29 Diarrhea, Constipation, and Probiotics (2) Flashcards Preview

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1

Intestinal Mucosa

  • The intestinal mucosal 
    • surface area
    • continuously exposed to
    • mucosal homeostasis
  • At birth, the neonate/
    • Within the first few hours of birth/
    • A huge variety of factors influences the initial colonization process/
    • The maternal flora/
    • The first bacteria colonizing the neonatal colon/
    • In breastfed babies/

  • The intestinal mucosal
    • has a surface area approximating that of a tennis court.
    • continuously exposed to foreign antigens of both nutritional and bacterial origin.
    • In order to maintain normal absorptive function, mucosal homeostasis is necessary, requiring close regulation of the intestinal epithelial barrier to allow for efficient uptake of nutrients without eliciting an inappropriate immune reaction, and at the same time protecting the host from foreign invasion.
  • At birth, the neonate leaves a germ-free intrauterine environment and enters a highly contaminated extrauterine world.
    • Within the first few hours of birth, the process of intestinal colonization takes place.
    • A huge variety of factors influences the initial colonization process, such as gestational age, the mode of delivery, the neonatal diet, and genetic factors.
    • The maternal flora constitutes the predominant source of initial colonization.
    • The first bacteria colonizing the neonatal colon are thus Escherichia coli and various Enterococcus species.
      • Obligate anaerobes follow.
    • In breastfed babies, Bifidobacterium species predominate, whereas in formula-fed neonates Bacteroides species predominate and only a few Bifidobacterium sp. are present.

2

Intestinal Microflora (p.30)

  • the diversity of intestinal microbiota, 
    • comprises/
    • This microbiome contains/
  • biological advantage of harboring such an enormous biomass within the human gut. 
    • microbial genome may contain/
      • This genetic contribution may be/
    • in ruminants, the rumen flora contributes to/
    • the microbiota thus provides an advantage/
    • Additionally, intestinal flora regulates
  • the large numbers of commensal flora in the intestine compete with pathogens for the intraintestinal/host environment. 
    • Gut colonization with bacteria also triggers/
    • microbiota in the intestine exerts/
    • Indirect effects on the immune system are mediated by/

  • the diversity of intestinal microbiota,
    • comprises hundreds of different species that form a complex and highly interactive biomass (microbiome) of at least 1014 bacteria within the human gastrointestinal tract
    • This microbiome contains more than 100-fold more genes than the human genome.
  • biological advantage of harboring such an enormous biomass within the human gut.
    • microbial genome may contain coded information for functions that the human species have not developed during evolution.
      • This genetic contribution may be a major ecological and biological advantage.
    • in ruminants, the rumen flora contributes to fermentation of ingested nondigestible polysaccharides and resulting monosaccharides into short-chain fatty acids.
    • the microbiota thus provides an advantage in energy storage after a low intake of energy.
      • Bacterial enzymes allow the host to salvage energy from otherwise indigestable dietary polysaccharides.
    • Additionally, intestinal flora regulates vitamins, including B and K.
  • the large numbers of commensal flora in the intestine compete with pathogens for the intraintestinal/host environment.
    • Gut colonization with bacteria also triggers angiogenesis in intestinal mucosa.
    • microbiota in the intestine exerts stimulatory effects on the innate and adaptive intestinal immune systems, triggering the production of mucosal IgA secretion.
    • Indirect effects on the immune system are mediated by regulatory metabolites in the form of short-chain fatty acids such as lactate and butyrate, which exert immunomodulatory/anti-inflammatory effects.

3

Homeostatic Symbiosis

  • \an intact intestinal epithelial barrier 
    • This is a dynamic, complex physical and biological system composed of/
    • The epithelial cells have highly specific channels, allowing for/
    • Because of the mucous gel, the apical membrane of the enterocytes/
    • In addition to IgA, various antibacterial peptides are secreted into the intestinal lumen by/
  • In addition to direct barrier functions, the intestinal mucosal immune system is an important part of the body’s/
    • It makes up the majority of the body’s/
    • This allows for antigen sampling and presentation by specialized cells to/
    • Toll-like receptors and NOD molecules serve as/
    • An innate immune response may be triggered/
    • Complex mechanisms are in place to prevent/

