Gastrointestinal and Hepatobiliary Infections

OVERVIEW

Viewed in its simplest form, the gastrointestinal tract is a hollow digestive tube that extends through the center of the body from the mouth to the anus. The walls of the tube are lined with a diverse number of epithelial cells that function well at transmembrane secretion and absorption and maintain the barrier that protects the host from microbial pathogens. The barrier consists of the intact mucosal surface and a population of resident immune cells. The primary function of the gastrointestinal system is digestion and nutrient uptake.

The epithelial cells have a relatively short life, with most cells living between 48 and 72 hours. Because of the constant turnover of cells, it is difficult for pathogens to colonize the gastrointestinal tract. However, the disadvantage of the high rate of cell turnover is that the epithelial cells are more susceptible to mutagenic compounds and tumor formation.

All of the liquid and solid material ingested, along with bacteria, is carried through the tube. Bacteria colonize the areas of the tube that offer a suitable environment for growth. Soon after birth, a microbiota is established in each part of the tube. The oral cavity and the colon are at opposite ends of the tube and are heavily colonized with bacteria. The central part of the tube, the stomach, duodenum, jejunum, and the proximal half of the ileum, are lightly colonized.

Each portion of the gastrointestinal tract has special defense mechanisms that protect it from pathogenic microorganisms. When pathogenic microorganisms or their toxins breach these defense mechanisms, disease can occur.

Defense Mechanisms of the Gastrointestinal Tract

The following are some of the major defense mechanisms in the gastrointestinal tract that serve to prevent infection. There are other defense mechanisms, but they will not be discussed here because they are beyond the scope of these lectures.

· An unbroken mucosal epithelium lines all parts of the gastrointestinal system. The epithelial cells are continually sloughed off and replaced. If cell replacement is impeded (e.g., radiation therapy or cancer chemotherapy), ulceration of the mucosa can occur. The ulcer is no longer lined with epithelial cells and the surface of the ulcer can be infected. The infection can damage the blood vessels in the wall of the gastrointestinal tract, causing septicemia and fever.

· The glycocalyx is a glycoprotein and polysaccharide layer that covers the surface of the epithelial cells. This layer presents a thick physical barrier that prevents pathogens from attaching to the epithelial cells and serves as a chemical trap that binds microorganisms of the normal flora.

· Mucus plays two roles in disease prevention: (1) It acts as a physical barrier, making it more difficult for bacteria to access the epithelial cell surfaces; and (2) it coats the bacteria, making it easier to remove via peristalsis.

· The normal pH of the stomach is < 4 (i.e., acidic). This acidity spills into the small intestine and establishes a pH gradient that prevents most bacteria from colonizing the stomach, duodenum, jejunum, and the upper half of the ileum. Therefore, most ingested pathogens never reach the intestinal tract alive.

· Bile solubilizes lipids and inactivates organisms that have a lipid envelope. Most enveloped viruses are inactivated, and many bacteria are unable to grow at a high bile salt concentration.

· Secretory IgA helps prevent colonization by pathogens.

· Peristalsis contributes to the health of the gut by aiding in fluid absorption, maintaining appropriate dilution of indigenous enteric microflora, and ridding the host of pathogenic microorganism.

· Peyer patches are unencapsulated patches of lymph follicles in the mucosa and submucosa and provide a homing site for lymphocytes. M cells lining the intestine process antigens and present antigens to the lymphocytes in the Peyer patches. The intestinal mucosa is in a constant state of “physiologic inflammation.” The lamina propria is a thin layer of connective tissue that lies just below the intestinal epithelium. It contains capillaries and a central lacteal (lymph vessel) as well as numerous neutrophils, macrophages, plasma cells, and lymphocytes. After invasive infections, a vigorous inflammatory reaction ensues, resulting in many white blood cells entering the lumen of the intestine from the lamina propria.

· Most of the microbiota of the gastrointestinal tract is composed of anaerobic bacteria (over 99%). Many bacterial species have not been fully characterized because they have yet to be cultured. The microbiota competes with pathogens for nutrients and epithelial cell receptor sites and keeps them from causing disease. About 60% of the dry mass of the feces is bacterial. Most bacteria in the microbiota of the colon are part of the following phyla Firmicutes, Bacteroidetes, Actinobacteria and Proteobacteria. Most bacterial belong to the following genera Bacteroides (30% of all the bacteria in the colon), Clostridium, Faecalibacterium, Eubacterium, Ruminococcus, Peptococcus, Peptostreptococcus and Bifidobacterium. Other genera, such as Escherichia and Lactobacillus, are less numerous.

Factors that Compromise the Gastrointestinal Tract

The gastrointestinal tract is constantly challenged by pathogenic microorganisms that compromise the gastrointestinal tract.

· Ingestion of antacids neutralizes stomach acid and allows microorganisms to proliferate in areas that have very few organisms in the microbiota.

· Antibiotic therapy and Proton pump inhibitors kill bacteria in the microbiota and allows colonization by pathogens.

· Glucosteroid therapy inhibits the immune response, making it more conducive for gastrointestinal tract infections to develop.

