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We read with interest the recent articles on obesity, inflammation
and Colorectal cancer (CRC).1,2,3 Although insulin resistance is the most
widely accepted underlying mechanism explaining the association between
obesity and CRC, recent evidence suggests that the effects of obesity on
the immune system in general and specifically on the gut may play a role.
We propose that obesity predisposes to CR...
We read with interest the recent articles on obesity, inflammation
and Colorectal cancer (CRC).1,2,3 Although insulin resistance is the most
widely accepted underlying mechanism explaining the association between
obesity and CRC, recent evidence suggests that the effects of obesity on
the immune system in general and specifically on the gut may play a role.
We propose that obesity predisposes to CRC through its effects on innate
immune activation (IIA) and a consequent sub-clinical bowel inflammation.
We further propose that the role of insulin resistance is either
complementary or might merely represent an epiphenomenon. Explained below
is the justification of our argument.
We recently studied the determinants of whole gut inflammation in a
normal middle-aged population by determining levels of calprotectin in
faeces. Calprotectin is a calcium binding protein found only in
neutrophils and monocytes. Levels in faeces correlate well with faecal
levels of indium labelled white cells and inflammatory bowel disease
activity. It is well established that many risk factors for CRC influence
levels of IIA in the healthy individual. Lack of physical exercise for
instance is associated with increased serum levels of C-reactive protein,
as are body mass index, smoking and increasing age.4 We confirmed that
faecal levels of calprotectin also correlated directly with increasing
age, obesity and, lack of physical activity and fibre intake,
demonstrating that these same environmental risk factors are also
associated with bowel inflammation.5, (fig 1)
The link between chronic inflammation and CRC is well documented in
patients with Ulcerative colitis. In our late middle aged population 25%
of subjects had elevated faecal levels of calprotectin similar to those
found in inflammatory bowel disease. Although these cancers follow a
different histological course as compared to sporadic CRC, similar genetic
mutations tend to occur with similar frequencies in both the groups
suggesting that sporadic CRC could arise or be promoted on a background of
chronic sub-clinical inflammation.6 Many other common cancers are
associated with chronic inflammation including oesophageal, gastric,
pancreatic and lung cancer. Furthermore, epidemiological studies have
demonstrated the chemoprophylactic benefits of non-steroidal anti-
inflammatory agents in colorectal and oesophageal cancers supporting the
role of chronic inflammation in their pathogenesis.
The association between obesity, chronic sub-clinical bowel
inflammation and ultimately CRC could result from the effects of obesity
to promote generalised innate immune activation or through paracrine
effects of mesenteric or serosal adipose tissue. The enlarged adipocytes
of the obese synthesise increased amounts of various pro-inflammatory
adipokines such as TNFα and IL-6, as well as other adipokines known
to modulate immune function such as leptin (pro-inflammatory) and
adiponectin (anti-inflammatory).7 Adipokines exert autocrine, paracrine or
endocrine effects influencing various metabolic and immune processes. Many
of these cytokines and adipokines contribute strongly to insulin
resistance, which may merely be an epiphenomenon of this activation rather
than playing a direct role in CRC pathogenesis. Elevated levels of pro-
inflammatory cytokines and reduced levels of adiponectin have been noted
in the serum of asymptomatic obese individual; levels corresponding to the
degree of obesity. 7 Circulating mononuclear cells from the obese have
been shown to exhibit increased NFκB nuclear binding with decreased
levels of NFκB inhibitor, together with increased mRNA expression of
IL-6, TNFα and migration inhibition factor. Furthermore there is a
good correlation between the markers of macrophage activation and plasma
levels of free fatty acids which represents an additional mechanism
whereby adipose tissue could influence systemic inflammatory activity.8
Central or abdominal obesity more strongly correlates with the risk of
colorectal cancer suggesting that the paracrine effects of mesenteric or
serosal fat may be important. The association between lack of physical
exercise and colorectal cancer can also be explained by an activated
immune state secondary to a decreased vagal tone in the physically unfit.9
IIA and chronic inflammation are characterized by chronic NFκB
activation which in turn promotes tumourogenesis by inhibiting apoptosis.3
These findings suggest that environmental factors could influence CRC
development through activation of the innate immune system and its effect
on promoting gut inflammation.
Pro-inflammatory mediators have been shown to increase gut
permeability and consequently exposure to luminal antigens. For example,
patients with histologically proven quiescent CD have increase gut
permeability, attributable to the heightened local expression of
TNFα.10 Treatment with infliximab (anti-TNFα agent) is
associated with decrease in gut permeability in patients with active CD.11
Although most of the evidence emerges from studies in disease groups,
similar mechanisms, albeit at a sub-clinical level may operate in normal
obese subjects. Besides the increased circulating levels of pro-
inflammatory mediators and free fatty acids associated with innate immune
activation the paracrine effects of adipokines secreted by mesenteric or
serosal fat could directly influence gut barrier function. Increased
exposure to luminal antigens will induce a local immune response resulting
in mucosal inflammation.
Epidemiological and cell culture studies have shown a correlation
between CRC, hyperinsulinemia and increased IGF-1 levels. Although insulin
has been shown to directly stimulate growth of colon cancer lines in
vitro, its role in initiating tumourogenesis is doubtful as it is known to
have anti-inflammatory properties. The role of IGF-1 as a pro-carcinogen
is much better established, acting by promoting cell growth and inhibiting
apoptosis. However, as mentioned by Freeza et al. recent studies have not
shown a significant correlation between CRC and IGF-1 levels when a
Bonferroni adjustment was applied.1 Insulin resistance furthermore may be
the result of the IIA associated with obesity. This calls for a need to
reconsider 'insulin resistance' as the underlying mechanism.
In conclusion, IIA could be the link between environmental risk
factors and CRC. Processes secondary to IIA such as chronic gut
inflammation and insulin resistance promote tumourogenesis. We propose
that gut inflammation is the dominant mechanism responsible for the
increased incidence of CRC in the obese and believe that the role of
insulin resistance could represent an epiphenomenon. Further research in
this direction is warranted.
References
1. Frezza EE, Wachtel MS, Chiriva-Internati M. Influence of obesity
on the risk of developing colon cancer. Gut 2006;55(2): 285-91.
2. Hall NR. Survival in colorectal cancer: impact of body mass and
exercise. Gut 2006; 55(1):8-10.
3. Boland CR, Luciani MG, Gasche C, Goel A. Infection, inflammation,
and gastrointestinal cancer. Gut 2005;54(9):1321-31.
4. Mendall MA, Strachan DP, Butland BK, Ballam L, Morris J, Sweetnam
PM, Elwood PC. C-reactive protein: relation to total mortality,
cardiovascular mortality and cardiovascular risk factors in men. Eur Heart
J. 2000;21(19):1584-90.
5. Poullis A, Foster R, Shetty A, Fagerhol MK, Mendall MA. Bowel
inflammation as measured by fecal calprotectin: a link between lifestyle
factors and colorectal cancer risk. Cancer Epidemiol Biomarkers Prev.
2004;13(2):279-84.
6. Clevers H. At the crossroads of inflammation and cancer. Cell
2004;118:671-674.