  • A prerequisite for the homeostatic symbiosis is an intact intestinal epithelial barrier
    • This is a dynamic, complex physical and biological system composed of densely packed epithelial cells with tight intercellular junctions, and an overlying mucous gel secreted by goblet cells with high concentrations of IgA.
    • The epithelial cells have highly specific channels, allowing for sampling of substrates for absorption while maintaining a barrier to antigens.
    • Because of the mucous gel, the apical membrane of the enterocytes is rarely exposed directly to intestinal bacteria.
    • In addition to IgA, various antibacterial peptides are secreted into the intestinal lumen by enterocytes and Paneth cells.
  • In addition to direct barrier functions, the intestinal mucosal immune system is an important part of the body’s defense against enteric pathogens.
    • It makes up the majority of the body’s lymphoid tissue and is organized into Peyer’s patches and lymph nodes.
    • This allows for antigen sampling and presentation by specialized cells to the regional Peyer’s patches and lymph nodes.
    • Toll-like receptors and NOD molecules serve as pathogen recognition systems to recognize a limited number of bacterial motifs.
    • An innate immune response may be triggered very quickly through this interaction at the epithelial cell level.
    • Complex mechanisms are in place to prevent permanent and unwanted stimulation of the innate immune system, as can occur with inflammatory bowel disease.

4

Probiotics

  • Probiotics 
  • prebiotics
  • synbiotics
  • Probiotics are available in/
  • Most probiotics 

  • Probiotics
    • live microorganisms (in most cases, bacteria) that are similar to beneficial microorganisms found in the human gut.
    • also called "friendly bacteria" or "good bacteria."
    • "live microorganisms, which, when administered in adequate amounts, confer a health benefit on the host." Microorganisms include bacteria, viruses, and yeasts.
  • prebiotics
    • nondigestible food ingredients that selectively stimulate the growth and/or activity of beneficial microorganisms already present in people's colons.
  • When probiotics and prebiotics are mixed together, they form something referred to as a synbiotics.
  • Probiotics are available in foods and dietary supplements in the form mainly of capsules, tablets and powders.
    • Examples of foods containing probiotics are yogurt, fermented and unfermented milk, miso, tempeh, and some juices and soy beverages.
    • In probiotic foods and supplements, the bacteria may have been originally present or they have been added during preparation.
  • Most probiotics
    • bacteria similar to those naturally found in people's guts, especially in those of breastfed infants (who have natural protection against many diseases).
    • Most often, the bacteria come from two groups, Lactobacillus or Bifidobacterium.
    • Within each group, there are different species (for example, Lactobacillus acidophilus and Bifidobacterium bifidus),
    • within each species, different strains (or varieties).
    • A few common probiotics, such as Saccharomyces boulardii, are yeasts, or fungal, rather than bacterial. 

5

Probiotics:
Uses for Health Purposes

  • the world is full of microorganisms (including bacteria), and so are people's bodies
  • Friendly bacteria are vital to proper development of the immune system
  • This bacterial "balancing act" can be thrown off in two major ways:
    • By antibiotics/
    • "Unfriendly" microorganisms/

  • the world is full of microorganisms (including bacteria), and so are people's bodies
    • in and on the skin, in the gut, and in other orifices.
    • the GI tract contains 1014 bacteria which is tenfold more than the number of eukaryotic cells in the human body.
  • Friendly bacteria are vital to proper development of the immune system, to protect against microorganisms that could cause disease, and to digest and absorb food and nutrients.
    • Interactions between a person and the microorganisms in his body, and among the microorganisms themselves, can be crucial to the person's health and well-being.
  • This bacterial "balancing act" can be thrown off in two major ways:
    • By antibiotics, when they kill friendly bacteria in the gut along with unfriendly bacteria.
      • Some people use probiotics to try to offset side effects from antibiotics like gas, cramping, or diarrhea.
      • Similarly, some use them to ease symptoms of lactose intolerance—a condition in which the gut lacks the enzyme needed to digest significant amounts of the major sugar in milk, and which also causes gastrointestinal symptoms.
    • "Unfriendly" microorganisms such as disease-causing bacteria, yeasts, fungi, and parasites can also upset the balance.

6

Criteria for Probiotics

  • Nonpathogenic
  • Adhere to intestinal mucosa and colonize the gastrointestinal tract
  • Influence immune responses and metabolic activities
  • Documented health benefits
  • Of human origin
  • Easily grown in vitro and resistant to technological processing
  • Resistant to gastric acid, pancreatic enzymes, and bile

7

Probiotics in specific diseases

  • an appropriate microbial balance in the intestine is crucial for human health
  • Probiotics exert their benefits through several mechanisms:

  • an appropriate microbial balance in the intestine is crucial for human health.
    • Changes in diets and lifestyles over time, such as the reduced intake of fermented foods in Western diets in recent years, and the increased use of antibiotics are potential factors that can cause disruption in gut microbial homeostasis.
  • Probiotics exert their benefits through several mechanisms:
    • Prevention of colonization, cellular adhesion and invasion by pathogenic organisms.
    • They have direct antimicrobial activity and they modulate the host immune response.
    • Improve intestinal barrier function.
    • Modulation of pain perception, possibly through induction of expression of micro-opioid and cannabinoid receptors in intestinal epithelial cells, mediating morphine-like analgesia.

