Anatomy and Homeostasis of the GI Tract€¦ · Anatomy and Homeostasis of the GI Tract Dr Joanne Pennock Infection, Immunity and Respiratory Medicine [email protected]

Anatomy and Homeostasis

of the GI Tract

Dr Joanne Pennock

Infection, Immunity and Respiratory Medicine

[email protected]

Overview: The GI Tract is essentially a mucosal surface designed to protect us from potential infection whilst allowing absorption of essential nutrients

How does our GI tract keep us healthy?

Jejunum Colon

Overview: The GI Tract has an undulating surface which increases surface area for absorption and secretion

CRYPT VILLUS

SUBMUCOSA & MUSCLE

Stomach

Stomach:

Lumen pH 1-2

H+ Pepsin

HCO3-

Mucus pH 7

Pre-epithelial

Protection of gastric epithelium by mucus and secretion of neutralising bicarbonate by specialised epithelial cells

pH gradient

Stomach: The case for H pylori

1982: Lancet Robin Warren and

Barry Marshall published a study

with 100 patients showing that H

pylori strongly associated with

gastric and (later) duodenal ulcers.

In 1988 published showing that

in 92% of patients where H pylori

had been cleared with

antibiotics, their ulcer had

healed.

Gastric/duodenal ulcers caused by: NSAIDS (20%) H pylori (80%)

Figure 1 Demonstration of Helicobacter pylori by the four

staining methods: (A) modified Giemsa, (B) anti-H pylori

antibody immunostain, (C) modified McMullen's method,

(D) H pylori silver staining (HpSS) method.

Rotimi et al. J Clin Pathol 2000;53:756-759


http://jcp.bmj.com/content/53/10/756/F1.large.jpg


Atuma C et al. Am J Physiol Gastrointest Liver Physiol 2001;280:G922-G929

The GI tract is lined with a variable layer of mucus

• Lubricant

• Prevents mechanical stress

on epithelium

• Thick layer provides stable

microenvironment

• Prevents invasion

• Essential environment for

microflora

Johansson M E V et al. PNAS 2008;105:15064-15069

Mucus is secreted by goblet cells

Mucus in the GI tract:

World's largest E. coli outbreak kills 14 in Germany (May 2011)

3,500 infected 855 developed rare haemolytic uraemic syndrome (HUS) 53 died

Enteroaggregative strain of E. coli had acquired Shiga toxin which caused HUS

Mucus in the GI tract: A layer of mucus is essential to health

Muc5ac: a critical component mediating the rejection of enteric nematodes. Hasnain et al. Exp Med. 2011 May 9;208(5):893-900. Epub 2011 Apr 18.

Mucus in the GI tract: All mucus is not created equal…

Mucus and the microbiome:

Johansson M E V et al. PNAS 2008;105:15064-15069

Upper layer of mucus is colonised by bacteria

Mouth Anus


?


Antimicrobial Peptides: a and b defensins, Reg3a

Antimicrobial Peptides:


Essential for bacterial

clearance.

Eg Salmonella

typhimurium

• Administration of antibiotics can downregulate

antimicrobial peptides and increase susceptibility to some virulent bacteria

• eg hospital patients became susceptible to ancomycin-

resistant Enterococcus • In mice giving microbial products (LPS) after antibiotics, can

increase resistance and upregulate antimicrobial peptides


i.e. gut bacteria actually stimulate secretion of antimicrobial peptides maintaining homeostasis

BEVINS C L et al. Gut 1999;45:911-915

Copyright © BMJ Publishing Group Ltd & British Society of Gastroenterology. All rights reserved.

‘’Twenty years ago you wouldn't have expected this, but

there's been a dramatic change in the view of what

microorganisms like bacteria can do to host physiology,"

[Sven Pettersen] said.

The microbiome is essential to health:

The absence of gut bacteria affects:

• Behaviour

• Gut homeostasis

• Immune response under stress

• Body weight

• Brain development and gene expression

Heijz et al PNAS 2011

Why not switch to ‘healthy’ bacteria??

•‘Mutaflor’ •Ulcerative Colitis •Gastroenteritis •IBS •Pouchitis •Crohn’s disease

Each capsule 2.5-25x10(9) viable cells

The microbiome is essential to health:

Faecal transplant therapy

Faecal transplant therapy

A recent systematic review concluded that, although there are a variety of methods used to infuse intestinal microorganisms (as part of a suspension of healthy donor stool) into the intestine of patients in order to restore the microbiota, of 317 patients treated across 27 case series and reports, this approach was highly effective at achieving resolution of recurrent CDI (92% resolved). Adverse events have rarely been reported (Gough et al., 2011). Typically, fresh manipulated faeces (30–50g) from a healthy donor is administered in normal saline by enema, slurries via nasogastric tube, or colonoscopy.

Public Health England 2013

• The leading cause of health care-associated infectious diarrhea (1,646 deaths

in England and Wales 2012)

• Caused by a spore-forming gram positive bacillus which is part of normal

healthy flora in 4% of healthy individuals.

• Spores are resistant to stomach acid

• Once in intestine, germinate and move into vegetative state

Clostridium difficile infection

Asymptomatic Severe diarrhea

Severe abdominal pain

White blood cell count >15000 cells/ul

Toxic megacolon

Organ failure

Mortality rate 35-80%


• Virulence is evolving

• Total cases rose dramatically

1999-2005

• Reported infections still on the

rise

• Reported deaths falling

• Considered a new ‘epidemic’??

• Most often found in a health care setting

• Spores are easily spread

• Recent administration of antibiotics is key risk factor

• Change in flora facilitates colonization & proliferation


Taken from: Clostridium difficile infection: how to deal with the problem. Department of Health & Health Protection

Agency 94 cases reported in Jan and Feb 2015 in University Hospital of South Manchester alone.


van Nood E et al. N Engl J Med 2013;368:407-415.

Rates of Cure without Relapse for Recurrent Clostridium difficile Infection.

Clostridium difficile infection: First randomised clinical trial 2013

The microbiome is essential to health

IgA is a GI specific antibody responsible for primary defence against bacteria

Secretory IgA

http://www.calier.es/

Secretory IgA

•1 in 700 Europeans are IgA deficient •The most common immunodeficiency •Many have no symptoms…. BUT

•IgA deficient patients suffer more episodes of: •bronchitis •pneumonia •chronic diarrhea •conjunctivitis •sinusitis

•1 in 700 Europeans are IgA deficient •The most common immunodeficiency •Many have no symptoms…. BUT

•IgA deficiency often presents with IgG2 deficiency •Increases susceptibility to certain bacteria

The role of secretory antibodies in infection immunity Richard A. Strugnell & Odilia L. C. Wijburg Nature Reviews Microbiology 8, 656-667 (September 2010)

http://www.nature.com/nrmicro/journal/v8/n9/full/nrmicro2384.html

SIgA coats colitogenic bacteria with high affinity:

Palm et al Cell 2014 158: 1000

SIgA coats colitogenic bacteria with high affinity in

Crohn’s and UC patients:

Authors found: • Colitogenic bacteria were highly coated

with IgA

• Antigen specific IgA production

• CD and UC patients each had unique bacterial populations coated with IgA

• When isolated, these bacteria exacerbated colitis in mice

• IgA response is insufficient to clear /neutralize bacteria

• Can IgA coating be used to identify disease-promoting bacteria in individual patients? Palm et al Cell 2014 158: 1000

Natural defences: Mucus, microbiome & antibody BUT the GI tract is also lined with a single layer of epithelial cells which delineate our host tissue from the outside environment

Pre-epithelial

Simple columnar Epithelium

Sub-epithelial

Bacteria Mucus IgA Innate & adaptive cellular responses

Epithelium:

Stomach Jejunum Colon

Epithelium:

Epithelium: Houses key effector cells

Paneth cells

Stem

cells

Proliferative

zone

Differentiation

zone

Epithelium: Cell renewal & differentiation

Need to strike a balance between apoptosis and proliferation


Damage resulting in denuding of epithelium

Restitution Healing Healing completed

• Most common intestinal parasite found in the USA.

• 10-25 cysts can cause clinical disease.

• Pathology results from vilous atrophy and crypt hyperplasia.

• Parasite increases enterocyte apoptosis – ultimately resulting in atrophy,

malabsorption, and weight loss.

Giardia intestinalis


Volta and Villanacci Cellular & Molecular Immunology (2011) 8, 96–102;

Coeliac disease

Pasparakis Nature Reviews Immunology 9, 778-788 (November 2009)


Pre-epithelial

Epithelial

Sub-epithelial

Bacteria Mucus IgA Innate & adaptive cellular responses

Sub-Epithelium:

Sub-Epithelium:

Focus on: Lamina propria Lymphocytes

How does the immune system put a brake on inflammation?

Glocker et al N Engl J Med. 2009 November 19; 361(21): 2033–2045.

A case in point: A deficiency in IL10 receptor

Glocker et al N Engl J Med. 2009 November 19; 361(21): 2033–2045.

