This document provides an overview of the histology of the gastrointestinal tract. It begins by describing the general structure of the GI tract wall and its four main layers - mucosa, submucosa, muscularis, and adventitia/serosa. It then describes key features of the esophagus, stomach, and small and large intestines. For each region, it details the epithelial cell types present, gland types, and distinguishing histological characteristics. The document aims to describe the microscopic anatomy and cellular composition of the entire GI tract.

1. Cell Structure & Function Digestive System 2: Upper & Lower G.I. Tract page 1
HISTOLOGY OF THE G.I. TRACT
Scheduled Lecturer: Resa Chase, M.D.
Primary reference – Ross & Pawlina: Histology 6th
ed., chapter 17
Lecture Objectives:
1. Describe the general plan of the alimentary tube (GPAT).
2. Describe the enteric nervous system. State the location and function of interstitial cells of Cajal
and characteristic immunohistochemical features. Recognize submucosal & myenteric ganglia in
photographs and diagrams. [You won’t be asked to recognize interstitial cells of Cajal without a specific
immunohistochemical stain.]
3. Name the component tissues of the esophagus. Describe the glands present in the esophagus.
Discuss how the upper and lower portions of esophagus differ.
4. List the histologic regions of the stomach. Describe the overall organization of gastric mucosa,
listing the similarities & difference of each region, including types of glands and cells in each region
and their functions. Include definitions and descriptions of rugae and gastric pits (foveolae).
Identify the regions and their component glands and cells in photographs and diagrams.
5. Describe the structure, function and location of the following cells in the stomach:
surface/foveolar epithelium, mucous neck cells [know they exist; you won’t be asked to recognize mucous neck
cells], stem cells [know they exist; you won’t be asked to recognize stem cells], chief cells, parietal cells
(worthy of extra effort in learning both morphology & mechanisms of function), enteroendocrine
cells / cells of the diffuse neuroendocrine system (especially G cells & enterochromaffin-like
cells[ECLs]).
6. Distinguish between “open” and “closed” enteroendocrine cells. Identify each (as appropriate) in
photographs and diagrams.
7. Describe the architecture of the small intestine, including definitions and descriptions of plicae
circulares, villi, intestinal glands, lymph nodules and Peyer’s patches. Describe characteristic
features of duodenum and ileum.
8. Describe the large intestine and state how it differs from small intestine. List the functions of the
colon. Describe the appendix. Identify the large intestine and appendix in photographs and
diagrams, distinguishing them from each other and from the small intestine.
9. Describe the structure (light microscopic & ultrastructural) and general function of the following
cells of the large & small intestines: enterocytes, goblet cells, Paneth cells, stem cells [know they exist;
you won’t be asked to recognize stem cells], M cells and enteroendocrine cells / cells of the diffuse
neuroendocrine system. State their location in the intestinal mucosa and any characteristic
distribution in regions of the intestines. Identify each in photographs and diagrams.
10. Contrast the architecture and morphologic features of the gastroesophageal (cardiac) junction,
pyloric junction, the ileocecal junction, and anal junction. List differentiating features. Identify each
in photographs and diagrams.
Secondary References:
Cross: Cell and Tissue Ultrastructure, p. 284-301

2. Cell Structure & Function Digestive System 2: Upper & Lower G.I. Tract page 2
HISTOLOGY OF THE G.I. TRACT
I. General plan of the alimentary tube (GPAT)
A. Lumen
B. Wall structure – four principal layers
1. Mucosa
- epithelium
- basement membrane
- tunica (lamina) propria
- - glands
- - areolar connective tissue
- lymphatic tissue (diffuse & nodular), plasma cells, eosinophils, macrophages
- muscularis mucosae
- - inner circular, outer longitudinal smooth muscle
2. Submucosa
- areolar connective tissue (often fatty)
- nerve plexus & ganglion cells (submucosal/Meissner’s), Cajal cells
- blood plexus
- lymphatics
- glands may be present: esophagus and duodenum
3. Muscularis
- inner circular
- nerve plexus & ganglion cells (myenteric/Auerbach’s), Cajal cells
- outer longitudinal
4. Adventitia - loose connective tissue
or
Serosa - thin layer of loose connective tissue and a mesothelium

3. Cell Structure & Function Digestive System 2: Upper & Lower G.I. Tract page 3
5. Enteric nervous system
- An ‘independent’ nervous system arranged in ganglia (myenteric/Auerbach and
submucosal/Meissner) with extensive interconnections. These ganglia
contribute to control of GI tract motility, absorption, secretion and blood flow.
Interstitial cells of Cajal are non-neural pacemaker cells (probably modified
myofibroblasts) that receive, transmit and integrate neurogenic signals (of both
autonomic and enteric nervous systems) and muscular activity. They express a
tyrosine kinase receptor designated CD117 (c-kit). [Defects in the interstitial cells of
Cajal are thought to contribute to both congenital and acquired motility disorders. Some
sarcomas of the GI tract also express CD117 & there is a drug directed against CD117 which
results in long-term remission of these previously fatal cancers.]
II. Esophagus
A. Mucosa
- epithelium - - This is non-keratinized stratified squamous
- lamina propria - - Lymphoid tissue may be here
- muscularis mucosae - - Present, GPAT
B. Submucosa – Scattered mucous esophageal glands; submucosal veins drain to both
portal and systemic venous systems (and thus may dilate in portal hypertension due
to shunting from portal to systemic circulations)
C. Muscularis - In the upper 1/3 (or less) this is skeletal muscle (from the cricopharyneal &
inferior pharyngeal constrictor muscles); in the middle 1/3 mixed skeletal and smooth
muscle and in the lower 1/3 (or more) smooth muscle only
D. Adventitia (in thorax) & serosa (in abdomen)
III. Stomach
A. Regions
- Cardia is at the junction of the esophagus and stomach. It is a very narrow region &
may be absent in some people.
- Fundus and body do not differ histologically and are referred to as the oxyntic (“acid
producing”) or fundic stomach.
- Pyloric antrum of the stomach & the pylorus are next to the duodenum.
B. Mucosa - Rugae are non-permanent longitudinal folds of the mucosa and submucosa.
Gastric pits (foveolae) are crevices leading down from the surface and serve as
ducts for the gastric and pyloric glands which are also part of the mucosa. The
transition from gastric pit (foveolae) to gland is the isthmus/neck region. The pits
are straight ducts that connect the branched, coiled glands of the stomach with the
gastric lumen.

4. Cell Structure & Function Digestive System 2: Upper & Lower G.I. Tract page 4
1. Surface & Foveolar Epithelium - The entire luminal surface is covered with a
simple columnar cell type (foveolar cell) which produces alkaline mucus that
protects the epithelium against stomach acid. The same cell type lines the
gastric pits.
2. Lamina (tunica) propria - This is filled with glands that extend from the gastric pits
to the muscularis mucosae. The 3 regions of the stomach have different types
of glands: cardiac (considered with cardiac junction) glands produce mucus,
fundic/oxyntic glands produce enzymes & HCl, and pyloric glands produce
mucus. Glands are surrounded by a small amount of loose connective tissue.
3. Neck/Isthmus region (Note: The textbook lists isthmus and neck regions separately but other
references combine them as one region.)
- Mucous neck cells are different from the surface mucous (foveolar) cells
- Stem cells. The stem cells in the isthmus/neck then differentiate into the other
cells types, moving up to become foveolar mucous cells or moving down to
become parietal, chief, enteroendocrine or pyloric mucous cells.
4. Fundic (gastric, oxyntic) glands - The thickness of the glands is greater than the thickness
of the pits/foveolae in a longitudinal section, in contrast to the gastric antrum where pits are
almost as deep as the glands.
- Cell types present in oxyntic/fundic glands are:
a. Parietal cells - These are scattered between chief cells, and are more common
in the upper portions of fundic glands. Their cytoplasm is eosinophilic
and the cells tend to be round with central nuclei. Parietal cells have the
most mitochondria of any cell in the GI system, necessary for pumping
hydrogen ions. These proton pumps are incorporated in the membrane of
a unique intracellular canalicular system which is lined with microvilli.
After a meal more microvilli are added to the canalicular/apical plasma
membrane. The extra plasma membrane is stored in the tubulovesicular
system in the cytoplasm between meals when there are fewer microvilli.
Parietal cells produce hydrochloric acid in response to cholinergic input,
histamine and gastrin. They also produce intrinsic factor, which is
necessary for the absorption of vitamin B12 by the intestine.
b. Chief cells - Also called zymogenic cells because of their zymogen granules,
chief cells are typical protein producing cells for export. They have rough
endoplasmic reticulum in a basal location and apical zymogen granules.
They produce pepsinogen and gastric lipase.
d. Enteroendocrine cells - These are scattered individual endocrine cells of
multiple types secreting a variety of hormones, varying with location in
the stomach (and entire GI tract). Their secretion granules are oriented
toward the basement membrane. These cells are part of the larger concept
of the ‘diffuse neuroendocrine system’ composed of individual endocrine
cells found in multiple different organs throughout the body.
- The GI tract has 2 morphologic types of enteroendocrine cells: Open &

5. Cell Structure & Function Digestive System 2: Upper & Lower G.I. Tract page 5
Closed. Closed enteroendocrine cells sit on the basement membrane and
are covered over by adjacent epithelial cells. Open enteroendocrine cells
extend from the basement membrane to the lumen, where they can sample
luminal contents & release hormones based on that sampling.
- The major endocrine cell of the gastric body/fundus is the ECL
(‘enterochromaffin-like’) cell, which produces histamine & stimulates
HCl production by parietal cells. ECLs are stimulated by gastrin, made by
G cells of the gastric antrum.
5. Pyloric glands - (The relative thicknesses of pits and glands are about equal.) The glands
produce mucus and lysozyme. Some parietal cells may still be seen in this
region. Enteroendocrine cells here include G (gastrin) cells, which directly
stimulate parietal cell HCl production as well as indirectly by stimulating
histamine release by ECLs.
6. The muscularis mucosa of the stomach lies directly beneath the glands and
distinguishes the mucosa from the submucosa.
C. Submucosa - The submucosa is present as in the GPAT and forms the core of the rugae.
The stomach does not have submucosal glands.
D. Muscularis – The stomach has 3 layers rather than the usual 2 layers of classic GPAT.
It has an added inner oblique layer. At the pylorus, the middle circular layer
thickens to form the pyloric sphincter. A serosa is present.
E. Junctions
a. Cardiac - This is where esophagus meets the fundic stomach. Non-keratinized
stratified squamous abruptly changes to simple columnar (foveolar)
epithelium with associated mucus-secreting cardiac glands or oxyntic type
gastric glands.
b. Body-antrum – the transition is gradual, with parietal cells still seen
occasionally in otherwise classic antral type mucous glands.
c. Pyloric - The pyloric stomach meets the duodenum. While the stomach side of
the junction has pyloric glands above the muscularis mucosae, Brunner’s
glands of the duodenum are in the submucosa and break up the muscularis
mucosae as they deliver contents to the duodenal lumen. In contrast to the
stomach, the duodenum has villi and goblet cells.
IV. Small intestine - It is about 5 meters (16.4 feet) in length and consists of the duodenum,
jejunum and ileum. The mucosa and submucosa form permanent folds termed plicae
circulares (or valves of Kerckring). Villi are upward projections of mucosa (which vary
somewhat in shape in the different segments of small intestine). In cross to oblique section, villi
show epithelium surrounding lamina propria. The intestinal glands (also called crypts
of Lieberkuhn) when sectioned in the same way, show epithelium surrounded by
lamina propria. The crypts are found between the villi and the epithelium is continuous