7. Kershaw EE, Flier JS. Adipose Tissue as an Endocrine Organ. The J
Clin Endoc & Metab 2004;89(6):2548-2556.
8. Ghanim H, Aljada A, Hofmeyer D, Syed T, Mohanty P, Dandona P.
Circulating mononuclear cells in the obese are in a proinflammatory state.
Circulation 2004;110(12):1564-71.
9. Pavlov VA, Tracey KJ. The cholinergic anti-inflammatory pathway.
Brain Behav Immun 2005;19(6):493-9.
10. Soderholm JD, Streutker C, Yang PC, Paterson C, Singh PK, McKay
DM, Sherman PM, Croitoru K, Perdue MH. Increased epithelial uptake of
protein antigens in the ileum of Crohn's disease mediated by tumour
necrosis factor alpha. Gut 2004;53(12):1817-24.
11. Suenaert P, Bulteel V, Lemmens L, Noman M, Geypens B, Van Assche
G, Geboes K, Ceuppens JL, Rutgeerts P. Anti-tumor necrosis factor
treatment restores the gut barrier in Crohn's disease. Am J Gastroenterol
2002;97(8):2000-4.
Fig.1 Relationships between age, body mass index, physical activity, and fiber intake with fecal calprotectin geometric mean; bars, ±1 SE (Y axis logarithmic scale). Age quartiles 1 = 50–54, 2 = 55–59, 3 = 60–64, and 4 = 65–70. Body mass index quartiles 1 = 17.6–23.5, 2 = 23.6–25.6, 3 = 25.7–28.1, and 4 = 28.2–41.2. Fiber quartiles (%) 1 <9.8, 2 = 10–13.9, 3 = 14–16.7, and 4 = 17–38.8. 5
Cyclosporine (CsA) is an established treatment in severe, intravenous-
corticosteroid-resistant ulcerative colitis (UC). Although one third of UC
patients relapse during pregnancy, experience with CsA use during this
period is limited to a few case reports.[1][2] Most of the available data
on CsA administration and pregnancy outcome have been obtained from the
transplantation literature.[3] We read the...
Cyclosporine (CsA) is an established treatment in severe, intravenous-
corticosteroid-resistant ulcerative colitis (UC). Although one third of UC
patients relapse during pregnancy, experience with CsA use during this
period is limited to a few case reports.[1][2] Most of the available data
on CsA administration and pregnancy outcome have been obtained from the
transplantation literature.[3] We read the letter of Jayaprakash et al.
who described the case of a patient with fulminant corticosteroid-resistant distal UC successfully treated with CyA and delivering a healthy
baby.[2]
Herein we report the dramatic case of a 21-year-old primigravida
with the diagnosis of UC since April 2000 who experienced a fulminant
flare at the end of her first trimester despite immunosuppressive
treatment and whose pregnancy could only be preserved by i.v. CsA therapy.
At time of conception in June 2003 the patient was in stable clinical
remission, receiving 40mg/d of thioguanine, 2g/d of mesalamine and 50mg/d
of sertraline due to chronic active disease resistant to azathioprine. In
the 13th gestational week the patient was admitted to hospital because of
a fulminant relapse of ulcerative colitis despite 50 mg oral steroids
which had been self-administered for 1 week. At admission laboratory tests
showed C-reactive protein level of 9.36mg/dl and hemoglobin of 8.9g/dl.
Thioguanine was discontiunued and after the patient had failed to respond
to intravenous prednisolone at a dose of 75 mg for 9 days abortion was
discussed but declined by the patient. Therefore intravenous cyclosporine
at a dosage of 2mg/kg/d was started. Careful monitoring of creatinine and
serum CsA levels leading to levels of 200-300 ng/ml was done and repeated
sonography of the foetus was performed. Erythrocyte concentrates were
required due to progressive anemia. Induction of response was delayed
resulting in an unusual long term CsA treatment period of 3 weeks. The
symptoms of UC improved, CyA was switched to oral administration (100mg
b.i.d.) and the patient was discharged after 5 weeks, although complete
remission was never achieved. Besides the occurrence of hypertrichosis CsA
was well tolerated by the patient. In the 29th gestational week, a
cesarean section was necessary because of premature rupture of fetal
membranes and growth retardation. The patient delivered a female baby with
a birth weight of 893g and a length of 35 cm (APGAR: 9/10/10). Typical
problems of preterm births such as respiratory distress syndrome, acute
enterocolitis necroticans, sepsis and anemia were successfully handeled at
the ICU and the girl had a normal growth and development further on.
Echocardiography detected a peripheral pulmonary artery stenosis and a
small ASD II which regressed and spontaneously occluded after 10 months of
birth, respectively. Two small hemangiomas on the head and back were also
found but became smaller in size. After discontinuation of cyclosporine
postpartum symptoms of UC deteriorated the mother’s condition beyond
control by conservative measures. Colectomy with ileostomy was performed
in June 2004. Currently the patient is pregnant again, and mother and
foetus are in good health.
While standard medication like 5-ASA, azathioprine / 6-mercaptopurine, and
corticosteroids are considered to be safe in the treatment of ulcerative
colitis during pregnancy, administration of CsA is discussed
controversially. Intravenous CsA considerably improved symptoms of UC in
our patient without major toxicity. The premature delivery with all its
consequences could be related to deterioration of UC or CsA therapy, as
both reported in literature, whereas the role of thioguanine still remains
unclear. However, due to CsA treatment the pregnancy could be prolonged
and the foetus reached a gestational age which allowed an alive delivery.
Acute colectomy, which is associated with a tremendous maternal and fetal
risk, could be avoided.[4] On account of this positive experience and the
available data so far we believe that CsA treatment should be considered
as last medical resort to prevent medical abortion in fulminant UC during
pregnancy.
References
1 Bertschinger P, Himmelmann A, Risti B, et al. Cyclosporine
treatment of severe ulcerative colitis during pregnancy. Am J
Gastroenterol 1995;90(2):330.
2 Jayaprakash A, Gould S, Lim AG, et al. Use of cyclosporin in
pregnancy. Gut 2004;53(9):1386-7.
3 Armenti VT, Ahlswede KM, Ahlswede BA, et al. National
transplantation Pregnancy Registry--outcomes of 154 pregnancies in
cyclosporine-treated female kidney transplant recipients. Transplantation
1994;57(4):502-6.
4 Willoughby CP, Truelove SC. Ulcerative colitis and pregnancy. Gut
1980;21(6):469-74.
Approximately 4% of the H. pylori genome, significantly more than
that of any other known bacterial species is composed of genes encoding
outer membrane proteins (OMPs). The best described H. pylori OMP is the
adhesin BabA, which is thought to mediate host/bacterial interactions and
has been linked to microbial pathogenicity (1-4). The dissection of OMP
function helps understanding the complex gastri...
Approximately 4% of the H. pylori genome, significantly more than
that of any other known bacterial species is composed of genes encoding
outer membrane proteins (OMPs). The best described H. pylori OMP is the
adhesin BabA, which is thought to mediate host/bacterial interactions and
has been linked to microbial pathogenicity (1-4). The dissection of OMP
function helps understanding the complex gastric biology of infection and
may offer a possibility to identify persons with an increased risk for
disease development.
