Gerardus Kelleger GERARDUS PRESS
Read this first before using: Web side of see Gerardus press for details.
Notifications URGENT information
to read first, urgent
32495 converted by the media
The bible stories
32496 Aut Nihil
Aut Ceasar
32497 or just a simple flooding
Noah's ark
32498 The artificial created anti-Semitism
32499 proof later
Believing first
32500 or just faith.....
An addiction
32501 Bestowed upon us by God
The manner of love
32502 of all.....
The saviour
32503 Who is fooling who
The main question
32504 But who is doubtingh the creation
Some doubt
32505 will He return to us.....
2000 years ago
32506 The story of the Ukraine
Bandera the so admired killer in WW2 by the EU.
32507 With the devil on your side
Who can fail.....
32508 It grows.
Belief is like a tree
32509 I will presch........
Being the least of all saints
32510 The bibles answers
Who can.......
32511 Antique books.
Killing off a market
32512 A path for us.....
God has laid out
32513 You can move mountains.
If you belief
32514 without a church
Spreading the word
32515 On heaven and Earth
Praising the Lord
32516 or are they not?
Are they?
32517 Let us pray.....
When we say.....
32518 wrote those words?
Did Mordecai
32519 Without Jesus?
Would the Hebrew be known
32520 Any real proof of Jesus?
But is there any?
32521 a belief?
32522 Immunity
A system
32523 Revive thy work
Oh Lord
32524 What to do with him
A masn called Christ
32525 Spirits, deities and gods
first three pages
32526 Are the churches getting the hungry
To the table...
32527 Called Jesus.
What tyo do with a man
32528 The mediator
32529 Spirits, Deities, Gods
second part
32530 I should do.
What is it....
32531 It rules religion
32532 full of self control
See a man
32533 Spirits, Deitie, Gods
part four
32534 In the hand of God
We are sinners
32535 Are you?
Iam a Christian
32536 The microben
Human health
32537 Where is my strenght
Heavenly father
32538 Spirits, Deities, Gods
Part four
32539 He shall help us
Do not hesitate
32541 Microbal inflamation
Maladaption of the body
32542 of the feet
The washing.....
32543 Spitits, Deities, Gods
Part five
32544 from gopfor wood
Make yourself an ark
32545 What is life to you,
Our life,
32546 Use it well
Time is short,
32547 When old passes away
All becomes new
32548 Spirits, Deities, Gods
part Six
32549 His love will remove it.
32550 It stirs up your love
His love
32551 The holy spit works.
Through providence
32552 Hell for you.
Hell will be.....
32553 Spirits, Deities, Gods
part seven
32554 Rejoice.......
All the people......
32555 The killing of Floyd
The previous history of
32556 Language
streken Frysk
32557 Karaites
The story
32558 God
The concurend
32559 Atheist
Part two
32560 McCarthyism
A look in the past
32561 a view of God
The Western countries
32562 It's burning
The Negev....
32563 Anti-Semitism
The misuse
32564 The Karaites
Part 2
32565 Is Britian changing
Is it really?
32566 Part 3
The Karaites
32567 Britain
Slowly changing
32568 Sliding back?
The 30tier years
32569 Part 4
The Karaites
32570 non-Jews included
32571 in the past.
Back to the future
32572 Part 5
The karaites
32573 Or hit him with the sword
Shall I beat him with a whip
32574 Follow the first reason
To follow the rest

32536 The microben

The impact of the micro biota on human health is best exemplified by studies in IBD, such as Crohn's disease and ulcerative colitis. Both represent serious medical disorders marked by aberrant inflammation within the human gastrointestinal (GI) tract, resulting in severe clinical outcomes in affected patients. The causes for these diseases are complex, and include the contributions of genetic, geographic and habitual factors. IBD (particularly Crohn's disease) is generally thought to be driven by T lymphocytes.

