mni Nigam is professor in biomedical science; John Knght s associate With the exception of inges tion, the small and large intestines carry out all the major functions of the digestive system. This is where the ‘real business’ of digestion takes place. The intestines take up most of the space in the abdominal cavity and constitute the greatest portion of the gastrointestinal (GI) tract in terms of mass and length. Part 4 in this sixpart series on the GI tract described the anatomy and function of the small intestine (Bit.ly/NTGITract4). Part 5 describes the anatomy and functions of the large intestine, as well as common pathologies that affect both the small and large intestine. Anatomy of the large intestine The large intestine is approximately 1.5m long and comprises the caecum, colon, rectum, anal canal and anus (Fig 1). The structure of the large intestine is very sim ilar to that of the small intestine (see part4), except that its mucosa is com Caecum and appendix Chyme that has not been absorbed by the time it leaves the small intestine passes through the ileocaecal valve and enters the large intestine at the caecum. On receipt of the contents of the ileum, the caecum con tinues the absorption of water and salts. The caecum is about 6cm long and extends downwards into the appendix, a winding tubular sac containing lymphoid tissue. The appendix is thought to be the vestige of a redundant organ; its narrow and twisted shape makes it an attractive site for the accumulation and multiplica tion of intestinal bacteria. Colon At its other end, the caecum seamlessly joins up with the colon, this is the longest portion of the large intestine (Fig 1). Food residue starts by travelling upwards through the ascending colon, located on the right side of the abdomen. The ascending colon bends near the liver at the right colic flexure (or hepatic flexure) and becomes the transverse colon, passing professor in biomedical science; Nkki Wiiams is associate professor in respratory physiology; all at the Colege of Human Heath and Sciences, Swansea Unversity. Abstract In the large intestine the fina section of the gastrointestna tract absorption of water and eectrolytes takes pace and coonic bacteria complete the process of chemica digestion. The large intestine is aso where faeces are formed from the remains of food and fluid combined with byproducts of the body. Intestinal content s pushed back and forth by haustra contractions and antiperistatic contractions, unti faeces are finally pushed towards the anal cana by mass movements. Ths article, the fifth n a sixpart series exporing the gastrointestinal tract, describes the anatomy and functions of the large intestine. Citation Nigam Y et a (2019) Gastrontestina tract 5: the anatomy and functons of the arge intestne Nursing Times [onine]; 115: 10, 5053 pletely devoid of villi.

1. Cytoplasm
• The cytoplasm comprises cytosol – the gel-like substance enclosed within the
cell membrane – and the organelles – the cell's internal sub-structures and the
cytoskeleton
• Cytosol
• The cytosol is the portion of the cytoplasm not contained within membrane-
bound organelles
• Cytosol makes up about 70% of the cell volume and is composed of water, salts
and organic molecules
• The cytosol also contains the protein filaments that make up the cytoskeleton,
as well as soluble proteins and small structures such as ribosomes,
proteasomes

2. Cytoskeleton
• The cytoskeleton is composed of three well-defined filamentous structures—
microtubules, microfilaments, and intermediate filaments
• Together these form an elaborate interactive network
• Each of the three types of cytoskeletal filaments is a polymer of protein subunits
held together by weak, non-covalent bonds
• Each cytoskeletal element has distinct properties
• Microtubules are long, hollow, unbranched tubes composed of subunits of the
protein tubulin
• Microfilaments are solid, thinner structures, often organized into a branching
network and composed of the protein actin
• Intermediate filaments are tough, rope-like fibers composed of a variety of
related proteins

4. Functions of the cytoskeleton
1. Provide structural support that can determine the shape of the cell and resist
forces that tend to deform it
2. Responsible for positioning the various organelles within the interior of the
cell. This function is particularly evident in polarized epithelial cells, in which
certain organelles are arranged in a defined order from the apical to the basal end
of the cell
3. Direct the movement of materials and organelles within cells
• E.g. the delivery of mRNA molecules to specific parts of a cell, the movement
of membranous carriers from the endoplasmic reticulum to the Golgi complex,
and the transport of vesicles containing neurotransmitters down the length of
a nerve cell
• Microtubules are the tracks over which the peroxisomes are transported in
mammalian cells
4. The force-generating apparatus that moves cells from one place to another
Single-celled organisms move either by “crawling” over the surface of a solid
substratum or by propelling themselves through their aqueous environment with
the aid of specialized, microtubule-containing locomotor organelles (cilia and
flagella) that protrude from the cell’s surface