In an interesting and comprehensive study, Yoshio Yamaoka and co-workers analyzed expression of several outer membrane proteins (BabA, BabB, SabA, OipA) in a large number of H. pylori strains and described
their association with gastroduodenal diseases (Yamaoka Y, Gut, Dec 1,
2005). One important finding was the strong linkage of OipA expression
with the cag pathogenicity island (cagPAI), a major H. pylori virulence
factor. The authors showed that in 94% of Columbian and U.S. H. pylori
strains, CagA and OipA phenotypes are identical.
OipA expression is regulated by slipped strand mispairing based on
the number of CT dinucleotide repeats in the 5´ region of the gene. We
sequenced this genetic region of H. pylori strains from 53 German patients
with chronic gastritis and further determined the presence of the cagPAI
marker gene cagA, as described previously (3;5). Similarly to Yamaoka and
colleagues, we found linked expression of CagA and OipA in our European
strain population, with 83% concordance (Figure 1A). The reason for this
strong association is not understood. However, as there is no obvious
common genetic mechanism controlling expression of the two genes, linkage
of cagA and oipA seems to be based on selection in the host. Indeed, it
has been demonstrated that H. pylori is capable to regulate OMP expression
in vivo by phase variation as a mechanism of adaptation to changing
environmental conditions (2). It is thus conceivable that OipA offers a
selective advantage for cagPAI-positive bacteria that may for example
prefer a gastric microenvironment in which OipA expression is beneficial.
The influence of OipA on proinflammatory signalling has been
discussed controversially (5-9). To investigate whether OipA is directly
linked to pathogenesis, we performed mutagensis of the oipA and cagE genes
for functional investigations in vitro. As shown in figure 1B, incubation
of the cagA+/oipA+ strain B128 with KATO-III gastric epithelial cells
leads to increased expression of IL-8, a signature chemokine of gastric
inflammation. Whereas the isogenic oipA-knockout strain induces IL-8
expression to a similar extent, the cagE-deficient strain, which lacks a
functional cagPAI, is severily impaired in its IL-8 inducing capacity.
Despite using varying concentrations of bacteria (MOI 1-100), different
cell lines and several independent oipA mutants of the H. pylori strains
B128 and G27, we could not detect an influence of OipA on IL-8
expression/secretion (not shown). Similarly, we found no independent
influence of OipA on gastric IL-8 expression and inflammation in vivo. As
shown in figure 1C, IL-8 expression was higher in the mucosa of patients
infected with cagA-positive strains than in patients infected with cagA-
negative strains. However, in both groups chemokine expression was
independent of the oipA status.
Bacterial OMPs have multiple functions, e.g. as adhesins, porins, or
play a role in complement resistance and immune regulation. Although
several studies investigated the physiological role of OipA (5-9), its
precise function is still not fully clear. The strong linkage with the
cagPAI however, suggests that differential regulation of OipA expression
by phase variation may contribute to the fitness of cagPAI-positive or -
negative strains in vivo. This idea is supported by the finding that oipA-
mutated cagPAI-positive H. pylori strains are impaired in their ability to
colonize mongolian gerbils (9).
Anar Dossumbekova*, Christian Prinz*, Markus Gerhard*, Lena Brenner*,
Steffen Backert#, Johannes G Kusters&, Roland M Schmid*, Roland Rad*
*2nd Department of Internal Medicine and Gastroenterology
Technical
University of Munich
81675 Munich
Germany
#Institue of Medical Microbiology
Otto-von-Guericke-Universität
Magdeburg
Germany
&Department of Gastroenterology and Hepatology
Erasmus MC-University
Medical Centre
Rotterdam
The Netherlands
References
(1) Aspholm-Hurtig M, Dailide G, Lahmann M et al. Functional
adaptation of BabA, the H. pylori ABO blood group antigen binding adhesin.
Science 2004;305(5683):519-22.
(2) Solnick JV, Hansen LM, Salama NR et al. Modification of
Helicobacter pylori outer membrane protein expression during experimental
infection of rhesus macaques. Proc Natl Acad Sci U S A 2004;101(7):2106-
11.
(3) Rad R, Gerhard M, Lang R et al. The Helicobacter pylori blood
group antigen-binding adhesin facilitates bacterial colonization and
augments a nonspecific immune response. J Immunol 2002;168(6):3033-41.
(4) Prinz C, Schoniger M, Rad R et al. Key importance of the
Helicobacter pylori adherence factor blood group antigen binding adhesin
during chronic gastric inflammation. Cancer Res 2001;61(5):1903-9.
(5) Yamaoka Y, Kwon DH, Graham DY. A M(r) 34,000 proinflammatory
outer membrane protein (oipA) of Helicobacter pylori. Proc Natl Acad Sci U
S A 2000;97(13):7533-8.
(6) Ando T, Peek RM, Jr., Blaser MJ. Host cell responses to
genotypically similar Helicobacter pylori isolates from United States and
Japan. Clin Diagn Lab Immunol 2002;9(1):167-75.
(7) Odenbreit S, Kavermann H, Puls J et al. CagA tyrosine
phosphorylation and interleukin-8 induction by Helicobacter pylori are
independent from alpAB, HopZ and bab group outer membrane proteins. Int J
Med Microbiol 2002;292(3-4):257-66.
(8) Yamaoka Y, Kikuchi S, el-Zimaity HM et al. Importance of
Helicobacter pylori oipA in clinical presentation, gastric inflammation,
and mucosal interleukin 8 production. Gastroenterology 2002;123(2):414-24.
(9) Akanuma M, Maeda S, Ogura K et al. The evaluation of putative
virulence factors of Helicobacter pylori for gastroduodenal disease by use
of a short-term Mongolian gerbil infection model. J Infect Dis
2002;185(3):341-7.
(10) de Jonge R, Durrani Z, Rijpkema SG et al. Role of the
Helicobacter pylori outer-membrane proteins AlpA and AlpB in colonization
of the guinea pig stomach. J Med Microbiol 2004;53(Pt 5):375-9.
Figure 1: Influence of OipA and the cagPAI on IL-8 expression in
vitro and in vivo. (A) Genetic characterization of H. pylori strains from
53 patients according to the cagA and oipA status. The cagA gene was
detected by PCR as described previously (3). The oipA status was
determined after sequencing of the 5´region of the gene. The "on" or "off"
status depends on the number of CT dinucleotide repeats that render the
gene in or out of frame. In 83% of strains, the cagA and oipA status
identical. (B) IL-8 expression in gastric cancer cell line KATO-III after
incubation with the H. pylori strain B128 and its isogenic oipA and cagE
mutant strains at an MOI of 50. Bacterial mutagenesis was performed as
described previously (10). Cytokine expression was analyzed by real-time
RT-PCR and normalized to GAPDH expression, as described previously (3).
Bars indicate the arithmetic mean and SEM from five samples per group.
Shown is one out of 10 similar experiments. (C) IL-8 expression in the
gastric mucosa of the 53 patients infected with the H. pylori strain types
shown in (A). Statistically significant differences were found between any
cagA- and cagA+ group (p<0,05, Student´s t-test). In contrast, there
was no significant independent association of the oipA-on status with
increased IL-8 expression.