The disease has classically been characterized by increases in pro-inflammatory cytokines such as tumour-necrosis factor (TNF) and interferon-γ (IFNγ). Recently, a new population of inflammatory T cells, termed T helper 17 (TH17) cells, have been implicated in the pathogenesis of human and experimental colitis. These cells are characterized by their expression of the pro-inflammatory cytokine interleukin-17 (IL-17), and require IL-23 for their maintenance and function. Specialized T cells, known as regulatory T cells act to counter-balance these pro-inflammatory responses. FOXP3 is a transcription factor believed to be the ‘master regulator’ of Treg cells, and its absence results in massive multi-organ lymphoproliferative disease.

The mechanisms by which Tregs are able to suppress inflammation are quite diverse. These include the expression of inhibitory cytokines such as IL-10, TGF-β, and IL-35; disruption of cellular metabolism by expression of the IL-2 receptor, CD25; cytolysis, and targeting the maturation of DCs through surface expression of molecules such as CTLA-4 and LAG-3. A population of intestinal dendritic cells expressing the surface antigen CD103 have recently been demonstrated to be instrumental in the development and function of intestinal Foxp3+ Tregs. CD103+ DCs, but not CD103− DCs are able to ‘convert’ CD4+Foxp3− T cells into CD4+Foxp3+ Tregs cells in a TGF-β and retinoic acid dependent manner, demonstrating that specialized mechanisms exist within the intestine to promote induction and maintenance of Tregs.

The importance of Tregs in regulation of intestinal homeostasis is best demonstrated by the ability of these cells to prevent induction of experimental colitis upon transfer into diseased hosts. The ability of Tregs to secrete IL-10 and IL-35 has been reported to be important during protection. Indeed, Treg cells deficient in either of the two subunits of IL-35 (Ebi3 and IL-12a), are unable to cure experimental colitis. Additionally, animals in which the anti-inflammatory cytokine IL-10 has been specifically ablated from CD4+FOXP3+ T cells succumb to inflammatory disease of the intestine (as well as skin and lung), but show no signs of autoimmunity. Thus, it appears that cytokine production by Treg cells may be a primary protective mechanism that limits uncontrolled immune responses at environmentally-exposed surfaces such as the gut.

Recent evidence has begun to reveal mechanisms of intestinal immune modulation by the micro biota. Germ-free animals are deficient in the development of TH17 cells in the small intestine. In this report, the reduction in IL-17 production is reciprocally coupled to an increase in CD4+FOXP3+ Treg cells in the germfree colon. Reconstitution of animals with a complex and diverse micro biota that does not contain the prominent phyla Bacteroidetes is unable to restore proper immune balance, suggesting that discrete organisms may have the capacity to modulate pro- and anti-inflammatory responses in the gut.

The identity of specific bacterial species and particular molecules with dedicated functions to regulate T-helper/TReg-cell profiles in the gut remain unknown. However, ‘general’ bacterial products appear to have immunomodulatory affects. ATP produced by intestinal bacteria specifically increases colonic IL-17 production (and not IFNγ production). Consistent, with this, germ-free animals have reduced IL-17 and ATP levels in the colon. Additionally, commensal bacterial DNA triggers TLR9 to confer resistance to the enteric parasite Encephalitozoon cuniculi.

 Antibiotic treatment of animals to eliminate gut bacteria results in increased susceptibility to infection by this parasite, consistent with findings from studies in germ-free mice. Treatment of infected animals with DNA extracted from the intestinal micro biota up-regulated Th1 and Th17 responses, while suppressing Treg activity resulting in decreased parasite burden. Previous work had implicated TLR signaling as being important for gut homeostasis; therefore these recent findings extend this observation to suggest that a molecular dialogue between immune receptors and microbial molecules confers resistance to enteric infection.

The contribution of the micro biota to the development of Tregcells remains unclear as multiple studies have revealed conflicting results. An earlier report demonstrated a deficiency in the percentage of Foxp3+ cells within the CD4+CD25+ subset within the MLNs of germfree mice when compared to conventionally colonized animals. Foxp3 mRNA levels were also lower in CD4+CD25+ isolated from total lymph nodes of germfree mice. Supporting this, another study reported lower expression of the Foxp3 transcript in CD4+CD62L− T cells from germfree mice.