5. Functions of Cytoskeleton
• Multicellular animals have a variety of cells that are capable of independent
locomotion, including sperm, white blood cells, and fibroblasts (Figure 9.3).
• The tip of a growing axon is also highly motile and its movement resembles a
crawling cell
5. An essential component of the cell’s division machinery
• Cytoskeletal elements make up the apparatus responsible for separating the
chromosomes during mitosis and meiosis and for splitting the parent cell into
two daughter cells during cytokinesis

7. MICROTUBULES
• Structure and Composition
• Microtubules are hollow, relatively rigid, tubular structures, and they occur in
nearly every eukaryotic cell
• Microtubules are components of many structures, including the mitotic spindle
of dividing cells and the core of cilia and flagella
• Microtubules have an outer diameter of 25 nm and a wall thickness of
approximately 4 nm,
• They may extend across the length or breadth of a cell
• The wall of a microtubule is composed of globular proteins arranged in
longitudinal rows, known proto-filaments, that are aligned parallel to the long
axis of the tubule
• Cross-section view reveal that microtubules consist of 13 proto-filaments
aligned side by side in a circular pattern within the wall
• Non-covalent interactions between adjacent proto-filaments play an important
role in maintaining microtubule structure
• Each proto-filament is assembled from dimeric building blocks consisting of one
a-tubulin and one b-tubulin subunit

8. Microtubules: Structure and composition
• The two types of globular tubulin subunits have a similar three-dimensional
structure and fit tightly together
• The tubulin dimers are organized in a linear array along the length of each
proto-filament
• Because each assembly unit contains two non-identical components (a
heterodimer), the protofilament is asymmetric, with an a-tubulin at one end
and a b-tubulin at the other end.
• All of the protofilaments of a microtubule have the same polarity
• Consequently, the entire polymer has polarity
• One end of a microtubule is known as the plus end and is terminated by a row
of b-tubulin subunits
• The opposite end is the minus end and is terminated by a row of a- tubulin
subunits
• The structural polarity of microtubules is an important factor in the growth of
these structures and their ability to participate in directed mechanical activities

9. Microtubule proteins
• Microtubules from living tissue typically contain additional proteins, called
microtubule-associated proteins (or MAPs)
• MAPs comprise a heterogeneous collection of proteins
• The first MAPs to be identified are referred to as “classical MAPs” and typically
have one domain that attaches to the side of a microtubule and another
domain that projects outward as a filament from the microtubule’s surface
• Some MAPs can be seen in electron micrographs as cross-bridges connecting
microtubules to each other, thus maintaining their parallel alignment
• MAPs generally increase the stability of microtubules and promote their
assembly
• The microtubule-binding activity of the various MAPs is controlled primarily by
the addition and removal of phosphate groups from particular amino acid
residues
• An abnormally high level of phosphorylation of one particular MAP, called tau,
has been implicated in the development of several fatal neurodegenerative
disorders, including Alzheimer’s disease

10. Microtubule proteins
• The brain cells of people with these diseases contain strange, tangled filaments
(called neurofibrillary tangles) consisting of tau molecules that are excessively
phosphorylated and unable to bind to microtubules
• The neurofibrillary filaments are thought to contribute to the death of nerve
cells
• Persons with one of these diseases, an inherited dementia called FTDP-17, carry
mutations in the tau gene, indicating that alteration of the tau protein is the
primary cause of this disorder

11. Functions of microtubules: Support
• Microtubules are stiff enough to resist forces that might compress or bend the
fiber
• This property enables them to provide mechanical support
• The distribution of cytoplasmic microtubules in a cell helps determine the
shape of that cell
• In cultured animal cells, the microtubules extend in a radial array outward from
the area around the nucleus, giving these cells their round, flattened shape
• In contrast, the microtubules of columnar epithelial cells are typically oriented
with their long axis parallel to the long axis of the cell (Figure 9.1a)
• This configuration suggests that microtubules help support the cell’s elongated
shape
• The role of microtubules as skeletal elements is particularly evident in certain
highly elongated cellular processes, such as cilia and flagella and the axons of
nerve cells
• Microtubules also play a key role in maintaining the internal organization of
cells

12. Functions of microtubules: Organization
• Treatment of cells with microtubule-disrupting drugs can seriously affect the
location of membranous organelles, including the ER and Golgi complex
• The Golgi complex is typically located near the center of an animal cell, just
outside the nucleus
• Treatment of cells with nocodazole or colchicine, which promote microtubule
• disassembly, can disperse the Golgi elements into the peripheral regions of the
cell
• When the drug is removed and microtubules reassemble, the Golgi membranes
return to their normal position in the cell interior
• Functions of microtubules: Intracellular motility
• The transport of materials from one membrane compartment to another
depends on the presence of microtubules because specific disruption of these
cytoskeletal elements brings the movements to a halt
• For e.g.intracellular motility by focusing on nerve cells whose intracellular
movements rely on a highly organized arrangement of microtubules and other
cytoskeletal filaments.

13. Functions of microtubules: Intracellular motility
• Axonal Transport The axon of an individual motor neuron may stretch from the spinal
cord to the tip of a finger or toe
• The manufacturing center of this neuron is its cell body, a rounded portion of the cell
that resides within the spinal cord
• When labeled amino acids are injected into the cell body, they are incorporated into
labeled proteins that move into the axon and gradually travel down its length
• Many different materials, including neurotransmitter molecules, are
compartmentalized within membranous vesicles in the ER and Golgi complex of the
cell body and then transported down the length of the axon
• Non-membrane-bound cargo, such as RNAs, ribosomes, and even cytoskeletal
elements are also transported along this vast stretch of extended cytoplasm
• Different materials move at different rates, with the fastest axonal transport occurring
at velocities of 5 m per second
• At this rate, a synaptic vesicle pulled by nanosized motor proteins can travel 0.4 meter
in a single day, or about halfway from your spinal cord to the tip of your finger
• Structures and materials traveling from the cell body toward the terminals of a neuron
are said to move in an anterograde direction
• Other structures, including endocytic vesicles that form at the axon terminals and
carry regulatory factors from target cells, move in the opposite, or retrograde,
direction—from the synapse toward the cell body
• Defects in both anterograde and retrograde transport have been linked to several
neurological diseases

14. INTERMEDIATE FILAMENTS
• The second of the three major cytoskeletal elements to be discussed was seen
in the electron microscope as solid, unbranched filaments with a diameter of
10–12 nm.
• They were named intermediate filaments (or IFs). To date, intermediate
filaments have only been identified in animal cells.
• Intermediate filaments are strong, flexible ropelike fibers that provide
mechanical strength to cells that are subjected to physical stress, including
neurons, muscle cells, and the epithelial cells that line the body’s cavities.
• Unlike microfilaments and microtubules, IFs are a chemically heterogeneous
group of structures that, in humans, are encoded by approximately 70 different
genes.
• The polypeptide subunits of Ifs can be divided into five major classes based on
the type of cell in which they are found (Table 9.2) as well as biochemical,
genetic, and immunologic criteria.
• We will restrict the present discussion to classes I-IV, which are found in the
construction of cytoplasmic filaments

15. Intermediate filaments
• IFs radiate through the cytoplasm of a wide variety of animal cells and are
often interconnected to other cytoskeletal filaments by thin, wispy cross-
bridges (Figure 9.40).
• In many cells, these cross-bridges consist of an elongated dimeric protein
called plectin that can exist in numerous isoforms.
• Each plectin molecule has a binding site for an intermediate filament at one
end and, depending on the isoform, a binding site for another intermediate
filament, microfilament, or microtubule at the other end.
• Although IF polypeptides have diverse amino acid sequences, all share a
similar structural organization that allows them to form similar-looking
filaments. Most notably, the polypeptides of IFs all contain a central, rod-
shaped, -helical domain of similar length and homologous amino acid
sequence.
• This long fibrous domain makes the subunits of intermediate filaments very
different from the globular tubulin and actin subunits of microtubules and
microfilaments.
• The central fibrous domain is flanked on each side by globular

17. Properties and Distribution of the Major Mammalian
Intermediate Filament Proteins

18. Types and Functions of Intermediate Filaments
• Keratin filaments constitute the primary structural proteins of epithelial cells
(including epidermal cells, liver hepatocytes, and pancreatic acinar cells)
• Figure 9.43a shows a schematic view of the spatial arrangement of the keratin
filaments of a generalized epithelial cell, and Figure 9.43b shows the actual
• arrangement within a pair of cultured epidermal cells.
• Keratin-containing IFs radiate through the cytoplasm, tethered to the nuclear
envelope in the center of the cell and anchored at the outer edge of the cell by
connections to the cytoplasmic plaques of desmosomes and hemidesmosomes
(pages 251 and 244).
• Figure 9.43a also depicts the interconnections between IFs and the cell’s
microtubules and microfilaments, which transforms these otherwise separate
elements into an integrated cytoskeleton.
• Because of these various physical connections, the IF network is able to serve
as a scaffold for organizing and maintaining cellular architecture and for
absorbing mechanical stresses applied by the extracellular environment.

19. IFs
• The cytoplasm of neurons contains loosely packed bundles of intermediate
filaments whose long axes are oriented parallel to that of the nerve cell axon
(see Figure 9.13b).
• These IFs, or neurofilaments, as they are called, are composed of three distinct
proteins: NF-L, NF-H, and NF-M, all of the type IV group of Table 9.2. Unlike the
polypeptides of other
• IFs, NF-H and NF-M have sidearms that project outward from the
neurofilament. These sidearms are thought to maintain the proper spacing
between the parallel neurofilaments of the axon (see Figure 9.13b).
• In the early stages of differentiation when the axon is growing toward a target
cell, it contains very few neurofilaments but large numbers of supporting
microtubules. Once the nerve cell has become fully extended, it becomes filled
with neurofilaments that provide support as the axon increases dramatically in
diameter.
• Aggregation of NFs is seen in several human neurodegenerative disorders,
including ALS and Parkinson’s disease. These NF aggregates may block axonal
transport, leading to the death of affected neurons.

20. Ifs functions
• Efforts to probe IF function have relied largely on genetically engineered mice
that fail to produce a particular IF polypeptide (a gene knockout) or produce an
altered IF polypeptide.
• These studies have revealed the importance of intermediate filaments in
particular cell types. For example, mice carrying deletions in the gene encoding
K14, a type I keratin polypeptide normally synthesized by cells of the basal
epidermal layer, have serious health problems.
• These mice are so sensitive to mechanical pressure that even mild trauma, such
as that occurring during passage through the birth canal or during nursing by the
newborn, can cause severe blistering of the skin or tongue. This phenotype
bears strong resemblance to a rare skin-blistering disease in humans, called
epidermolysis bullosa simplex (EBS).3 Subsequent analysis of
• EBS patients has shown that they carry mutations in the gene that encodes the
homologous K14 polypeptide (or the K5 polypeptide, which forms dimers with
K14).
• These studies confirm the role of IFs in imparting mechanical strength to cells
situated in epithelial layers.

21. Ifs functions
• Similarly, knockout mice that fail to produce the desmin polypeptide exhibit
serious cardiac and skeletal muscle abnormalities.
• Desmin plays a key structural role in maintaining the alignment of the myofibrils
of a muscle cell, and the absence of these IFs makes the cells extremely fragile.
• An inherited human disease, named desminrelated myopathy, is caused by
mutations in the gene that encodes desmin.
• Persons with this disorder suffer from skeletal muscle weakness, cardiac
arrhythmias, and eventual congestive heart failure.
• Not all IF polypeptides have such essential functions. For example, mice that
lack the vimentin gene, which is expressed in fibroblasts, macrophages, and
white blood cells, show relatively minor abnormalities, even though the
affected cells lack cytoplasmic IFs.
• It is evident from these studies that IFs have tissue-specific functions, which are
more important in some cells than in others.