We read with interest the well constructed and stimulating review on
ghrelin that was recently published in Gut (1). Indeed, the scenario of
the hormones and peptides involved in the control of gastrointestinal
function, from the point of view of motility or secretion, is getting
every year more complicated, with new “players” entering the field (2,3).
Ghrelin in particular, making part of the same...
We read with interest the well constructed and stimulating review on
ghrelin that was recently published in Gut (1). Indeed, the scenario of
the hormones and peptides involved in the control of gastrointestinal
function, from the point of view of motility or secretion, is getting
every year more complicated, with new “players” entering the field (2,3).
Ghrelin in particular, making part of the same family of motilin and
growth hormone secretagogue receptor, most represented in the stomach,
despite having been identified by Kojima and co-workers in 1999, who later
has summarized what is known on the peptide (4,5), still awaits a thorough
description of its function and controversial data have been published on
some aspects.
Probably the most important role of Ghrelin is the orexigenic signal (6,7) but our interest on Ghrelin was raised, in the context of a study aimed
at re-evaluating gastric enterochromaffin-like cell (ECL) hyperplasia, by
having found a paper reporting a correlation between ECL hyperplasia and
increased ghrelin levels (8). As previously mentioned and as stated by
Peeters (1), few studies have addressed the role of Ghrelin in the control
of acid secretion and the results obtained are not clear-cut, with
inhibition, stimulation or no effect at all having been reported (9,10,11). For this reason we decided to include the peptide among the
parameters investigated in our study and we thought it could be of
interest to report the data we obtained, in order to further stimulate the
discussion on the topic.
Our experience is based on an investigation of 62 patients with ECL
hyperplasia and or gastric carcinoid (no. 6), 26 of whom with auto-immune
gastritis and 30 without, whose overall results will be reported when
completed. In our study, Ghrelin plasma fasting levels (Ghrelin total RIA
kit, GHRT-89HK, Linco Research, Inc., Missouri USA) were, as opposite to
what expected, significantly lower than those observed in a group of
controls (patients lacking any significant gastric mucosa change) included
in the study. Also, no correlation was found between the peptide levels
and the severity of ECL hyperplasia (linear, micronodular, nodular,
adenomatoid, carcinoid) or with the degree of atrophy. Additionally, in
patients with auto-immune gastritis, Ghrelin was significantly and
directly correlated with total gastrin levels and inversely with PGI and
PGI/PGII ratio. Finally a significant correlation was detected with plasma
histamine levels. These data were confirmed both when plain Ghrelin levels
and those corrected for BMI were used.
How can these data fit within the complex network described by Peeters and
the authors quoted in his review? The first consideration to do is that it
is difficult not to conceive an involvement in the feed-back mechanisms of
gastric secretion for a peptide whose levels are strictly correlated with
the hormone that regulates gastric function. This is supported also by the
correlation with histamine, whose release is induced by gastrin in gastric
ECL cells (12). Which could be the role of ghrelin? Since no effect, in
cell culture, on D cells, G cells or ECL cells has been demonstrated, a
part in the endocrine control had been excluded. Others, however, reported
a stimulation of acid secretion following ghrelin administration, possibly
due an activation of the vagal pathway and even a ghrelin capacity of
stimulating gastrin release, again via a vagal stimulation, has been
indeed suggested (13,14,15).
In our experimental setting however, the conditions were not physiologic.
In a similar pathologic scenario, a paper by Schenk and co-workers (16)
described a reduced, albeit not-significantly so, vagal nerve function, a
fact that stands against the possibility of a vagal stimulation and this
has been also supported by a recent paper by Chen (17) that deny any
influence by ghrelin on vagal pathway. It is still to be assessed
therefore whether a vagal stimulation occurring due to hypochloridria and
hypergastrinemia could be responsible for the increased Ghrelin levels we
documented.
Even more difficult to explain is the inverse correlation with PGI and
PGI/PGII ratio (that testifies of the integrity/atrophy of the gastric
body and fundic mucosa). Since ghrelin and PGI are secreted by cells
positioned in the glands of the same part of the stomach (i.e. the body-fundic area), one would expect to see them both reduced in auto-immune
atrophic gastritis. The inverse correlation observed therefore is
intriguing, even though it might only represent a spurious and surrogate
correlation with increased gastrin, given the well known inverse
correlation between gastrin and PGI levels in auto-immune gastritis.
The model involved in our study obviously does not allow any direct
inference on the physiologic role of Ghrelin but, as previously reported,
sound inferences are hardly obtained even in very elegant physiology
studies (1,18). Whatever the results obtained so far, as Peeters
correctly underlined, the role of Ghrelin in normal, physiologic
conditions as well as in the various diseases of the stomach (H.pylori-
related or not), that are characterized either by impairment or by up-
regulation of the feed-back mechanisms of gastric function, are eagerly
awaited.
References
1. Peeters TL. Ghrelin in the control of gastrointestinal functions. Gut
2005;54;1638-1649.
2. R.G. Smith et al. A nonpeptidyl growth hormone secretagogue. Science
260, 1640-1643 (1993).
3. Tomasetto C, Karam SM, Ribieras S, Masson R, Lefebvre O, Staub A,
Alexander G, Chenard MP, Rio MC. Identification and characterization of a
novel gastric peptide hormone: the motilin-related peptide.
Gastroenterology. 2000 Aug;119(2):395-405.
4. Kojima M, Hosoda H, Date Y, Nakazato M, Matsuo H, Kangawa K. Ghrelin is
a growth-hormone-releasing acylated peptide from stomach. Nature. 1999 Dec
9;402(6762):656-60.
5. Kojima M, Kangawa K. Ghrelin: structure and function. Physiol Rev. 2005
Apr;85(2):495-522.
6. Shintani M, Ogawa Y, Ebihara K, Aizawa-Abe M, Miyanaga F, Takaya K,
Hayashi T, Inoue G, Hosoda K, Kojima M, Kangawa K, Nakao K. Ghrelin, an
endogenous growth hormone secretagogue, is a novel orexigenic peptide that
antagonizes leptin action through the activation of hypothalamic
neuropeptide Y/Y1 receptor pathway. Diabetes. 2001 Feb;50(2):227-32.
7. Chen HY, Trumbauer ME, Chen AS, Weingarth DT, Adams JR, Frazier EG,
Shen Z, Marsh DJ, Feighner SD, Guan XM, Ye Z, Nargund RP, Smith RG, Van
der Ploeg LH, Howard AD, MacNeil DJ, Qian S. Orexigenic action of
peripheral ghrelin is mediated by neuropeptide Y and agouti-related
protein. Endocrinology. 2004 Jun;145(6):2607-12. Epub 2004 Feb 12.
8. Srivastava A, Kamath A, Barry SA, Dayal Y. Ghrelin expression in
hyperplastic and neoplastic proliferations of the enterochromaffin-like
(ECL) cells. Endocr Pathol. 2004 Spring;15(1):47-54
9. Sibilia V, Muccioli G, Deghenghi R, Pagani F, De Luca V, Rapetti D,
Locatelli V, Netti C. Evidence for a Role of the GHS-R Receptors in
Ghrelin Inhibition of Gastric Acid Secretion in the Rat. J
Neuroendocrinol. 2006 Feb;18(2):122-8.