 Additionally, studies have shown that Treg cells from germ-free animals were not as potent in suppressing CD4 T-cell proliferation in vitro as cells from conventionally colonized animals. Populations of TReg cells from germ-free animals expressed less IL-10, and were unable to prevent disease in a transfer model of experimental colitis. In contrast, recent studies have reported no change in the percentage of CD4+Foxp3+ subset of T cells within the colonic lamina propria, while yet another study reported elevated percentages of CD4+TCRβ+Foxp3+ within the small intestine.

These differences might be attributable to the specific subsets of TReg analyzed, differences in experimental methodologies and/or the tissues from which TReg were harvested. Alternatively, the particular diet given to the animal might influence Treg subsets within the intestine as most animal food, even if autoclaved, may have varying amounts of microbial molecules (such as TLR ligands). However, these data collectively suggest that intestinal bacteria interact with the mammalian immune system to direct the linage differentiation of both pro- and anti- inflammatory T-cell populations. Therefore, induction of effector T-cell responses and modulation of TReg -cell function by the micro biota may be a crucial component of diseases such as IBD. It is possible that different classes (or even species) of bacteria induce diverse immunological functions. Therefore, the equilibrium between inflammation and regulation in the gut may be due to the community structure of the micro biota.

IBD involves a shift from regulated intestinal immune responses to one that is driven by unrestrained immune-cell activation and pro-inflammatory cytokine production. The cause of this increase in immune stimulation is of great interest, and several lines of evidence indicate a significant role for commensally bacteria in the progression of disease. Patients with IBD respond favourably to antibiotic treatment and fecal diversion, and have greater antibody titters against indigenous bacteria than unaffected individuals. In addition, inflammatory lesions are more pronounced in areas of the intestine that contain the greatest number of bacteria. The data in animal models provide further evidence for the involvement of gut bacteria in IBD. Pre-treatment with antibiotics has been shown to alleviate intestinal inflammation in several animal models.

 HLA-B27-transgenic rats, interleukin-10 (IL-10)-and IL-2-deficient mice spontaneously develop chronic colitis, whereas germ-free animals of all backgrounds fail to develop intestinal inflammation. In a model of disease induced by the adoptive transfer of pathogenic T cells into immunodeficient (Scid−/− or Rag−/−) recipient mice, colonization of animals with intestinal pathogens such as Helicobacter hepaticus was found to exacerbate inflammation. Moreover, pathogenic T cells can be transmitted to healthy animals through the adoptive transfer of T cells that are reactive against specific commensally organisms.

 The only organism reported to be strongly associated with Crohn's disease is adherent-invasive E.coli (AIEC). However, it appears that inflammatory responses during human and experimental IBD are directed towards certain subsets of commensally organisms with pathogenic potential such as Helicobacter, Clostridium and Enterococcus species. Curiously, these organisms are abundant commensally, and not typically infectious pathogenic agents. As the micro biota of all mammals contains these potentially harmful species, known as pathobionts (commensalism with pathogenic potential), the reason why inflammation ensues only in subjects affected by IBD is not entirely known. Genetic factors play an important role in the pathogenesis of IBD.

This is demonstrated by familial aggregation of IBD and increased concordance for IBD in monozygotic twins. Genome wide association studies have identified genetic defects which are highly linked to disease. Mutations in bacterial sensing (NOD2/Card15) and T cell immunity (IL-23R) have highlighted the connection between microbes and inflammation in IBD. Additionally, experimental systems have demonstrated the importance of host genetics during induction of IBD.

Indeed, microorganisms such as E.coli and E. faecalis, that do not initiate disease in an immunologically competent host, do so when introduced into genetically pre-disposed strains. Some have predicted that IBD, at least in part, results from an imbalance in the normal micro biota (termed dysbiosis) without acquisition of an infectious agent. It remains unclear whether dysbiosis directly causes disease or is a result of the altered intestinal environment. Future studies using animal models whereby the micro biota can be selectively manipulated during the course of experimental disease may begin to address this important issue. However, genetic and habitual/lifestyle factors play a crucial role in maintaining health.


Text-only version of this page  |  Edit this page  |  Manage website  |  Website design: