galicie et de Volhynie dura encore plus d’un siècle, s’élevant par
intermittence à une puissance considérable. En lui se perpétuait la
vie intellectuelle et politique de l’Ukraine. Mais par suite de l’hostilité
des Tartares, qui ne permirent jamais à cet état de s’étendre vers
l’est, les anciens plans de Roman et de Danilo tendant à unifier et à
réunir sous le même sceptre tous les pays ukrainiens ne purent
jamais être réalisés, tout aussi bien dans la partie occidentale du
pays qu’à l’orient.
Quant aux contrées de Kiev et de Péreïaslav, nous ne possédons
presque pas de renseignements relatifs à cette époque : il est
probable que le régime princier y avait été renversé par le
mouvement des communautés, car, lorsque plus tard, au XIVe siècle,
nous y retrouvons des princes, ils apparaissent tout-à-fait faibles et
sans autorité. Dans le pays de Tchernihiv, la famille régnante
s’accrut de telle sorte qu’en fin de compte la plupart de ses membres
en furent réduits au rang de grands seigneurs fonciers. La partie
méridionale, comprenant les villes de Tchernihiv, de Poutivl et de
Koursk, dépérit tout-à-fait. Dans le nord seulement se conserva une
lueur de vie politique.
Par suite de la disparition de l’importance sociale et de l’influence
des boïards dans le bassin du Dniéper, il se produisit un événement
d’importance capitale pour l’évolution historique postérieure : le
transfert du métropolite de Kiev dans les pays du nord. Le clergé,
nous le savons déjà, était habitué à vivre sous la protection du
prince et de l’aristocratie. Or les pays du bassin du Dniéper avaient
perdu leurs princes et leur aristocratie, sans qu’ils eussent été
complètement dépeuplés, comme on l’a quelquefois écrit. Au nord,
au contraire, dans le bassin de la Volga, les princes et les boïards
consolident leur autorité sur les classes inférieures sous le couvert
du joug tartare. Là le clergé se sentira plus rassuré. Les métropolites
de Kiev commencent à se rendre de plus en plus fréquemment dans
les cours du nord, ils y séjournent de plus en plus longtemps, enfin,
après une incursion des mongols en 1299, le métropolite s’y
transporta une dernière fois pour ne plus en revenir. Les princes de
Galicie réussirent à obtenir du patriarche de Constantinople un
métropolite particulier. On se prit à donner au ressort du nouveau
dignitaire le nom d’église métropolitaine de la « Petite Russie », pour
la distinguer de celle de Kiev, transférée à Vladimir du nord (sur la
Klazma), à laquelle on avait donné le nom d’église métropolitaine de
la « Grande Russie ». Les princes de Galicie, qui portaient le titre de
« rois de Russie » (comme par exemple Georges, petit-fils de
Danilo), furent appelés couramment, à l’instar de leur métropolite,
princes de la « Petite Russie ». C’est ainsi que prit naissance cette
appellation, qui a paru symboliser au cours des siècles l’hégémonie
de la Russie du nord sur la Russie du sud, sur l’Ukraine.
Le fait que l’Ukraine orientale, au lieu de rester dans le ressort
ecclésiastique soit de Halitche, soit de Vladimir de Volhynie, devint
suffragante du métropolite du nord, scella le caractère local et point
du tout pan-ukrainien du royaume de Galicie et de Volhynie. Ainsi fut
retardé une fois de plus le processus de cristallisation des trois
grandes nations, que devaient former les Slaves orientaux.
X.
Les princes de Lithuanie et ceux de
Pologne se rendent maîtres des
principautés ukrainiennes.
Réduits, sous la pression des hordes tartares, à abandonner