10. Levin F, Edholm T, Ehrstrom M, Wallin B, Schmidt PT, Kirchgessner AM,
Hilsted LM, Hellstrom PM, Naslund E. Effect of peripherally administered
ghrelin on gastric emptying and acid secretion in the rat. Regul Pept.
2005 Nov;131(1-3):59-65
11. Dornonville de la Cour C, Lindstrom E, Narlen P, et al. Ghrelin
stimulatesb gastric emtying but is without effect on acid secretion and
gastric endocrine cells. Regul Pept 2004; 120: 23-32.
12. C. Prinz, R Zanner, M. Gerhard, S. Mahr, N. Neumayer, B. Hohne-Zell e
M. Gratzl The mechanism of histamine secretion from gastric
enterochromaffin-like cells. American Journal of Physiology – Cell
Physiology, 1999; 277 (5): 845-855.
13. Masuda Y, Tanaka T, Inomata N, Ohnuma N, Tanaka S, Itoh Z, Hosoda H,
Kojima M, Kangawa K. Ghrelin stimulates gastric acid secretion and
motility in rats.
Biochem Biophys Res Commun. 2000 Oct 5;276(3):905-8
14. Simonian HP, Kresge KM, Boden GH, Parkman HP. Differential effects of
sham feeding and meal ingestion on ghrelin and pancreatic polypeptide
levels: evidence for vagal efferent stimulation mediating ghrelin release.
Neurogastroenterol Motil. 2005 Jun;17(3):348-54.
15. Lee H.M., Wang G, Englander E.W. et al. Ghrelin, a new
gastrointestinal endocrine peptide that stimulates insulin secretion:
enteric distribution, ontogeny, influence of endocrine, and dietary
manipulations. Endocrinology 2002; 143: 185-190
16. B.E. Schenk, E.J. Kuipers, E.C. Klinkenberg-Knol, E. Bloemena, G.F.
Nelis, H.P.M. Festen, E.H. Jansen; I. Biemond, C.B.H.W. Lamers e S.G.M.
Meuwissen Hypegastrinemia during long-term omeprazole therapy: influences
of vagal nerve function, gastric emptying and Helicobacter pylori
infection Aliment Pharmacol Ther 1998; 12: 605-
17. Chen CY, Inui A, Asakawa A, Fujino K, Kato I, Chen CC, Ueno N,
Fujimiya M. Des-acyl ghrelin acts by CRF type 2 receptors to disrupt
fasted stomach motility in conscious rats. Gastroenterology, 2005 Jul; 129
(1): 8-25.
18. Locatelli V, Bresciani E, Bulgarelli I, Rapetti D, Torsello A, Rindi
G, Sibilia V, Netti C. Ghrelin in gastroenteric pathophysiology. J
Endocrinol Invest. 2005 Oct;28(9):843-8. Review
Effectively, the biopsies of the gastric mucosa revealed H. Pylori and had
been eradicated. But our patient did not improve. It is interresting to
look the relation between Menetrier's disease and H Pylori in a multicentric prospective study.
Elliott et al. (Gut 2005; 54: 1818-19) present an interesting
and clinically useful finding of successful treatment of a patient with
severe Crohn’s disease and circumferential narrowing of the ileo-colonic
anastomosis treated with 750 mg ciprofloxacin plus 400mg metronidazole
daily for almost three years, resulting in complete healing and opening up of
the stenosed anastomosis.
Elliott et al. (Gut 2005; 54: 1818-19) present an interesting
and clinically useful finding of successful treatment of a patient with
severe Crohn’s disease and circumferential narrowing of the ileo-colonic
anastomosis treated with 750 mg ciprofloxacin plus 400mg metronidazole
daily for almost three years, resulting in complete healing and opening up of
the stenosed anastomosis.
The authors list a number of bacterial species known to be
susceptible to these antibiotics. However, they have omitted perhaps the
most important potential pathogen, Mycobacterium avium ss paratuberculosis
(MAP), the leading candidate causal agent of Crohn’s disease[1,2]. It is
well known that ciprofloxacin exhibits marked activity against
Mycobacterium avium[3]. It is also known that metronidazole can be
bactericidal against dormant M. tuberculosis in anaerobic conditions[4].
Although no such data are yet available concerning other mycobacteria, the
role of metronidazole in affecting M. avium ss. paratuberculosis cannot be
excluded, when these bacteria persisted in anaerobic conditions. It is
indeed very unlikely that the success of metronidazole/ciprofloxacin
combination had much to do with luminal flora bacteria, but more likely,
it treated indolent tissue MAP, which may explain the need for prolonged
therapy. We can be even more certain that luminal flora was not the only
target of these antibiotics, especially ciprofloxacin, because more than
10 prolonged trials of various combinations of anti-tuberculosis
antibiotics were inactive against MAP, were active against luminal flora
bacteria, yet still failed to improve the outcome of Crohn’s disease[5]. On
the other hand, in our experience[6] with specific anti-MAP treatment, we
have reported five patients whose terminal ileal strictures returned to
normal, an indication that prolonged, targeted anti-microbial therapy is
necessary to inhibit tissue MAP and its consequent inflammation and
oedema[6].
In retrospect it was difficult to accept that a chronic infection
with a previously poorly-known organism could cause such widespread gastro
-duodenal disease. In the pre-Helicobacter era bismuth was thought to
“chelate with protein at an acid pH...may stimulate release of mucus”[7,8]
when actually it was acting via a completely different mechanism,
inhibiting growth of Helicobacter pylori. Similarly, in this case report
one could initially postulate that metronidazole+ciprofloxacin exerts its
effect by inhibiting local bowel flora. On closer examination it becomes
more plausible that data presented in this case report supports
involvement of MAP in causation of inflammation, oedema and stenosis in
Crohn’s disease and that prolonged anti-MAP treatment can progressively
reduce inflammation.
References
1. Bull TJ, McMinn EJ, Sidi-Boumedine K, et al. Detection and verification
of Mycobacterium avium subsp. paratuberculosis in fresh ileocolonic
mucosal biopsy specimens from individuals with and without Crohn’s
disease. J Clin Microbiol 2003; 41: 2915-23.
2. Naser SA, Ghobrial G, Romero C, Valentine JF. Culture of Mycobacterium
avium subspecies paratuberculosis from the blood of patients with Crohn’s
disease. Lancet 2004; 364: 1039-44.
3. Heifets LB, Lindholm-Levy PJ. Bacteriostatic and bactericidal activity
of ciprofloxacin and ofloxacin against Mycobacterium tuberculosis and
Mycobacterium avium complex. Tubercle 1987; 68: 267-76.
4. Wayne LG, Sramek HA. Metronidazole is bactericidal to dormant cells of
Mycobacterium tuberculosis. Antimicrob Agents Chemother 1994; 38: 2054-8.
5. Greenstein RJ. Is Crohn’s disease caused by a mycobacterium?
Comparisons with leprosy, tuberculosis and Johne’s disease. Lancet Infect
Dis 2003; 3: 507-14.
6. Borody TJ, Leis S, Warren EF, Surace R. Treatment of severe Crohn’s
disease using antimycobacterial triple therapy – approaching a cure? Dig
Liver Dis 2002; 34: 9-12.
7. Salmon P, Brown P, Williams R, Read A. Evaluation of colloidal bismuth
(TDB) in treatment of duodenal ulcers employing endoscopic selection and
followup. Gut 1974; 15: 189-93
8. Jagu J. Bismuth in medicine. Bull Bismuth Inst 1971; 2:1.
The Editor’s quiz in Novembers Gut featured a most interesting
presentation of Ménétrier’s disease (hypertrophic protein losing
gastropathy). There is a recognised association between Ménétriers disease
and infection with Helicobacter pylori. In two retrospective studies
between 30% and 90% of patients with Ménétriers disease were associated
with H pylori1-4. Furthermore, Bayerdörffer et al reported...
The Editor’s quiz in Novembers Gut featured a most interesting
presentation of Ménétrier’s disease (hypertrophic protein losing
gastropathy). There is a recognised association between Ménétriers disease
and infection with Helicobacter pylori. In two retrospective studies
between 30% and 90% of patients with Ménétriers disease were associated
with H pylori1-4. Furthermore, Bayerdörffer et al reported marked
improvement of the condition following eradication of H pylori. Is it
possible that the reported case in the Editor’s Quiz was colonised with H
pylori and if so, would the patient benefit from eradication therapy?
Dr G Sisson; Dr A W Harris
Department of Gastroenterology
Kent and Sussex Hospital, Tunbridge Wells, Kent TN4 8AT.
References
1.Wolfsen HC, Herschel A, Carpenter A, et al. Ménétrier’s disease: A
form of hypertrophic gastropathy of gastritis. Gastroenterology
1993;104:1310-1319
2.Bayerdörffer E, Ritter MM, Hatz R et al. Ménétrier’s disease and
Helicobacter pylori. NEJM 1993;Jul:60
3.Herz R, Lombardi E, Wipping F, et al. Helicobacter pylori-
associated hypertrophic gastritis. Imitation of Ménétrier’s disease.
Fortschr-Med 1992;110(4):37-40
4.Lepore MJ, Smith FB, Bonanno CA, Campylobacter-like organisms in
patients with Ménétrier’s disease. Lancet 1988:466
I read with interest the article by Hui et al. reporting hepatitis B reactivation after withdrawal of pre-emptive lamivudine in patients with hematological malignancy on
completion of cytotoxic chemotherapy.[1] Reactivation of hepatitis B virus (HBV) infection is a well-recognized complication of chemo/immunosuppressive therapy in
HBs-Ag positive inactive carriers.[2][3] It occurs in 14% to 50% of such in...
I read with interest the article by Hui et al. reporting hepatitis B reactivation after withdrawal of pre-emptive lamivudine in patients with hematological malignancy on
completion of cytotoxic chemotherapy.[1] Reactivation of hepatitis B virus (HBV) infection is a well-recognized complication of chemo/immunosuppressive therapy in
HBs-Ag positive inactive carriers.[2][3] It occurs in 14% to 50% of such individuals.[2][3]
Several investigators have examined the efficacy and tolerability of lamivudine therapy as a prophylactic agent preventing HBV reactivation in inactive HBV carriers
with hemato/oncological malignancies who receive chemotherapy.[4][5][6] The principal aims of these studies have been 1) to determine the effect of lamivudine prophylaxis on the rate of HBV reactivation in such individuals, and 2) to define the safety and
duration of lamivudine prophylaxis in these cases. Based on the results of these studies, current investigators have
drawn the following conclusions: First, lamivudine prophylaxis prevents hemotherapyinduced
HBV reactivation in these cases. Second, lamivudine is safe and tolerable in such individuals.[4][5][6]
There are no clear data in the literature to indicate how long prophylactic lamivudine therapy should be continued in HBV carriers with hemato/oncological
malignancy who will receive chemotherapy. Lamivudine produces a rapid reduction in HBV replication within
days to weeks of its initiation in immunocompetent individuals with chronic HBV infection.[7] In immunocompetents, long-term (> than 1 year) antiviral therapy is required to eradicate HBV infection because of the high rate of HBV replication (plasma half-life of HBV, 24 hours) and the relatively slow turnover rate of HBV-infected hepatocytes (half life, 10-100 days). In immunosuppressive subjects, several investigators have suggested that the duration of lamivudine treatment in cases with inactive HBV infection receiving hemo/immunosuppressive therapy should continue for at least six months following the last dose of therapy.[4][5][6][8]
In our experience, because one HBV reactivation in the
3
lamivudine untreated group occurred 12 months after the individual’s
chemotherapy had been
discontinued, lamivudine prophylaxis was maintained for a full year
following
discontinuation of any chemotherapy.[6] Hui et al. reported a high rate
of HBV reactivation
(23.9%) after withdrawal of lamivudine in the lamivudine treatment group.[1] The
investigators reported that several factors are responsible for this high
recurrence rate, such as
high HBV-DNA levels and e-antigen positivity prior to chemotherapy.[1]
However, based on
the results of previous studies, a short term (3 months) between the end
of chemotherapy and
lamivudine discontinuation may also affect HBV reactivation in such
individuals. Thus, longterm
lamivudine prophylaxis in individuals with hemato/oncological malignancy
at risk for
HBV reactivation seems to be reasonable.
According to published data, the risk of developing lamivudine-resistant HBV
increases with the duration of lamivudine treatment.[7] Resistance rates
between 15% and
40% have been reported after two years of lamivudine treatment in
immunocompetents with
chronic HBV infection.[7] None of the individuals with hematological
malignancy who
received lamivudine in our experience developed a lamivudine-resistant
virus after a mean of
14 months of continuous lamivudine therapy.[6] This result was comparable
with that of
Rossi et al. who reported no development of lamivudine resistance in HBV
carriers with
lymphoid malignancies treated with chemotherapy.[4]
In conclusion, although the ideal protocol of lamivudine prophylaxis
for the
prevention of HBV reactivation in individuals receiving chemotherapy for
hemato/oncological malignancies is not yet established, it would appear
prudent to begin
lamivudine at the time of the initiation of the chemotherapy and to
continue it throughout the
period of chemotherapy administration and for at least one but possibly
two years following
the discontinuation of the chemotherapy.
Address for correspondence:
Ramazan Idilman, M.D.,
Associate Professor
Ankara University School of Medicine,
Department of Gastroenterology,
Ibn-i Sina Hospital,
Sihhiye, Ankara-Turkey
06100
e-mail: idilman@dialup.ankara.edu.tr
Fax: +90 312 363 6213
References
1. Hui CK, Cheung WWW, Au WY, et al. Hepatitis B reactivation after
withdrawal of pre-emptive lamivudine in patients with hematological
malignancy on completion of cytotoxic chemotherapy. Gut 2005;54:1597-
603.
2. Hoofnagle JH, Dusheiko GM, Schafer DF, et al. Reactivation of
chronic
hepatitis B virus infection by cancer chemotherapy. Ann Intern Med 1982;
96:447-49.