· Cancer chemotherapy and radiation therapy reduces the microbiota and the cellular and humoral immunity as well as the integrity of the intestinal epithelium.

· Ingestion of preformed microbial toxins can interfere with normal cell functions and cause cell death and disease.

· Microorganisms produce toxins, enzymes, and immunosuppressive factors that can overcome the host defenses and cause disease.

· An obstruction to the flow of liquids removes a powerful defense mechanism of the gastrointestinal tract (see above). Large diverticula and stasis of the intestines following abdominal surgery can result in severe complications for many patients.

Etiology

The Table below is an incomplete list of organisms that cause these diseases.

Table GI-1. Microorganisms that Cause Gastrointestinal Diseases and the Site Most Often Affected
Microbial Agent	Disease			Site Affected
Bacteria
Corynebacterium diphtheriae	Diphtheria			Oropharynx
Streptococcus pyogenes	Pharyngitis			Oropharynx
Biofilms (plaque) that contain high numbers of cariogenic bacteria (e.g., Mutans group Streptococcus S. mutans and S. sobrinus, Lactobacillus casei, Actinomyces species, Bifidobacterium species, and low-pH tolerant Streptococcus species)	Dental caries			Teeth
Biofilms (plaque) that contain high numbers of Anaerobic Gram negative bacteria and spirochetes	Gingivitis, periodontal disease, dentoalveolar abscess, periodontal abscess, Ludwig’s angina			Gums for all but Ludwig’s angina Ludwig’s angina: sublingual and submandibular spaces
Helicobacter pylori	Gastritis, peptic ulcer disease			Stomach and duodenum
Staphylococcus aureus, enterotoxin producing	Nausea and vomiting and diarrhea			Increased serotonin release in intestine stimulates vagal afferent neurons
Bacillus cereus	Type 1 with nausea and vomiting Type 2 with diarrhea			Type 1 uncouples oxidative phosphorylation in liver mitochondria Type 2 in small intestine
Campylobacter jejuni	Diarrhea, dysentery, and fever			Intestine
Enterotoxigenic Escherichia coli, Enteropathogenic E coli, Enteroaggregative E coli	Diarrhea			Intestine
Enterohemorrhagic E coli	Diarrhea followed by bloody diarrhea, hemolytic uremic syndrome			Intestine, kidney
Enteroinvasive E coli	Diarrhea occasionally becoming dysentary			Intestine
Shigella sonnei, S flexneri	Diarrhea followed by dysentery			Intestine
Microbial Agent		Disease	Site Affected
Bacteria
Salmonella enterica		Diarrhea sometimes followed by dysentery.	Intestine
Salmonella entericaserovar Typhi		Typhoid fever, enteric fever	Intestine, liver, spleen, blood, bone marrow, gallbladder
Salmonella enterica serovar ParatyphiA, Salmonella enterica serovar Schottmuelleri, Salmonella enterica serovar Hirschfeldii		Paratyphoid fever, enteric fever	Intestine, liver, spleen, blood, bone marrow
Clostridioides difficile		Diarrhea, pseudomembranous colitis, toxic megacolon	Colon
Virus
Epstein-Barr virus		Infectious mononucleosis; pharyngitis	Oropharynx
Herpes simplex virus types 1 and 2		Gingivostomatitis	Gums, mucosa of mouth, lips, esophagus
Human immunodeficiency virus		Esophagitis	Esophagus
Rotavirus		Diarrhea	Intestine
Caliciviruses (Noroviruses, Sapovirus, Astroviruses)		Diarrhea	Intestine
Coronavirus (SARS CoV-2)		Diarrhea	Intestine
Adenovirus		Diarrhea	Intestine
Hepatitis A, B, C, D, and E viruses		Hepatitis	Liver
Fungus
Candida albicans		Pseudomembranous candidiasis (thrush), esophagitis	Mouth, esophagus
Parasite
Ascaris lumbricoides		Abdominal tenderness diffuse with partial or complete bowel obstruction	Intestine, appendix, bile duct, liver
Cryptosporidium parvum		Diarrhea	Intestine
Cyclospora cayetanensis		Diarrhea	Intestine
Giardia lamblia		Diarrhea	Intestine
Strongyloides stercoralis		Anorexia, weight loss, nausea, chronic diarrhea or constipation, bloating	Intestine
Entamoeba histolytica		Dysentery	Colon
Enterobius vermicularis		Anal pruritus	Rectum

Manifestations

Despite all of the defense mechanisms that serve to prevent infection in the gastrointestinal tract, there are numerous diseases associated with the gastrointestinal and hepatobiliary systems.

Areas Affected and Manifestations of Diseases

· Mouth: Ulcers on mucosal surfaces in the mouth, white plague on teeth, white or erythematous lesions on mucosa, dental caries, tooth pain and sensitivity to heat or cold, bleeding gums, petechia, facial pain or swelling, abscess, and cellulitis.

· Salivary glands: Jaw pain when swallowing and swelling under jaw.

· Esophagus: Dysphagia (difficulty in swallowing), odynophagia (painful swallowing; unique to infectious causes of esophagitis), heartburn, atypical chest pain, and regurgitation.

