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com/1007-9327office World J Gastroenterol 2012 April 21; 18(15): 1708-1722
wjg@wjgnet.com
doi:10.3748/wjg.v18.i15.1708
Etiology of inflammatory bowel disease: A unified hypothesis
Xiaofa Qin
Xiaofa Qin, Department of Surgery, UMDNJ-New Jersey Med-
ical School, Newark, NJ 07103, United States
Author contributions: Qin X is the sole author and contributed
entirely to this paper.
Correspondence to: Xiaofa Qin, MD, PhD, Department of
Sur­gery, UMDNJ-New Jersey Medical School, 185 South Oran­
ge Avenue, Newark, NJ 07103, United States. qinxi@umdnj.edu
Telephone: +1-973-9722896 Fax: +1-973-9726803
Received: October 25, 2011 Revised: February 20, 2012
Accepted: February 26, 2012
Published online: April 21, 2012
Abstract
Inflammatory bowel disease (IBD), including both ul-
cerative colitis (UC) and Crohn’s disease (CD), emerged
and dramatically increased for about a century. Despite
extensive research, its cause remains regarded as un-
known. About a decade ago, a series of findings made
me suspect that saccharin may be a key causative fac-
tor for IBD, through its inhibition on gut bacteria and
the resultant impaired inactivation of digestive proteas-
es and over digestion of the mucus layer and gut bar-
rier (the Bacteria-Protease-Mucus-Barrier hypothesis).
It explained many puzzles in IBD such as its emergence
and temporal changes in last century. Recently I fur-
ther found evidence suggesting sucralose may be also
linked to IBD through a similar mechanism as saccharin
and have contributed to the recent worldwide increase
of IBD. This new hypothesis suggests that UC and CD
are just two symptoms of the same morbidity, rather
than two different diseases. They are both caused by
a weakening in gut barrier and only differ in that UC is
mainly due to increased infiltration of gut bacteria and
the resultant recruitment of neutrophils and formation
of crypt abscess, while CD is mainly due to increased
infiltration of antigens and particles from gut lumen
and the resultant recruitment of macrophages and
formation of granulomas. It explained the delayed ap-
pearance but accelerated increase of CD over UC and
many other phenomena. This paper aims to provide a
detailed description of a unified hypothesis regarding
WJG|www.wjgnet.com
ISSN 1007-9327 (print) ISSN 2219-2840 (online)
© 2012 Baishideng. All rights reserved.
REVIEW
the etiology of IBD, including the cause and mechanism
of IBD, as well as the relationship between UC and CD.
© 2012 Baishideng. All rights reserved.
Key words: Etiology; Inflammatory bowel disease; Ul-
cerative colitis; Crohn’s disease; Dietary chemicals; Sac-
charin; Sucralose
Peer reviewer: Andrew Day, Professor, University of Otago,
Christchurch Hospital, 8140 Christchurch, New Zealand
Qin X. Etiology of inflammatory bowel disease: A unified hy-
pothesis. World J Gastroenterol 2012; 18(15): 1708-1722 Avail-
able from: URL: http://www.wjgnet.com/1007-9327/full/v18/
i15/1708.htm DOI: http://dx.doi.org/10.3748/wjg.v18.i15.1708
INTRODUCTION
As we know, inflammatory bowel disease (IBD) refers
to ulcerative colitis (UC) and Crohn’s disease (CD), two
highly related debilitating diseases of the digestive tract
with similar clinical, pathological, and epidemiological
features[1,2]. Although some descriptions in ancient books
had been suspected as symptoms of IBD, clustered cases
only started to emerge around the end of the 19th cen-
tury[1]. Right now, IBD has become one of the most com-
mon chronic inflammatory conditions only after rheuma-
toid arthritis, with millions of patients all over the world[3].
It is most prevalent in young adults and remains regarded
as incurable, with the patients usually requiring lifelong
heavy medication and multiple devastating surgeries like
bowel resection, proctocolectomy, ileostomy, and ileal
pouch-anal anastomosis, etc.[2,4]. As stated by Dr. Kirsner,
“ulcerative colitis and Crohn’s disease today represent two
of the more challenging diseases in all of medicine”[1].
Since its appearance, people had been puzzled by the
constant changes of manifestations of IBD in age, gen-
der, ethnic, temporal and geographical distributions[3,5,6].
Great efforts have been taken to find out its cause. Many
factors had been suspected, including bacteria such as
1708 April 21, 2012|Volume 18|Issue 15|

Bacillus coli, Bacillus proteus, Bacillus pyocyaneus, Bacillus lactis
aerogenes, diplostreptococci, dysentery bacillus, Spheropho-
rus necrophorus, Bacillus morgagni, Escherichia coli, spirochetes,
Mycobacteria (Mycobacteria tuberculosis, Mycobacteria paratu-
berculosis and Mycobacteria kansasii), Pseudomonas maltophilia,
Bacillus vulgatus, Aerobacter aerogenes, Aerobacter coprococcus,
Aerobacter bifidobacteria, Campylobacter fetus ssp. jejuni, Yer-
sinia enterocolitica, and Chlamydia trachomatis, Aeromonas
hydrophila, Plesiomonas shigelloides, Edwardsiella tarda, Blas-
tocystis hominis, Bacteroides necrophorum, Bacteroides fragilis,
Pseudomonas maltophilia, Helicobacter hepaticus or pylori spe-
cies[1,7,8]; fungi like Histoplasma and Monilia[1]; virus such as
lymphopathia venereum, Behcet’s virus, cytomegalovirus,
Echo A, B adenovirus, Epstein-Barr, rotavirus, Norwalk
virus, influenza, mumps, measles, herpes, Coxsackie A and
B, Reovirus, Polio virus, Paramyxovirus[1,7,8]; protozoa and
parasites like Escherichia histolytica[1]; vaccines such as the tri-
valent measles, mumps and rubella and Bacillus Calmette-
Guérin[9,10]; microparticles of aluminum, titanium , silicon
oxides, calcium phosphate from the diet, tooth paste,
dust or soil[8,10-12]; drugs like oral contraceptives and non-
steroid anti-inflammatory drugs (NSAIDs)[10,13]; dietary
components like protein, fat, sugar, fruits and vegetables,
margarine, dairy products, coffee, coca cola, fast food[10],
or glycoalkaloids in potato[14], and carrageenan in sea-
weeds[15]; smoking[1]; and other factors like refrigeration
(cold chain)[8,10,16]. Despite that, the cause of IBD remains
virtually unknown, as none of them can well explain
the dynamically changed profiles of IBD. For instance,
smoking is currently regarded as the most determined
environmental factor for IBD: it reduces the risk of UC,
while exacerbates CD[2]. Despite that, the low prevalence
of CD in heavily smoking countries like China and high
prevalence of CD in the low smoking countries like
Canada suggest the contribution of smoking in the gen-
eral population being negligible and other factors in the
environment would have played the predominant role[2].
Another example would be the Mycobacterium avium
subspecies paratuberculosis (MAP), a bacteria that causes
Johne’s disease in cattle, that had been suspected the cau­
sative factor for CD as early as 1913[17]. Despite a century
long research and debate, a causal relationship between
MAP and CD still cannot be established[18,19]. MAP hy-
pothesis also failed to explain the cause of UC, which has
been the main form of IBD in most circumstances.
About a decade ago, I found that digestive proteas­
es like trypsin and chymotrypsin can be inactivated by
free (unconjugated or deconjugated) bilirubin but not
conjugated bilirubin or biliverdin. Further pursuit in
the literature led me to suspect that impairment in this
process due to inhibition of gut bacteria (thus the major
source of β-glucuronidase that is needed for deconjuga-
tion of the mostly conjugated biliary bilirubin) by dietary
chemicals like saccharin may have played an important
causative role in IBD, as the result of damage of the
protective mucus layer and the underlying gut tissue by
the poorly-inactivated digestive proteases[20]. Recently, I
further found that sucralose, the new generation of arti-
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Qin X. Etiology of IBD
ficial sweetener, may exert an even potent impact on gut
bacteria than saccharin and have probably contributed
to the record high incidence of IBD seen recently in
many countries[21]. Based on the evidences gathered and
thoughts evolved and developed in the last decade, this
paper aims to provide a detailed description of a unified
hypothesis regarding the etiology of IBD, including the
cause and mechanism of IBD, as well as the relationship
between UC and CD.
LARGE COMMERCIAL MARKETING OF
SACCHARIN IN 1887 AND THE EMERGE
OF CLUSTERED CASES OF ULCERATIVE
COLITIS SINCE 1888, STARTED FROM
THE UNITED KINGDOM
The discovery of saccharin in 1878 from coal tar and its
large-scale production and marketing since 1887
Saccharin was discovered in 1878 by Constantin Fahlberg,
a young chemist from Germany who engaged in research
in Professor Ira Remsen’s laboratory at Johns Hopkins
University in Baltimore, Maryland, the United States[22-24].
One evening, Fahlberg found extra sweetness of bread
and his hand during dinner, and tracked to its source to a
coal tar product in the lab. Later, it was revealed that this
chemical was 300 to 500 times as sweet as sugar and had
little toxicity[22-25]. In 1882, Constantin Fahlberg himself
consumed 10 g of the chemical and experienced no ad-
verse reactions[26]. Most of it passed the body unchanged,
through urine or feces[22,25]. In 1884, associated with his
uncle, Adolph List, of Leipzig, Germany, Fahlberg tried
pilot experimental production of this chemical in New
York and named it as saccharin (also called saccharine at
some occasions)[23]. Due to the high expenses of labor
and materials in New York, Fahlberg, together with his
cousin, established the firm Fahlberg, List and Co. and
built a factory in Salbke, Germany in 1886 for the com-
mercial production of saccharin[22-24,27]. Large quantities
of saccharin were produced and reached the market in
1887[28]. After that, more factories were established in
Germany[22]. The production of saccharin in Germany be-
fore its ban by the end of 1902 is showed in Table 1[29-33].
Since later 1890s, factories were also built in other coun-
tries like France[34] and the Switzerland [31,35]. In 1901,
John Francis Queeny established Monsanto in St. Louis,
Missouri, the United States for the sole purpose of sac-
charin production[27,36]. For the first several years, all the
saccharin it produced was sold to Coco Cola, then a small
company in Atlanta[27,36].
The favorite use of saccharin in United Kingdom since
1887 but dislike or ban of saccharin in Germany and
most of the other Western countries in the early years
Although saccharin was only produced in Germany in
the early years after its marketing in 1887, only about
3% of saccharin was actually consumed in Germany[37],
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 Qin X. Etiology of IBD
Table 1 Saccharin production in Germany before its ban by
the end of 1902
Year Number of factories Production (tons)
1888 1 5.2[29]
1889 1 14.6[30]
1896 3 33.5[31]
1897 4 34.7[31]
1898 5 78.4[31]
1899 6 130.3[31]
1900 6 159.4[32]
1901 6 189.7[31]
1902 6 174.8[31]
1903 1 40[33]
mainly due to the bad image of this coal tar product in
that country. Saccharin was regarded as being inferior
and only consumed by people who could not afford the
luxury of sugar[38]. A domestic servants’ club even ad-
vocated a commitment not to working for people who
sweetened their coffee with saccharin instead of sugar[38].
In 1902, saccharin production was eventually brought
under strict control in Germany[24]. Only one firm, Fahl-
berg, List and Co, among the six factories was allowed
to continue producing saccharin[24], and it was regulated
that saccharin can only be used for medicinal purpose
and available through pharmacies[24]. The production of
saccharin in Germany reduced from nearly 190 tons in
1901 to about 40 tons in 1903[33], among which only 3
tons were consumed within Germany, with the remaining
being exported to other countries[33]. Similar as Germany,
many other countries like France, Italy, Spain, Belgium,
Holland, Portugal, Russia, Austro-Hungary also put strict
regulations on the importation, production, and use of
saccharin during these early years[39,40]. These restrictions
greatly stimulated the smuggling of saccharin in Europe,
with saccharin being hidden in chocolate or match boxes,
oil or milk cans, artificial stones or candles, coats, vests,
suits with secret pockets, feed bags for horses, carousel,
or even coffin[41].