3. Yeo W, Chan PKS, Zhong S, et al. Frequency of hepatitis B virus
reactivation in cancer patients undergoing cytotoxic chemotherapy. J Med
Virol 2000;62:299-307.
4. Rossi G, Pelizzari A, Motta M, et al. Primary prophylaxis with
lamivudine
of hepatitis B virus reactivation in chronic HBsAg carriers with lymphoid
malignancies treated with chemotherapy. Br J Haematol 2001;115:58-62.
5. Shibolet O, Ilan Y, Gillis S, et al. Lamivudine therapy for
prevention of
immunosuppressive-induced hepatitis B virus reactivation in hepatitis B
surface antigen carriers. Blood 2002;100:391-96.
6. Idilman R, Arat M, Soydan E, et al. Lamivudine prophylaxis for
prevention
of chemotherapy-induced hepatitis B virus reactivation in hepatitis B
virus
carriers with malignancies. J Viral Hepatitis 2004;11:141-47.
7. Papatheodoridis GV, Dimou E, Papadimitropoulos V. Nucleoside
analogues
for chronic hepatitis B: Antiviral efficacy and viral resistance. Am J
Gastroenterol 2002;97:1618-28.
8. Idilman R. Lamivudine prophylaxis in HBV carriers with
hematooncological
malignancies who receive chemotherapy. J Antimicrob
Chemother 2005;55:828-31.
we read the recent debate from Taipei on which is the best image-
guided ablation therapy for Hepatocellular Carcinoma (HCC) by Lin et al
(1,2) and Huo et al (3), that represents a interesting topic for
hepatologists and gastroenterologists.
The papers by Lin et al stated that to treat HCC radiofrequency (RFA)
was superior to percutaneous ethanol injection (PEI) and percutaneous
acetic acid...
we read the recent debate from Taipei on which is the best image-
guided ablation therapy for Hepatocellular Carcinoma (HCC) by Lin et al
(1,2) and Huo et al (3), that represents a interesting topic for
hepatologists and gastroenterologists.
The papers by Lin et al stated that to treat HCC radiofrequency (RFA)
was superior to percutaneous ethanol injection (PEI) and percutaneous
acetic acid injection (PAI) with respect to local recurrence, overall
survival and cancer free survival, but RFA also caused more major
complications. By the contrary Huo stresses that PEI may still be a
preferred ablation method for small HCC considering that the complication
rate of RFA may be higher than previously assumed. In fact the rate of
death occurring with the two techniques is higher for RFA (0.3-0.5%) than
PEI (0.09%) (4,5). Moreover Huo reinforces his point of view by
emphasizing that RFA is affected by a higher mortality (risk ratio of 10.6
-fold) if the death rate is calculated on the basis of number of sessions
of treatment (4,5). The letter of Huo shows that a lack of standardization
persists in reporting results of ablation therapies. This is due to the
use of non-uniform terms and different parameters to calculate the rate of
complications.
Although the recent publication of the International Working Group on
Image-guided Tumor Ablation (6) has standardized terminology, thus
facilitating the communication between investigators and improving
comparison of the results of different ultrasound-guided treatments, some
doubts remain on which denominator should be used for the rate of
complications: number of patients, of sessions, of ablations or of tumors?
As far as mortality is concerned, it is clear that death should be
reported on a per-patient basis. If instead we indicate the number of
sessions as the denominator, as reported in the letter by Huo, then the
technique which employs a higher number of sessions to achieve ablation
obviously has a lower rate of complications, and this is particularly true
when we compare PEI with RFA. As regards treatment-related morbidity, i.e.
major (not death) and minor complications as defined by SIR classification
(7), it is more appropriate, in our opinion, to divide the number of
complications by the number of ablated nodules (i.e. cured).
Unlike the number of sessions, ablations or tumors, the number of
ablated nodules represents the main objective for all ablation techniques
and only by using this parameter can we truly compare the incidence of
complications that occur after RFA, PEI or other image-guided tumor
ablation therapies.
In conclusion, we suggest using a sole parameter as the denominator,
i.e. the number of ablated nodules, since the future for prevention and
therapy for HCC will rest on comparative prospective studies based on
dedicated databases (8).
References
1) Lin SM, Lin CJ, Lin CC, Hsu CW, Chen YC. Randomised controlled
trial comparing percutaneous radiofrequency thermal ablation,
prercutaneous ethanol injection, and percutaneous acetic acid injection to
treat hepatocellular carcinoma of 3 cm or less. Gut 2005;54:1151-1156.
2) Lin SM, Lin CJ, Lin CC, Hsu CW, Chen YC. Radiofrequency ablation
improves prognosis comparerd with with ethanol injection for
hepatocellular carcinoma ¡Ü 4 cm. Gastroenterology 2004;127:1714-1723.
3) Huo TI, Lee SD, Wu JC. Ethanol injection versus radiofrequency
ablation for hepatocellular carcinoma: which is better? Gastroenterology
2005 Mar;128(3):806-7
4) Livraghi T, Solbiati L, Meloni MF, Gazelle GS, Halpern EF,
Goldberg SN. Treatment of focal liver tumors with percutaneous radio-
frequency ablation: complications encountered in a multicenter study.
Radiology 2003 Feb;226(2):441-51.
5) Di Stasi M, Buscarini L, Livraghi T, Giorgio A, Salmi A, De Sio I,
Brunello F, Solmi L, Caturelli E, Magnolfi F, Caremani M, Filice C.
Percutaneous ethanol injection in the treatment of hepatocellular
carcinoma. A multicenter survey of evaluation practices and complication
rates. Scand J Gastroenterol 1997 Nov;32(11):1168-73.
6) Goldberg SN, Grassi CJ, Cardella JF, et al. Image-guided tumor
ablation: standardization of terminology and reporting criteria. Radiology
2005;235:728-739.
7) Sacks D, McClenny TE, Cardella JF, Lewis CA, et al. Society of
Interventional Radiology clinical practice guidelines. J Vasc Interv
Radiol 2003;14:S199-S202.
Intestinal microbiota have become subject of intense investigation in
inflammatory bowel disease (IBD) during the last years after some groups
could demonstrate that significant alterations of the composition of
enteric bacteria might be related to the underlying inflammatory process
(1-5). However, the complexity of intestinal microbiota and the
availability of a variety of different experimental a...
Intestinal microbiota have become subject of intense investigation in
inflammatory bowel disease (IBD) during the last years after some groups
could demonstrate that significant alterations of the composition of
enteric bacteria might be related to the underlying inflammatory process
(1-5). However, the complexity of intestinal microbiota and the
availability of a variety of different experimental approaches generated a
patchwork of sometimes conflicting and inconsistent data. Manichanh et al.
recently published an extensive study using metagenomic libraries, a novel
molecular technique allowing the recruitment of full molecular information
of complex microbial habitats (1). In metagenomic clone libraries with
more than 25.000 clones that were generated from fecal samples of healthy
subjects and active Crohn patients a significant loss of indigenous
bacteria was found (1).