· Stomach: Epigastric pain and tenderness that occurs 90 minutes to 3 hours after eating; vomiting, belching, indigestion, and heartburn.

· Small intestine: Large volume watery diarrhea; fatty stools, increased bowel sounds, cramps, diffuse abdominal pain; no guarding or rebound tenderness.

· Large intestine: Diarrhea or small volume bloody diarrhea with mucus (dysentery); cramps, diffuse abdominal pain, white blood cells frequently found in stool, fever; rarely any guarding or rebound tenderness.

· Liver: Upper right quadrant abdominal pain; fever, icterus, clay-colored stools, and dark urine.

· Peritoneum: Sharp, localized abdominal pain aggravated by motion; fever, chills, constipation, abdominal distension, decreased bowel sounds; guarding and rebound tenderness.

Epidemiology

Gastrointestinal diseases are the second most common reason for a patient to see their physician. Diarrhea is one of the most common gastrointestinal diseases among adults. Approximately 270 million cases of diarrhea in adults result in about 600,000 hospitalizations and 3000 deaths annually in the U.S. An etiologic agent is identified in less than 10% of these cases. Most adults have at least one episode of diarrhea each year, and children have an average of two to three episodes per year. Worldwide, diarrhea kills 2,195 children every day—more than AIDS, malaria, and measles combined. Diarrheal diseases account for 1 in 9 child deaths worldwide, making diarrhea the second leading cause of death among children under the age of 5.

A large number of patients with diarrhea acquire the organism that causes their illness while ingesting contaminated food. The Centers for Disease Control and Prevention estimates that each year roughly 1 in 6 Americans (or 48 million people) get sick, 128,000 are hospitalized, and 3,000 die of foodborne diseases.

Pathogenesis

The pathology associated with a particular gastrointestinal tract disease depends on the site infected or intoxicated. There are two basic mechanisms that infectious agents utilize in causing disease in these systems. One mechanism involves ingesting a preformed toxin that will cause symptoms such as food poisoning. This is called intoxication. The most common cause of food poisoning in the US is due to an enterotoxin produced by Staphylococcus aureus. Symptoms of intoxication usually occur relatively rapidly, with an incubation period as brief as 30 minutes after ingestion of the toxin.

The other mechanism that infectious agents utilize to cause disease in the gastrointestinal tract involves attachment to or infection of the host cells. Some pathogens only attach to the surface of the epithelial cells and produce toxins while attached to the host cell, which causes cell damage or death. This process often results in a watery diarrhea without inflammatory cells, blood in the stools, or fever. After attaching to the cells, other pathogens enter the cells and damage or kill them. Depending on how deep the infection goes, symptoms can vary from a watery diarrhea (gastroenteritis), to bloody mucus-covered stool (dysentery), to invasion of the bloodstream from the intestine (enteric fever). In cases of dysentery, red blood cells and fecal leukocytes are frequently present in the feces and are a good clinical indicator of an invasive inflammatory gastrointestinal tract infection. Symptoms occur about 24–72 hours after ingestion and if the host mounts a significant immune response, patients may have a fever. Note that the incubation period is usually much longer in this process than when the mechanism for causing a disease is intoxication.

Diagnosis

Localizing where pathology is occurring in the gastrointestinal tract is essential to knowing how to treat the patient. Many gastrointestinal tract infections are self-limiting whereas others require treatment to prevent severe complications. In many cases, the manifestations observed in the patient can help the physician determine the specific area of the gastrointestinal tract that is affected (e.g., diarrhea usually indicates a patient has an intestinal disease).

Once the affected area of the gastrointestinal tract is identified, procedures (e.g., endoscopy) can be performed to visualize the pathology associated with the disease and samples (e.g., stools, blood) obtained to determine the cause of the disease.

Treatment and Prevention

The treatment and prevention of a particular infection depends on the site of the infection and the pathogen causing the disease. These topics will be discussed in more detail later.

To prevent many gastrointestinal tract infections, patients should be encouraged to maintain good oral hygiene, properly cook and store all food, drink safe water, take special precautions when traveling to countries outside the U.S. Patients should avoid using illegal intravenous drugs, having multiple sexual partners, and drinking excessive amounts of alcohol.

All travelers to countries where diarrheal diseases are common should only drink water that has been boiled or treated with chlorine or iodine and remember that ice is frequently made with contaminated tap water. Freezing and thawing of ice does not kill many of the organisms and is a source of infection for many travelers. Eat only foods that have been thoroughly cooked and are still hot, or consume fruit that can be peeled just before eating. All vegetables should be cooked; salads should never be eaten because vegetables are washed with tap water. Undercooked or raw fish or shellfish should not be eaten; perishable seafood should not be taken from the restaurant. Foods and beverages should not be purchased from street vendors. A simple rule of thumb to follow when traveling overseas is to boil it, cook it, peel it, or forget it!

The Gastrointestinal content is divided into 6 sections;

Infections of the teeth, gingivae, and jaws
Infections of tongue, mouth, and parotid glands
Infections of the esophagus, stomach, and upper duodenum
Infections of the liver
Infections of the small intestine
Infections of the large intestine

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