8

Diseases the benefit from probiotics

  • Antibiotic-associated diarrhea
  • Infectious diarrhea
  • Traveler’s diarrhea

  • Antibiotic-associated diarrhea
    • for every 7 pediatric patients with AAD, 1 was spared by the use of probiotics.
    • reduction of more than 50% (95% CI 35%–65%) in the occurrence of acute AAD with probiotic prophylaxis.
    • in 9 of 10 trials reporting on the incidence of diarrhea, a statistically significant effect was observed that favored probiotic groups over control groups.
  • Infectious diarrhea
    • The mechanisms by which probiotics are effective in preventing or shortening infectious diarrhea
      • competition with pathogens for adhesion sites, strengthening of the mucosal barrier and tight junctions between enterocytes, and/or enhancement of the mucosal IgA-mediated immune responses to pathogens.
      • Secretion of antimicrobial substances and induction of intestinal mucin production
    • the use of probiotics significantly reduced the risk that diarrhea would persist for more than 3 days.
    • the use of those probiotics shortened the duration of diarrhea by 0.7 days
    • use of probiotics reduced the risk of diarrhea lasting 3 or more days by 0.40.
  • Traveler’s diarrhea
    • less readily prevented by probiotics.
    • The beneficial and preventive effect of probiotics on diarrhea was dependent on age

9

Diseases the benefit from probiotics:
Rotavirus

  • Probiotics may have a role in hastening recovery from acute rotavirus diarrhea in children.
  • a combination of oral probiotics significantly reduced hospitalization and duration of diarrhea compared with oral rehydration formula alone.
  • The effects of probiotics were similar to nitazoxanide, an established treatment of rotavirus diarrhea.
  • Lactobacillus GG decreased fecal shedding of rotavirus in a dose dependent effect

10

Diseases the benefit from probiotics:
Clostridium difficile associated diarrhea (CDAD) (p.40-41)

  • The most frequent etiologic agent in AAD in older adults is toxin-secreting Clostridium difficile
  • a pandemic among hospitalized people, especially in Western societies.
  • development of CDAD likely depends less on exposure and more on a lack of host defense mechanisms, namely, normal intestinal flora and barrier function.
  • Strategies for dealing with C. difficile colitis include treatment of active infection
  • Some bacterial probiotic organisms produce H2O2 and short-chain fatty acids which lower pH in the colon, acting to inhibit spore germination.
  • Some may also boost defense mechanisms such as IgA production, and work through competitive exclusion for available space and nutrients.
  • S. boulardii, a yeast strain not typically found in the human intestine but rather on the lychee fruit, produces a protease which destroys the intestinal receptor site for C. difficile toxin A.
  • only S boulardii was effective against CDAD in adults
  • probiotic yogurt drink containing L. casei and found a significant reduction in development of CDAD 
  • Only S. boulardii has data supporting efficacy for secondary prevention of CDAD when used in combination with oral vancomycin to treat the recurrent episode.
  • bacteria needs to be cleared by other mechanisms before benefit is seen from the probiotic.

11

Inflammatory Bowel Disease:
Probiotics that have shown promise in the treatment of ulcerative colitis

  • The combination of VSL#3 (four strains of lactobacilli, three strains of bifidobacteria, and one strain of Streptococcus salivarius subspecies thermophilus) plus balsalazide was slightly more effective than balsalazide or mesalazine alone
    • VSL#3 was more effective than placebo in maintaining remission when given in conjunction with steroid induction and mesalamine maintenance treatment.
  • Lactobacillus GG appeared to be more effective than standard treatment involving mesalazine in prolonging relapse-free time but did not influence relapse rates in patients with quiescent ulcerative colitis.
  • The combination of a prebiotic and a probiotic (Bifidobacterium longum) was associated with improvement in histologic scores and measures of immune activation
  • VSL#3 can induce a remission and improve disease activity in patients with mild/moderate active UC.

12

Inflammatory Bowel Disease:
Probiotics in the treatment of Crohn's disease

  • Clinical trials of probiotics in Crohn's disease have shown mixed results.
  • This may be due to heterogeneity among treatment populations, types and doses of probiotics used, differences in study design such as treatment duration, etc.