The article confirms our report that reduced bacterial diversity
seems to be a hallmark of the biofilm in IBD 5. Using colonic biopsies we
had found a loss of bacterial diversity of the mucosal microbiota in a
large cohort of patients with IBD using different 16S rDNA-based detection
techniques (5). Differently from the citation in the article of Manichanh
et al., the taxa of the bacterial phylotypes were determined in our study
by sequence homology analysis in clone libraries and not only by SSCP (5).
The metagenomic approach used by Manichanh et al. is likely to be the most
informative way of collecting microbial data of complex bacterial
communities. Notably, this demonstrates that assessment of 16S rDNA based
signals, especially when using large-scale clone libraries as in our
paper, has sufficient power to determine bacterial richness and diversity.
This is not too surprising because the taxonomical classification of
metagenomic fragments is mainly based on 16S rDNA anchor genes.
In some aspects there are discrepancies between the different
molecular studies. Manichanh et al. only demonstrate alterations of the
fecal microbiota (1). As previously demonstrated, different compartments
in the intestine contain complex ecological systems that are distinctly
different (6). Therefore, the composition of bacterial consortia in the
human feces, which contain a high number of transient bacteria, does not
fully represent the mucosal microbiota (7, 8). Mucosa-related microbes
(including intracellular microorganisms), however, seem to be a
functionally relevant part of the intestinal microbiom directly
interacting with the host immune system.
Generating and analyzing metagenome libraries is enormously
expensive. Therefore, the number of patients that can be analysed will
remain relatively small (1). The confirmation of a reduced bacterial
diversity, however, could be now followed by a deep analysis of the
functional capacities of the bacterial communities. These next steps would
convert descriptive approaches into a mechanistic understanding. Manichanh
et al. have introduced the metagenomic approach as a novel technique of
collecting data from complex human biofilms.
Address all correspondence to:
Stefan Schreiber, M.D.
Institute for Clinical Molecular Biology
Christian-Albrechts-University Kiel
Schittenhelmstr. 12
24105 Kiel, Germany
Phone: +49 431 597 2350
Fax: +49 431 597 1842
E-mail: s.schreiber@mucosa.de
References
1. Manichanh C, Rigottier-Gois L, Bonnaud E, et al. Reduced diversity
of faecal microbiota in Crohn's disease revealed by a metagenomic
approach. Gut 2006;55:205-211.
2. Swidsinski A, Ladhoff A, Pernthaler A, et al. Mucosal Flora in
Inflammatory Bowel Disease. Gastroenterology 2002;122:44-54.
3. Seksik P, Rigottier-Gois L, Gramet G, et al. Alterations of the
dominant faecal bacterial groups in patients with Crohn's disease of the
colon. Gut 2003;52:237-42.
4. Prindiville T, Cantrell M, Wilson K. Ribosomal DNA Sequence
Analysis of Mucosa-Associated Bacteria in Crohn's Disease. Inflamm Bowel
Dis 2004;10:824-33.
5. Ott SJ, Musfeldt M, Wenderoth DF, et al. Reduction in diversity of
the colonic mucosa associated bacterial microflora in patients with active
inflammatory bowel disease. Gut 2004;53:685-693.
6. Bignell DE, Oskarsson H, Anderson JM. Distribution and abundance
of bacteria in the gut of a soil-feeding termite Procutiermes aburiensis
(Termitidae, Termitinae). J Gen Microbiol 1980;117:393-403.
7. Zoetendal EG, von Wright A, Vilpponen-Salmela T, et al. Mucosa-
associated bacteria in the human gastrointestinal tract are uniformly
distributed along the colon and differ from the community recovered from
feces. Appl Environ Microbiol 2002;68:3401-7.
8. Ott SJ, Musfeldt M, Timmis KN, et al. In vitro alterations of
intestinal bacterial microbiota in fecal samples during storage. Diagn
Microbiol Infect Dis 2004;50:237-45.
Dear Editor,
We read with interest the recent articles on obesity, inflammation and Colorectal cancer (CRC).1,2,3 Although insulin resistance is the most widely accepted underlying mechanism explaining the association between obesity and CRC, recent evidence suggests that the effects of obesity on the immune system in general and specifically on the gut may play a role. We propose that obesity predisposes to CR...
Dear Editor,
Cyclosporine (CsA) is an established treatment in severe, intravenous- corticosteroid-resistant ulcerative colitis (UC). Although one third of UC patients relapse during pregnancy, experience with CsA use during this period is limited to a few case reports.[1][2] Most of the available data on CsA administration and pregnancy outcome have been obtained from the transplantation literature.[3] We read the...
Dear Editor,
Approximately 4% of the H. pylori genome, significantly more than that of any other known bacterial species is composed of genes encoding outer membrane proteins (OMPs). The best described H. pylori OMP is the adhesin BabA, which is thought to mediate host/bacterial interactions and has been linked to microbial pathogenicity (1-4). The dissection of OMP function helps understanding the complex gastri...
Dear Editor,
We read with interest the well constructed and stimulating review on ghrelin that was recently published in Gut (1). Indeed, the scenario of the hormones and peptides involved in the control of gastrointestinal function, from the point of view of motility or secretion, is getting every year more complicated, with new “players” entering the field (2,3). Ghrelin in particular, making part of the same...
Dear Doctors,
Effectively, the biopsies of the gastric mucosa revealed H. Pylori and had been eradicated. But our patient did not improve. It is interresting to look the relation between Menetrier's disease and H Pylori in a multicentric prospective study.
Dear Editor,
Elliott et al. (Gut 2005; 54: 1818-19) present an interesting and clinically useful finding of successful treatment of a patient with severe Crohn’s disease and circumferential narrowing of the ileo-colonic anastomosis treated with 750 mg ciprofloxacin plus 400mg metronidazole daily for almost three years, resulting in complete healing and opening up of the stenosed anastomosis.
The author...
Dear Editor,
The Editor’s quiz in Novembers Gut featured a most interesting presentation of Ménétrier’s disease (hypertrophic protein losing gastropathy). There is a recognised association between Ménétriers disease and infection with Helicobacter pylori. In two retrospective studies between 30% and 90% of patients with Ménétriers disease were associated with H pylori1-4. Furthermore, Bayerdörffer et al reported...
Dear Editor,
I read with interest the article by Hui et al. reporting hepatitis B reactivation after withdrawal of pre-emptive lamivudine in patients with hematological malignancy on completion of cytotoxic chemotherapy.[1] Reactivation of hepatitis B virus (HBV) infection is a well-recognized complication of chemo/immunosuppressive therapy in HBs-Ag positive inactive carriers.[2][3] It occurs in 14% to 50% of such in...
Dear Editor,
we read the recent debate from Taipei on which is the best image- guided ablation therapy for Hepatocellular Carcinoma (HCC) by Lin et al (1,2) and Huo et al (3), that represents a interesting topic for hepatologists and gastroenterologists.
The papers by Lin et al stated that to treat HCC radiofrequency (RFA) was superior to percutaneous ethanol injection (PEI) and percutaneous acetic acid...
Dear Editor,
Intestinal microbiota have become subject of intense investigation in inflammatory bowel disease (IBD) during the last years after some groups could demonstrate that significant alterations of the composition of enteric bacteria might be related to the underlying inflammatory process (1-5). However, the complexity of intestinal microbiota and the availability of a variety of different experimental a...
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