leurs projets sur l’Ukraine orientale, les successeurs de Danilo
cherchèrent, comme je l’ai dit, des compensations à l’ouest et au
nord de leur pays. Malheureusement nos renseignements à cet
égard deviennent de plus en plus rares dès l’année 1289, époque à
laquelle s’arrête la chronique de Volhynie, qui renseignait jusqu’ici
sur les événements du royaume de Galicie et de Volhynie au XIIIe
siècle. Quelques informations accidentelles nous apprennent que
Léon, fils de Danilo, étant intervenu dans une lutte dynastique, qui
séparait les princes polonais, aurait cherché, au commencement du
XIVe siècle, à incorporer à la Galicie la principauté de Cracovie. Nous
savons encore que, lors de l’extinction de la dynastie Arpadienne,
les pays ukrainiens situés au delà des Carpathes furent annexés à la
Galicie et que les domaines de cette dernière principauté s’étaient
entre temps élargis vers le nord dans les contrées lithuaniennes.
Il paraît probable, en effet, qu’avant que la dynastie lithuanienne,
dont les plus célèbres représentants furent Ghedimine et Olguerd,
eût entrepris sa vaste politique d’extension dans les contrées des
Slaves orientaux, les princes de Galicie et de Volhynie avaient réussi
à étendre leur influence sur les pays lithuaniens. Mais l’apparition,
au commencement du XIIIe siècle, des chevaliers teutoniques sur les
frontières de la Lithuanie, en Livonie et en Prusse, aussi bien que les
dures méthodes qu’ils employaient tant pour soumettre les
populations voisines, que pour ravager par des incursions
dévastatrices les contrées plus éloignées, provoquèrent dans le
pays un mouvement, qui tendit à leur résister. Jusque-là protégée
par ses forêts impénétrables, la Lithuanie était restée
considérablement arriérée au point de vue intellectuel et politique. Il
n’y avait ni lois établies, ni organisation politique ; l’écriture même y
était inconnue. Ses princes essayaient d’introduire chez eux des
institutions modelées sur celles des populations slaves voisines : les
Blancs-Russes et les Ukrainiens. Les rapports entre les dynasties
qui régnaient sur les trois peuples étaient des plus étroits. Loin de
cesser dans le courant du XIIIe siècle, il arriva qu’à la suite de
combinaisons dynastiques, tantôt les princes slaves furent appelés à
régner sur les principautés lithuaniennes, tantôt les « Kounigas »
lithuaniens, qui étaient des guerriers intrépides, furent chargés par
les populations slaves d’organiser leur défense, ou en devinrent les
maîtres de quelque autre façon.
Un moment même, il fut question de réunir sous le gouvernement
d’un des fils de Danilo les principautés de Galicie et de Lithuanie.
Cette dernière principauté, fondée par Mindaug, avait d’abord paru si
menaçante à Danilo, qu’il s’était entendu avec les Polonais et les
Allemands pour la détruire de concert. Mais le prince lithuanien le
détourna de cette alliance en lui cédant pour son fils Roman
quelques-uns de ses domaines. Plus tard, le successeur de Mindaug
renonça définitivement à sa principauté au profit d’un autre fils de
Danilo, du nom de Chvarno. Cette combinaison d’ailleurs ne dura
pas longtemps. Au contraire, la nouvelle dynastie lithuanienne de
Poutouver-Ghedemine, qui s’établit vers la fin du XIIIe siècle, montra
une grande force d’expansion et soumit successivement à sa
domination les pays blanc-russiens et ukrainiens.
Comment s’accomplit cette mainmise ? Probablement sans
grands conflits : nous n’en connaissons que très peu les détails. Les
princes lithuaniens, après qu’ils se furent saisis du pouvoir,
s’appliquèrent à s’adapter le plus rapidement possible aux coutumes
de la vie locale, à ses lois, à sa civilisation ; ils en adoptèrent la
langue et l’écriture, se convertirent à la religion orthodoxe et
devinrent, en un mot, des princes blanc-russiens ou ukrainiens de
race lithuanienne, s’efforçant sincèrement de continuer les vieilles
traditions des pays occupés. Ils le faisaient d’autant plus
naturellement qu’ils ne possédaient pas eux-mêmes de lois propres,
comme nous l’avons dit plus haut.
Quant aux populations indigènes, elles voyaient sans regret
monter sur le trône un prince étranger, parce que cela mettait fin aux
querelles dynastiques, qui déchiraient le pays. Il en était de même
des communautés soumises à la suzeraineté directe des Tartares,
parce qu’elles en avaient senti le poids, surtout pendant la période
d’anarchie, qui se manifesta dans la horde à la fin du XIIIe siècle. La
Lithuanie, au contraire, était arrivée au commencement du XIVe
siècle à l’apogée de sa force, de sorte que les populations, en
acceptant un prince lithuanien comme chef, étaient sûres de trouver
dans les moments critiques le secours d’un bras puissant. Ceci
explique suffisamment la facilité avec laquelle ces princes établirent
leur autorité à cette époque sur les pays des Blancs Ruthènes et des
Ukrainiens.
Déjà, dans le premier quart du siècle, nous trouvons soumises à
leur domination la contrée de Brest-Dorohotchine, la principauté de
Tourov-Pinsk et une partie de la zone boisée des pays de Kiev. Kiev
lui-même est en 1320 sous l’influence de Ghedimine, quoique le
prince local, Théodore, dont l’autorité, comme tout porte à le croire,
est très affaiblie, reconnaisse encore la suzeraineté des Tartares. Il
n’est pas surprenant, qu’en de pareilles circonstances, les boïards
galiciens, après avoir fait disparaître leur prince à la suite d’un
complot, placèrent sur le trône, en 1340, le fils de Ghedimine,
Lubarte, qui, marié à une princesse de leur dynastie, possédait déjà
une des principautés de Volhynie.
La dynastie de Roman s’était déjà éteinte. Le petit-fils de Danilo,
Georges — Dominus Georgius rex Russiae, dux Vladimeriae,
comme on le lit en exergue de son sceau royal — laissa deux fils,
qui moururent vers 1324, sans laisser de postérité masculine. Les
boïards portèrent au trône un fils de leur sœur, mariée au prince
polonais Troïden de Masovie, du nom de Boleslav. Ce dernier
adopta la religion orthodoxe, prit le nom de son grand-père,
Georges, et devint ainsi, en 1325, prince de Galicie et de Volhynie.
Mais ses rapports ne tardèrent pas à se gâter avec les grands, qui
ne lui avaient probablement donné la couronne que pour gouverner
sous le couvert de son nom ; ce à quoi Georges-Boleslav ne se
prêta point. Il s’entoura, au contraire, de nouveaux conseillers venus
du dehors, surtout d’allemands. Cette attitude donna des gages à la
cabale : on l’accusa de n’être point favorable à la religion orthodoxe
et de vouloir introduire le catholicisme dans le pays.
Les rois de Pologne et de Hongrie, au courant du
mécontentement soulevé contre lui, conçurent le projet de profiter de
sa situation précaire pour s’emparer de ses états. Ils conclurent un
accord, dans le genre de celui de 1214, qui réglait d’abord leurs
successions respectives, puisqu’ils n’avaient ni l’un ni l’autre de
descendants mâles. Puis le roi de Hongrie, Charles, cédait à
Casimir, roi de Pologne, le droit d’occupation de la Galicie, tout en se
réservant un droit éventuel de rachat pour préserver les prétendus
anciens droits historiques de la couronne de Hongrie. Ce traité
venait d’entrer en vigueur quand éclata en Volhynie le coup d’état
mentionné plus haut : les boïards empoisonnèrent Georges-Boleslav
à Vladimir, après s’être entendus avec Lubarte, qu’ils placèrent sur
le trône. Le pouvoir en Galicie passa aux mains des grands, avec
Dmitro Dedko en qualité de provisor seu capitaneus terrae Russiae,
tandis que Lubarte prenait le titre de prince. A la nouvelle de cet
évènement, les troupes hongroises et polonaises entrèrent en
Galicie, afin de l’occuper. Mais Dedko appela à son aide les
Tartares. Les troupes alliées se retirèrent en toute hâte et Casimir
dut signer un traité, d’après lequel il s’engageait à ne plus toucher à