In contrast to the countries above, saccharin was great­
ly appreciated in the United Kingdom. Even before its
appearance on the market, saccharin had been highly
praised by some eminent authorities like Sir Henry E.
Roscoe, who had been a member of the parliament, a fel-
low of royal society, and presidents of Chemical Society,
the Society of Chemical Industry, and the British Associ-
ation[42-44]. In the presidential inaugural address on August
27, 1886, he stated that: “the most remarkable instance is
the production of an artificial sweetening agent, termed
saccharine, prepared by a complicated series of reactions
from coal tar”[42,43]. People were assured by official ana-
lysts and doctors that saccharin was harmless and enjoy-
able[45,46]. Pamphlets with detailed descriptions of many
formulae and uses of saccharin were written by professor
and editor and distributed to households[46,47]. As stated in
a publication in early twenty century: “Here we now have
a coal oil product deliberately recommended in England
as a valuable and suitable agent for sweetening mineral
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waters and, presumably, for use wherever it could take
the place of genuine sugar. It is altogether different in
France, where it has been entirely contraband and even
in Germany, where it is manufactured to so considerable
an extent, efforts are made to hold it under control”[48].
Therefore, it would be not surprising that, shortly after its
marketing, saccharin soon appeared in almost any family
grocer, instead of chemists’ shop in United Kingdom[49].
As the result, United Kingdom was the biggest buyer of
saccharin at that time. As stated in the publication: “the
American trade (of saccharin) has been inconsequential.
In 1891 the export to New York was only about eight
hundred kilograms (1800 pounds approximately), while
during the same period 7200 kg were shipped to Eng-
land”[50].
Emergence of clustered cases of ulcerative colitis since
1888, started from United Kingdom
Although it was suspected that some forms of diarrhea
described in ancient books could be sporadic case of
UC[1], it appeared that clustered cases of UC only started
to emerge after 1888. As stated by Dr. Sidney Philips in
his discussion during the first symposium on IBD in the
world in 1909 that presented a collection of more than
three hundreds of UC patients from 9 hospitals in Lon-
don: “Ulcerative colitis appeared to be much more com-
mon now in this country than formerly. There was no
mention of it in any of the published reports of any of
the London hospitals before 1888, when Dr. Hale White
published cases in Guy’s Hospital Reports. It was not
mentioned in St. Bartholomew’s or Westminster Hospital
Reports before 1893, nor in the London Hospital Re-
ports till 1897. And the textbooks used twenty or thirty
years ago, such as Bristowe’s and Hilton Fagge’s, made no
allusion to it. The speaker himself had seen many cases
at St. Mary’s Hospital and elsewhere since 1888, but not
before then”[51]. In addition, Dr. Philips even suspected
that the increase in UC might be caused by some food
additives. He stated: “Possibly the cause of acute ulcer-
ative colitis was connected with our food supply; tinned
or preserved foods might have something to do with it[51].
Interestingly, saccharin was largely used in early years in
canned foods to preserve vegetables, fruits and meats,
taking the advantage of both its sweet and antiseptic
properties[25,52].
THE WIDESPREAD USE OF SACCHARIN
DURING THE TWO WORLD WARS AND
THE SPREAD OF ULCERATIVE COLITIS IN
WESTERN COUNTRIES
During World War Ⅰ, the shortage of sugar caused great
demand for saccharin[53,54]. Figure 1 demonstrated this
dramatic increase of saccharin consumption in Germa­
ny[38,54]. The ban on saccharin was lifted in Germany and
other countries, accompanied by a striking increase in
saccharin production[53,54]. In 1916, saccharin production
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 Qin X. Etiology of IBD

600
Saccharin consumption in Germany (tons)

500

400

300

200

100

0
1887

1890

1893

1896

1899

1902

1905

1908

1911

1914

1917

1920

1923

1926

1929

1932

1935

1938

1941

1944
Figure 1 Saccharin consumption in Germany over time (1887-1944).

in Germany resumed to 1 ton per day[33]. In France, four literature on this disease, one is struck by the similarity
more factories were equipped to produce saccharin[55]. of the articles. It seems obvious that these writers from
In the United States, saccharin became allowed using in various countries are all dealing with the same condition,
soft drinks and foods[56]. In addition to increased produc- and not, as has been suggested, with different diseases
tion, the importation of saccharin in the United States brought under the same name-ulcerative colitis”[60].
increased from 8 pounds in 1914 to 5617 pounds in 1915 In the United States, more cases of UC were seen
and 12954 pounds in 1916[57]. Despite the increased pro- since World War Ⅰ. For instance, Logan reported 117 cas-
duction and importation, the price of saccharin in New es of UC treated in Mayo Clinic up to 1918, with 19 cases
York market increased from $1.15-1.25 per pound in being before 1915, 18 cases during 1915, 23 cases during
1914 to $2.85-11.50 in 1915, $11.50-21.50 in 1916, and 1916, 57 cases during 1917 and to April 1, 1918[61], while
$20.50-46.00 in 1917[53], reflected the great increases in there were 693 cases between 1923-1928[62,63]. In 1922,
the demand and consumption of saccharin during this Dr. Yeomans in the Department of Surgery, Columbia
period. University College of Physicians and Surgeons reported
In accordance with the spread use of saccharin since 65 cases of UC mostly observed during 1916 and 1921
World War Ⅰ, UC cases were also more frequently seen with only 6 cases before that[64]. During this period, many
in countries other than United Kingdom. As stated by UC patients were also reported in California[65], Massachu-
Dr. Evans: “During the recent war (1914-1918), while setts[66], and other places[67].
acting as surgeon to an improvised hospital for Turk- World War Ⅱ resulted in another jump in saccharin
ish prisoners in Mesopotamia, and later as civil surgeon consumption (Figure 1). In the United States, Sigma
of Baghdad, an opportunity arose of observing a large Chemical Co. was formed to manufacture saccharin and
number of cases of colitis; the majority were chronic Monsanto resumed large-scale production to meet the
and were complicated by scurvy. The combination of high demand[68]. Interestingly, record high incidence of
these two diseases made the colitis extremely intrac- IBD was also seen during this period. For instance, 525
table, and in consequence large numbers died. While in cases of UC were diagnosed in male United States Army
Mesopotamia Ⅰ performed appendicostomy for intrac- in 1944, with a rate as high as 12 per 100 000 in 40-45
table ulcerative colitis in ten patients-Turks, Arabs, and age group[69]. This may relate to the preferred use of
Indians”[58]. This helped the recognition of UC as an saccharin in the United States army. As early as in 1896,
independent entity other than, for instance, dysentery. United States army had chosen saccharin rather sugar as
As stated by Lups S: “In the latter part of the nineteenth the emergence ration for sweetening coffee or tea, taking
century most clinicians considered this affection which the advantage of its immaterial weight as well as the anti-
later was called ‘ulcerative colitis’ belonging to the dys- septic property to reduce the prevalence of diarrheas[70].
entery group, even after 1903, when Boas expressed the
view that ulcerative colitis was an independent disease. THE DRAMATIC INCREASE IN
About 1914, however, there was a marked change in the
viewpoints of many observers on this question although SACCHARIN CONSUMPTION SINCE
many still felt that it was of dysenteric origin. They knew 1950S AND THE REMARKABLE
full well that only in a few cases true dysenteric organ-
isms were found”[59]. In another paper published in 1928, INCREASE IN INFLAMMATORY BOWEL
Dr. Thorlakson stated that:“the subject of ulcerative DISEASE DURING 1950S AND 1970S IN
colitis has received a great deal of attention in the medi-
cal literature of all countries during the past decade. In COUNTRIES LIKE THE UNITED STATES
reviewing the English, German, French and American Although the shortage of sugar in World War Ⅰ and Ⅱ

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 Qin X. Etiology of IBD

A 90 UC sauces and dressings, canned fruits, dessert toppings, coo­

80 CD kies, cereals, gums, jams, candles, ice cream and puddings,
70
IBD
in addition to as a non-nutritive tabletop sweetener[72].
Number of IBD cases

60 It was also used in drugs, toothpaste, mouthwashes and

50
cosmetics[72].
In accordance with this dramatic increase in saccharin
40
consumption, the incidence of IBD also showed a strik-
30 ing increase during this period. This was clearly demon-
20 strated in the study by Stowe et al[73], which showed the
10 annual incidence of both UC and CD in Monroe County,
0 New York between 1920s and 1986 (Figure 2A). From
Figure 2B we can see the increase in IBD for up to later
1920

1930

1940

1950

1960

1970

1980

1990
1970s paralleled neatly with the increased consumption
of saccharin during the same period[74], with a very signif-
B Approval of aspartame use in soft drinks
icant correlation (Figure 2C). The correlation coefficient
Finding the carcinogenecity
between saccharin consumption in the United States and
Saccharin consumption in US (pounds)

7000 000 and attemting ban of saccharin 90

New IBD cases in Monroe County

Marketing of diet drinks 80 the new cases of UC, CD and IBD (UC + CD) in Mon-
6000 000
sweetened with saccharin 70 roe County were 0.930, 0.935 and 0.948, and the P value
5000 000
Beginning of 60 being 3.43 × 10-8, 1.90 × 10-8, and 3.85 × 10-9, respec-
4000 000 World War Ⅱ 50 tively.
3000 000 40
30
2000 000
20
DISCOVERY OF CARCINOGENICITY OF
1000 000 IBD
Saccharin
10 SACCHARIN IN LABORATORY ANIMALS
0 0
IN 1970S AND THE LEVELING OFF
1918
1922
1926
1930
1934
1938
1942
1946
1950
1954
1958
1962
1966
1970
1974
1978
1982
1986