A case in point: A deficiency in IL10 receptor

http://arthritis-research.com/content/7/2/62/figure/F1

Why IL10 receptor? Tregs are essential for control

T cell populations contribute to homeostasis

T cell populations contribute to homeostasis

•Ulcerative colitis (UC) •Crohn’s Disease (CD)

Inflammatory Bowel Disease

Crohn’s Disease

Barrier defects: Tight junction dysfunction

Paneth cell defects: Reduced secretion of HD5

Paneth cell defects: NOD2 polymorphisms Potentially affecting microbiome and response to commensal flora

Effector T cell / T reg imbalance

Defective cell migration

Defective neutrophil function



Dysregulation of host flora may cause disease

Homeostasis is key to regulating inflammation



• Inflammatory bowel disease (IBD) includes:

– Ulcerative colitis and

– Crohn’s disease

• The overall increased risk of colorectal cancer for someone with IBD is estimated to be 4-20 times higher than normal.

• Personal history of type 2 diabetes

– Increases your risk of having colorectal cancer and colorectal polyps by 50 percent

Having Inflammatory Bowel Disease and Type 2 Diabetes Are Risk Factors for

Colorectal cancer

Having Inflammatory Bowel Disease and Type 2 Diabetes Are Risk Factors for

Colorectal cancer

• Ten patients in each group • Relative abundance of bacterial

phyla shown

Unravelling the effects of the environment and host genotype on the gut microbiome Aymé Spor, Omry Koren & Ruth Ley Nature Reviews Microbiology 9, 279-290 (April 2011)



• In most people, colorectal cancers develop slowly over a period of several years.

– 10 to 20 years

• Chances of developing colorectal cancer sometime in your life:

– A man has a 1 in 17 chance.

– A woman has a 1 in 18 chance.

What is colorectal cancer?


• Colorectal cancer usually begins as a non-cancerous (or benign) polyp.

• A polyp

– is a growth inside the colon or rectum that is not normal.

– can be several types.

– is not always cancerous.


Inflammatory bowel disease and intestinal cancer: a paradigm of the Yin–Yang interplay between inflammation and cancer S Danese1 and A Mantovani2 Oncogene (2010) 29, 3313–3323

An inflammatory microenvironment promotes tumorigenesis

An inflammatory microenvironment promotes tumorigenesis

NOD2-mediated dysbiosis predisposes mice to transmissible colitis and colorectal cancer Couturier-Maillard et al. J Clin Invest 2013

Microbial Dysbiosis in Colorectal Cancer (CRC) Patients Sobhani et al. PLoS ONE Jan 2011 The Gut Microbiome Modulates Colon Tumorigenesis Zackular et al. Mbio Nov 2013

http://mbio.asm.org/search?author1=Joseph+P.+Zackular&sortspec=date&submit=Submit

Figure 1. Bacterial genera abundance differentiates cancer patients and normal colonoscopy

individuals.

Sobhani I, Tap J, Roudot-Thoraval F, Roperch JP, Letulle S, et al. (2011) Microbial Dysbiosis in Colorectal Cancer (CRC) Patients.

PLoS ONE 6(1): e16393. doi:10.1371/journal.pone.0016393

http://journals.plos.org/plosone/article?id=info:doi/10.1371/journal.pone.0016393

http://journals.plos.org/plosone/article?id=info:doi/10.1371/journal.pone.0016393

Dysbiosis promotes tumorigenesis

Intrinsic pathway to

inflammation (in tumour

cells)

Extrinsic pathway driven by chronic inflammation (eg

IBD, dysbiosis)

Tumour Progression

• Normal tissue homeostasis disrupted • Sequential mutations • Epigenetic alterations • Oxidative stress (Bcl2, p53) • Proliferation / apoptosis dysregulation

• Inflammatory tumour microenvironment • Inflammatory cytokines (TNFa, IFNg, IL1, IL6) • Reduced regulatory cytokines (IL10, TGFb) • Disrupted homeostasis • Proliferation / apoptosis disregulation

The Cancer-Inflammation Paradigm

Summary: • Many effectors play a role in gut homeostasis • Epithelial cells play a major role in maintaining a physical

barrier and triggering immune responses • Mucus, the microbiome and regulatory cells together are

essential for gut health • Sub-epithelial immune cells maintain homeostasis and

respond to the gut environment • Sub-epithelial cells are primed to respond to breaches in the

intestinal barrier

Anatomy and Homeostasis of the GI Tract€¦ · Anatomy and Homeostasis of the GI Tract Dr Joanne Pennock Infection, Immunity and Respiratory Medicine [email protected]

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