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Periparturient Diseases of Dairy Cows

A Systems Biology Approach 1st

Computer Controlled Systems with Delay A Transfer

Computational Psychiatry A Systems Biology Approach to

Atlas of Diffuse Lung Diseases A Multidisciplinary

Infectious Diseases: A Case Study Approach Jonathan Cho

Estimation and Inference in Discrete Event Systems A

Lysosomes Biology Diseases and Therapeutics 1st Edition

Evolutionary Biology A Transdisciplinary Approach

High Content Screening A Powerful Approach to Systems

ISBN 978-3-319-43031-7 ISBN 978-3-319-43033-1 (eBook)

Library of Congress Control Number: 2017959645

© Springer International Publishing Switzerland 2017

Printed on acid-free paper

This Springer imprint is published by Springer Nature

contribution that they are giving to the understanding of periparturient diseases of

Structure of the Book

Edmonton, AB, Canada Burim N. Ametaj

1 What Are Omics Sciences?������������������������������������������������������������������������ 1

10 Ketosis Under a Systems Veterinary Medicine Perspective ������������������ 201

About the Editor

Burim N. Ametaj, D.V.M., Ph.D., Ph.D. is a Professor of Animal Physiology and

Burim N. Ametaj, D.V.M., Ph.D., Ph.D. Department of Agricultural, Food and

Michael A. Steele, Ph.D. Department of Agricultural, Food and Nutritional

M. Vailati-Riboni, Ph.D. • V. Palombo, Ph.D. • J.J. Loor, Ph.D. (*)

© Springer International Publishing Switzerland 2017 1

The trademark characteristic of omics technologies is their holistic capability in the

analysis through cDNA sequencing on a massive scale (RNAseq) (Voelkerding

quantification of proteins possible through the AQUA (Absolute quantification of

The metabolome consists of the global profiling of metabolites in a biological

Omics technologies have contributed widely to the understanding of the delicate

B.N. Ametaj, D.V.M., Ph.D., Ph.D.

© Springer International Publishing Switzerland 2017 9

treatment of disease and development of prevention strategies. Some of the reasons

2.2  yth Number 1: A Metabolic Disease Is a Disturbance

According to Jack Payne (1977) “a metabolic disease is an abnormal change in the

inflammation, in order to make it difficult for pathogenic bacteria to freely access

several metabolites participate as components of the immune response and many

2.3 Myth Number 2: The Concept of Production Diseases

Cependant, depuis le XIe siècle, cette suprématie de Kiev

Frontières politiques aux XIIe–XIIIe siècles — les principautés de

Ce n’est pas seulement dans le nord que les populations

Le flot mongol poussé par Temoudjine atteignit l’Ukraine vers

Réduits, sous la pression des hordes tartares, à abandonner

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Structure of the Book

Edmonton, AB, Canada Burim N. Ametaj

1 What Are Omics Sciences?�� 1

10 Ketosis Under a Systems Veterinary Medicine Perspective �� 201

2.2 yth Number 1: A Metabolic Disease Is a Disturbance

2.3 Myth Number 2: The Concept of Production Diseases