OR DECREASE OF INFLAMMATORY
C BOWEL DISEASE OBSERVED IN MANY
r = 0.948
7000 000
Saccharin consumption in US (pounds)

P < 0.000 000 005 COUNTRIES SINCE THE SAME PERIOD

6000 000
5000 000
4000 000
3000 000
2000 000
1000 000
0
0 20
New IBD cases in Monroe County, New York
Figure 2 The dramatic increase in saccharin consumption since 1950s
and the remarkable increase in inflammatory bowel disease during 1950s
and 1970s in countries like the United States. A: Occurrence of ulcerative
colitis (UC), Crohn’s disease (CD), and inflammatory bowel disease [inflamma-
tory bowel disease (IBD) = UC + CD] in Monroe County, New York during 1920s
to 1980s; B: A comparison of the temporal change of IBD in Monroe County,
New York and the saccharin consumption in the United States; C: Correlation
between IBD in Monroe County, New York and the saccharin consumption in
the United States.
led to increased consumption of saccharin as a sugar
substitute, a huge increase only occurred since late 1950s,
when low calorie high intensity sweetener began to be
used in foods and drinks designated for special diets[56,71].
In 1976, approximately 7 million pounds of saccharin
were consumed in the United States, with soft drinks ac-
counted for 74 percent of those used in foods and bev-
erages[72]. Saccharin had been used in juices and drinks,
From Figure 2A, we can see the incidence of both UC
and CD in Monroe County reached a peak in 1978, fol-
lowed by a mysterious rapid decrease after that. Again,
this change was in accordance with the finding of the
carcinogenicity of saccharin in animals and the attempted
ban for its use in the United States in 1977[26]. Due to
the protest from the public the congress imposed a two
year moratorium instead of a complete ban on saccharin,
40 60 80 100 but passed the Saccharin Study and Labeling Act that re-
quired further studies on saccharin and putting a warning
label on products containing saccharin[26]. Study showed
that these events indeed affected saccharin consumption,
especially for those with high education and families with
children[75]. Not only in Monroe County in New York, the
leveling off or decrease in IBD in later 1970s and 1980s
was also seen in other cities of the United States such as
Olmsted County, Minnesota[76], as well as in many other
countries such as Canada[77], Demark[78,79], Germany[80],
Japan[81], Israel[82], Sweden[83-86] and United Kingdom[87-90]
(Figure 3). In 1981 aspartame was approved by Food and
Drug Administration (FDA) of the United States for use
in dry food products[91]. On July 8, 1983 FDA further ap-
proved the use of aspartame in carbonated beverages and
syrups[91]. Aspartame soon became the main high intensity
sweetener in the market, with a sharp decline in saccharin
use and consumption[91], which was in accordance with
the remarkable decrease in the incidence of UC and CD
observed in Monroe County at this period (Figure 2A).

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 Qin X. Etiology of IBD

12 Canada 8 7 Isreal

10 6
6 5
8
4
6 4
UC

UC
CD
3
4
2
2
2 UC, Alberta
1
CD, Alberta
0 0 0
1965 1970 1975 1980 1985 1965 1970 1975 1980 1985

10 Denmark 5 15 Sweden 10
9
8 4 8
7
10
6 3 6
5
UC

UC
CD

CD
4 2 UC, Orebro 4
3 5
UC, Uppsala
2 UC, Copenhagen 1 CD, Orebro 2
1 CD, Copenhagen CD, Stockholm
0 0 0 0
1960 1965 1970 1975 1980 1985 1990 1960 1965 1970 1975 1980 1985 1990

6 Germany 3 8 United Kingdom 8

5
6 6
4 2

3 4 4
UC

UC
CD

CD
CD, Blackpool
2 1
CD, Uppsala
2 2
UC, Tubingen UC, Cardiff
1
CD, Tubingen CD, Cardiff
0 0 0 0
1970 1975 1980 1985 1960 1965 1970 1975 1980 1985 1990

0.5 Japan 0.10 12 United States 10

10 8
0.4 0.08

8
0.3 0.06 6
6
UC

UC
CD

CD

0.2 0.04 4
4

0.1 UC, Nationwide 0.02 2

2 UC, Monroe UC, Olmsted
CD, Nationwide
CD, Monroe CD, Olmsted
0.0 0.00 0 0
1960 1965 1970 1975 1980 1985 1960 1965 1970 1975 1980 1985 1990

Figure 3 A leveling off or decrease of ulcerative colitis or Crohn’s disease during 1970s and 1980s in the different countries such as Canada, Demark, Ger-
many, Japan, Israel, Sweden, United Kingdom, and United States. UC: Ulcerative colitis; CD: Crohn’s disease.