13

Inflammatory Bowel Disease:
Pouchitis (p.46)

  • Total proctocolectomy with ileal pouch anal anastamosis (IPAA)
    • the preferred method of surgical treatment for ulcerative colitis and familial polyposis, preserving bowel continuity and sphincter function, while eliminating almost all of the colorectal mucosa. T
    • he most common complication of this is acute and chronic inflammation of the ileal pouch, known as pouchitis
  • Pouchitis
    • mediated by a dysregulated inflammatory response to bacterial organisms in the small bowel without normal small bowel flow.
    • increased rates of fusobacter and Clostridium sp.
    • lack of streptococcal sp. Antibiotics are a mainstay of induction of remission.
  • Probiotics have been evaluated in several small studies for the maintenance of remission following induction by other methods.
    • VSL#3 15 vs 100% relapse rates after nine months of daily therapy
    • patients with antibiotic induced remission maintained on VSL#3 found that only 6 patients remained on the probiotic after 8 months due to remission or adverse effects in the rest.
    • In a group of patients with new IPAA given daily therapy for a year, the rate of development of pouchitis was only 10% compared to 40% for placebo.

14

Irritable bowel syndrome

  • All studies demonstrated only short-term outcomes with modest benefit.
  • probiotics are most beneficial in the diarrhea-predominant subset of IBS patients
  • efficacy for Bifidobacterium infantis
    • the probiotic may help reduce a proinflammatory state associated with IBS.
  • VLS#3,
    • supplement for IBS,
    • no significant difference in colonic transit compared with baseline.
    • However, abdominal bloating was significantly reduced in the probiotic group compared with placebo.
    • No changes in other abdominal symptoms such as pain, gas, or urgency were observed.

15

Probiotics for other conditions

  • Lactose intolerance
  • Hepatic encephalopathy
  • Necrotizing enterocolitis

  • Lactose intolerance
    • Ingestion of lactase-containing probiotics has the potential to aid lactose digestion in patients with lactose intolerance. 
  • Hepatic encephalopathy
    • Alteration of gut flora (either with probiotics or with prebiotics such as fermentable fiber) has been associated with improvement in hepatic encephalopathy in pilot studies.
    • Such therapy appears to lower blood ammonia concentrations, possibly by favoring colonization with acid-resistant, non-urease producing bacteria. 
  • Necrotizing enterocolitis
    • use of probiotics in the prevention of NEC in preterm infants.
    • significant reduction in severe NEC and mortality 

16

Probiotics in allergic/atopic diseases

  • Probiotics have the potential to reduce intestinal permeability and the generation of proinflammatory cytokines that are elevated in patients with a variety of allergic disorders. 
  • Lactobacillus paracasei-33
  • Lactobacillus rhamnosus GG 
  • A combination of Lactobacillus rhamnosus 19070-2 and Lactobacillus reuteri DSM 122460
  • mixture of L. rhamnosus GG, L. rhamnosus LC705, B. breve Bb99, and Propionibacterium freudenreichii

  • Probiotics have the potential to reduce intestinal permeability and the generation of proinflammatory cytokines that are elevated in patients with a variety of allergic disorders.
    • probiotics in allergic conditions including rhinitis, atopic dermatitis, and food allergy.
    • positive findings.
  • Lactobacillus paracasei-33
    • improvement in overall scores on a pediatric rhinoconjunctivitis quality of life questionnaire 
  • Lactobacillus rhamnosus GG
    •  frequency of atopic eczema significantly reduced in the children at two years of age 
  • A combination of Lactobacillus rhamnosus 19070-2 and Lactobacillus reuteri DSM 122460
    • to children with atopic dermatitis effective in improving dermatologic symptoms.
  • mixture of L. rhamnosus GG, L. rhamnosus LC705, B. breve Bb99, and Propionibacterium freudenreichii
    • Finnish infants at risk for allergic diseases
    • reduced odds ratio (0.49) of IgE-associated disease
    • augmentation was hypothesized to clear the intestinal lumen of antigens.

17

Future directions and conclusions

  • While the focus of medicine in the past had been on treatment of enteric pathogens without concern over the natural flora in the gut,
  • the emerging pandemic of Clostridium difficile colitis has awakened an awareness of the delicate natural homeostatic symbiotic balance maintained within the intestine.
    • There is increasing evidence that this homeostasis is important not only from the standpoint of competition for intestinal/host environment resources, but also for maintaining a healthy immune response and barrier function to intestinal pathogens.
    • What is even more interesting is the role the intestinal immune system plays in systemic allergic disorders,