6. Cell Structure & Function Digestive System 2: Upper & Lower G.I. Tract page 6
from the villi into the gland.
A. Mucosa:
1. The epithelium is simple columnar and consists of several cell types.
a. Absorptive enterocytes- These cells proliferate at the bottoms of the intestinal
glands, then migrate up onto the villi and are lost at the villus tips. This
takes about 5 days. The cells are columnar with numerous microvilli (the
striated border of light microscopy) and a thick glycocalyx, the enteric coat.
Actin is present in the microvilli and interacts with myosin in the terminal
web to cause motility. Junctional complexes surround the apical (luminal)
ends of the enterocytes and help regulate paracellular barriers & transport.
Functions of absorptive enterocytes include:
- Digestion of oligo and disaccharides at the microvilli: Disaccharidases,
enzymes present as integral membrane proteins, complete the digestion.
The resulting monosaccharides are actively transported into the apical
region of the cell.
- Sodium transport: A sodium-potassium ATPase pumps sodium at the lateral
and basal plasma membrane. This results in a movement of salt and water
from the intestinal lumen to the nearby fenestrated capillaries. Glucose is
co-transported with sodium at the microvilli.
- Protein digestion: Proteins are broken down to amino acids by peptidases in
the enteric coat. These amino acids are actively transported into and
through the enterocytes to the basal and lateral plasma membrane where
they enter the extracellular space and then the capillaries.
- Fat digestion: Triglycerides are broken down to glycerol, free fatty acids and
monoglycerides in the lumen in emulsified micelles. These products then
diffuse across the microvilli. In the apical smooth endoplasmic reticulum,
triglycerides are reformed. Some protein is added and the resulting protein-
lipid packages, chylomicrons, are exocytosed at the basal and lateral plasma
membrane. Blind-ended lymphatic vessels, lacteals, pick up the
chylomicrons.
Villi & crypts Villi & crypts in
cross-section
A villus in
cross section
A gland in
cross section

7. Cell Structure & Function Digestive System 2: Upper & Lower G.I. Tract page 7
b. M cells are specialized enterocytes found immediately over intramucosal
lymphoid aggregates. They transport antigens from gut lumen to underlying
lymphoid tissues.
c. Goblet cells - These are scattered throughout the epithelium and produce
mucus. They increase in abundance from the duodenum to the ileum and
are even more numerous in the colon. They are not normally found in the
stomach.
d. Paneth cells - Clusters of these cells are located at the bottoms of the intestinal
glands. Their large and abundant red-orange secretion granules help
identify them. They produce lysozyme and ultrastructurally appear as
typical protein producing cells for export.
e. Enteroendocrine cells - This is a heterogeneous cell category. Some cells have
microvilli and contact the lumen (open type). Others contact only the
basement membrane (closed type). All types have their secretion granules
directed to the basement membrane.
- Enteroendocrine cells secrete different hormones in different regions of
the GI tract and are typically named by the type of hormone they secrete
or by where they are most commonly found. Examples of hormones
produced are pancreozymin/cholecystokinin, serotonin
(enterochromaffin EC cells), gastrin (G-cells), gastrin-inhibitory
polypeptide, secretin (S cells), and somatostatin.
* Older names include ‘APUD cells’, part of the so-called APUD system (amine
precursor uptake and decarboxylation cells). It was thought that all these cells were of
neural crest origin. More recently it has been shown that not all APUD cells are of neural
crest origin and some do not concentrate amine precursors. Other old nomenclatures are
based on patterns of silver staining and include ‘argentaffin cells’ and ‘argyrophil cells’.
f. Stem cells - these are generally located near the base of the crypt and can
differentiate into absorptive, goblet, endocrine or Paneth cells. Except for
Paneth cells (which remain in the base of the crypt), the differentiated cells
migrate to the tips of the villi, where the cells are sloughed or lost by
apoptosis.
2. Lamina propria - This forms the connective tissue in the villi and surrounds the
intestinal glands. It is composed of loose connective tissue, blood and lymph
vessels, nerves and smooth muscle. Plasma cells are common.
3. Muscularis mucosa - This is present as in the GPAT.
B. Submucosa - This is typical of the GPAT. In the duodenum, Brunner’s glands, which
are pure mucous, are most abundant closer to the pyloric stomach. They secrete an
alkaline mucus that protects the intestine against gastric acid. The other regions of
the small intestine do not have submucosal glands.
C. Muscularis propria (muscularis externa) - This is present as in the GPAT.