1980s, the increase again of IBD since 1990s was ob-

THE REBOUNDED USE OF SACCHARIN
served in many of these places such as Denmark[92], Swe-
AND THE INCREASE AGAIN OF den[86,93,94], United Kingdom[89], and the United States[76].
INFLAMMATORY BOWEL DISEASE This was again in accordance with the rebounded use of
saccharin. After finding the carcinogenicity of saccharin
SINCE 1990S in animals in 1970s, many studies were carried out. As
Although a leveling off or decrease in IBD was observed the result, most studies failed to show a link between sac-
in many places (Figure 3) during the later 1970s and early charin consumption and bladder cancer in humans[95,96].

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 Qin X. Etiology of IBD
People gradually regained confidence in saccharin con-
sumption. Saccharin production boomed again, largely
because saccharin is very cheap and also very stable thus
can be used in a wide range of drink and food products
and put on the shelf for a long time[97,98]. In China, sac-
charin production increased from about 8000 tons in
middle 1980s[99], to 13 126 tons in 1991 and 29 175 tons
in 1998, accompanied by dramatic increases in both do-
mestic use and exportation[100]. The great adverse impact
on sugar industry led the Chinese government adopting
strict measures to limit the production and domestic use
of saccharin. In the United States, after multiple times
of renewal of the two year moratorium, the National In-
stitute of Environmental Health Sciences finally delisted
saccharin from carcinogen list in 2000 and the “Sweetest
Act” of the Congress eliminated the requirement for put-
ting the warning label on saccharin products[26]. This is
accompanied by a dramatic increase in saccharin importa-
tion from 2 772 000 pounds in 2000 to 8 346 000 pounds
in 2008[101]. In 2007, 52 212 000 pounds of saccharin were
exported world wide, with millions of pounds of sac-
charin being imported in countries like Germany, Spain,
United Kingdom, South Korea, Japan, India and Brazil[101].
These massive use of saccharin may have contributed to
the worldwide increase of IBD in recent years[102].
SUCRALOSE, A NEW GENERATION OF
ARTIFICIAL SWEETENER, MIGHT BE
ANOTHER IMPORTANT RISK FACTOR
THAT CONTRIBUTED TO THE RECORD
HIGH INCIDENCE OF INFLAMMATORY
BOWEL DISEASE SEEN RECENTLY IN
MULTIPLE COUNTRIES
The evidences demonstrated above provided a simple
explanation for many puzzles of IBD such as the emer-
gence and temporal changes of IBD in last century. It
suggests saccharin might be the key causative factor for
IBD, by primarily its inhibition on gut bacteria[20]. This no­
tion is supported by the recent large-scare studies show-
ing antibiotics greatly increased the risk of IBD[103,104].
Although both saccharin[105-107] and antibiotics can inhibit
bacteria, saccharin would have a much more great im-
pact on the general population due to the wide extensive
use[108]. When United States FDA attempted a ban on
saccharin in 1977, saccharin was used as the only non-
nutritive sweetener by up to 70 million Americans[74].
Saccharin was the first and oldest artificial sweetener.
From its marketing in 1887 until a temporary decline
in the market due to the heavy use of aspartame since
1980s saccharin had been the only or the predominant
artificial sweetener, which made it a key dietary chemical
in last century. However, more and more chemicals were
introduced and became heavily used as food additives in
modern society. It would be no surprising that some of
them may also have a significant impact on gut bacteria,
WJG|www.wjgnet.com
thus IBD. Recently, I found evidences suggesting sucra-
lose, the new generation of artificial sweetener, might
be just an example. Sucralose is synthesized by replacing
three hydroxyl groups of sucrose with three chlorides,
which makes it 600 times as sweet as sucrose[109]. Like
saccharin, sucralose is stable under heat and over a broad
range of pH, and most of it passes through the body
without further metabolism[97,109]. However, sucralose has
a much lower absorption rate but a much high acceptable
daily intake and thus a more potent impact on gut bac-
teria[97,110]. Sucralose was first approved for use in drinks
and foods in Canada in 1991, which was in accordance
with the dramatic increase of IBD seen in Alberta[111]
and CD in Montreal[112] since early 1990s, as well as the
finding in recent studies that Canada suddenly became a
country with the highest incidence of IBD[113,114]. After
Canada, sucralose was approved in Australia in 1993, in
New Zealand in 1996, in the United States in 1998, and
in the European Union in 2004, which was again in ac-
cordance with the dramatic increase or the record high
incidence of IBD in Australia[115], New Zealand[116], the
United States[117] and Norway[118] (Figure 4)[21]. Currently,
sucralose has been approved for use in more than 80
counties[119], and started to appear in rivers and other
surface waters of many countries[120]. In countries like the
United States artificial sweeteners are now used by more
than half of the population, with sucralose by far the
number one in the market and being used in thousands
of food and drink products[121]. This unrestricted use
of sucralose may be also the explanation for the recent
remarkable increase of IBD in children as observed in
many studies[122]. We may expect to see more reports on
record-breaking incidence of IBD, both in adults and
children.
THE POSSIBLE MECHANISM OF
INFLAMMATORY BOWEL DISEASE: THE
BACTERIA-PROTEASE-MUCUS-BARRIER
HYPOTHESIS
After the emergence of IBD about a century ago, numer-
ous hypotheses had been suggested as the possible mech-
anism, which included infection, toxicants, psychogenic
disturbances, nutritional deficiencies, allergy to pollens or
foods, abdominal trauma, impaired vascular or lymphatic
circulation, lysozymes and other enzymes[1,123,124], or the
excessive or deficient immune response due to reduced
exposure to bacteria or helminthes[125,126]. Most of them
were invalidated and forgotten. Up to date, a full coher-
ent mechanistic explanation for IBD is still lacking, but
people start to realize that the pathogenesis of IBD in-
volves four fundamental components: the environment,
gut microbiota, the immune system and the gene[127-129].
Currently, the dominant theory regarding the increase of
IBD (as well as other autoimmune and allergic diseases)
in modern society is the “hygiene hypothesis”, which
proposes that these diseases are caused by an aberrant
1714 April 21, 2012|Volume 18|Issue 15|
 Qin X. Etiology of IBD