8. Cell Structure & Function Digestive System 2: Upper & Lower G.I. Tract page 8
D. Serosa or adventitia - The duodenum is retroperitoneal, so it has an adventitia, but the
jejunum and ileum are intraperitoneal and so are covered with a mesothelial
(serosal) surface.
E. Regional variations
1. Pyloric junction - Here pyloric stomach meets the duodenum.
2. Duodenum - The presence of any of the following 3 features is diagnostic of
duodenum:
- Brunner’s glands may be present.
- The ampulla of Vater where the common bile duct and main pancreatic duct
empty into the duodenum, may be present.
- Pancreas may be present, since the duodenum curls around the head of the
pancreas.
3. Ileum: characterized by the presence of Peyer’s patches. These are aggregations of
MALT (GALT), involving both mucosa and submucosa. At the Peyer’s patches
modified epithelial cells (m cells, for microfold) cover the aggregated lymph
nodules. M cells endocytose antigens and pass the antigens along to the
underlying lymphocytes.
4. Small intestine - If none of the features of duodenum or ileium are seen, then it is
small intestine not otherwise specified.
5. Ileocecal junction - The ileum meets the colon. The junction functions as a valve,
tending to prevent backflow from cecum into ileum. This is accomplished by
having the smaller diameter ileum protrude into the lumen of the larger diameter
cecum at the transition point. On the ileal side villi are present, but on the colon
side there are colonic-type intestinal glands and no villi.
V. Large intestine
A. Regions - Cecum; ascending, transverse, descending and sigmoid colon; rectum; anal
junction.
B. Mucosa - No plicae circulares, no villi, just intestinal glands are present.
1. Epithelium - This is much like the small intestine, with absorptive cells, goblet
cells, M cells, enteroendocrine cells and stem cells.
Differences from small intestine:
- there are no Paneth cells (a few scattered Paneth cells are normal in the cecum but their
presence distally indicates metaplasia associated with chronic disease)
- there are more goblet cells
2. Lamina propria - More individual nodules of lymphatic tissue are present here than
in the small intestine, but no large aggregates like Peyer’s patches. Blood

9. Cell Structure & Function Digestive System 2: Upper & Lower G.I. Tract page 9
capillaries are present but lymphatic vessels are limited to immediately adjacent
to the muscularis mucosae. (The limited presence of lymphatic vessels in the lamina
propria is important in understanding the biology of colon cancer.)
4. Muscularis mucosae - Normal GPAT.
C. Submucosa - Normal GPAT. No submucosal glands
D. Muscularis propria (muscularis externa) - The usual inner circular layer is present,
but the outer longitudinal layer forms 3 bands (taenia coli) which cause the
entire wall structure to sacculate. Blood and lymph vessels penetrate from the
mesocolon through the muscularis to supply and drain the mucosa and
submucosa. (Weak points in the muscular wall where blood vessels penetrate contribute to
the formation of diverticula, a common disease condition associated with a low fiber diet and
increased intracolonic pressures.)
E. A serosa or adventitia is present, depending on location.
F. Function: The large intestine produces mucus and absorbs water. It serves as
storage for feces until defecation. Flatus, water & short-chain fatty acids are
produced as byproducts of carbohydrate-consuming bacteria that are normal
flora of the colon.
G. Regional variations
1. Ileocecal junction - The ileum meets the colon.
2. Anorectal junction - Here the simple columnar epithelium (with abundant goblet
cells) of the colon abruptly meets the stratified squamous epithelium of the
anal canal. The irregular region where these two mucosal types meet is the
‘anal transitional zone.’ The non-keratinized anal mucosa (without skin
appendages) gradually becomes typical thin skin (perianal skin).
Hemorrhoidal veins are sometimes quite prominent and may be seen under
both colonic (rectal) mucosa and squamous (anal) mucosa.
VI. Appendix. This resembles a miniature colon usually with abundant lymphoid tissue. The
outer longitudinal layer of the muscularis is complete however, with no taenia.
A. The appendix is another MALT (GALT) organ. Large amounts of lymphatic tissue
with nodules usually fill the lamina propria and submucosa. Numerous M-cells
cover the lymphoid nodules.
B. Crypt epithelium includes goblet cells, absorptive columnar cells, endocrine cells and
stem cells. Paneth cells may sometimes be seen.