A 7 Canada B 7 Canada

6 6

Prevalence of CD in Quebec
Incidence of IBD in Alberta

5 5

4 4

3 3

2 2
Approval of sucralose Approval of sucralose use
1 use in Canada in 1991 1 in Canada in 1991

0 0
1983
1984
1985
1986
1987
1988
1989
1990
1991
1992
1993
1994
1995
1996
1997
1998
1999
2000
2001
2002
2003
2004
2005

1990
1991
1992
1993
1994
1995

1996
1997
1998
1999
2000
2001
2002
C 300 Australia D 10 United States
9
New cases of IBD in Brisbane

in children in north California

Incidence of IBD (CD + UC)
250
8
7
200
6
150 Approval of 5
sucralose use in 4
100 Australia in 1993 3
Approval of sucralose use
2 in United States in 1998
50
1
0 0
1990
1991
1992
1993
1994
1995
1996
1997
1998
1999
2000
2001
2002
2003
2004
2005

1996

1997

1998

1999

2000

2001

2002

2003

2004

2005

2006
E 12 Norway
Incidence of pediatric IBD in Oslo

10

4
Approval of sucralose use by
European Union in 2004
2

0
1990
1991
1992
1993
1994
1995
1996
1997
1998
1999
2000
2001
2002
2003
2004
2005
2006
2007

Figure 4 Relationship between the increase of inflammatory bowel disease and approval of sucralose in countries like Canada, Australia, United States
and Norway. IBD: Inflammatory bowel disease; UC: Ulcerative colitis; CD: Crohn’s disease.

development and response of the immune system due nism for the increased intestinal permeability as well as
to the reduced exposure to microorganisms such as the IBD, featured by the Bacteria-Proteases-Mucus-Barrier
microbes in the gut[127,128]. However, this theory neglected hypothesis.
another fact: the increased intestinal permeability, which As shown in Figure 5, this hypothesis proposes that
has been observed not only in these patients and their the increased intake of dietary chemicals like saccharin
healthy relatives[130,131], but also in their spouse[130,132], sug- and sucralose caused a significant reduction in gut bac-
gesting likely a prerequisite condition for these diseases. teria, along with a failure for prompt replenishment due
As the gut contains such a large amounts of bacteria that to the improved hygiene in modern society. This led to a
are ten times of the number of cells of our body and can remarkable decrease in β-glucuronidase in gut lumen, re-
kill the host thousands of times over, I believe it would sulting in impaired deconjugation of the biliary bilirubin
be the permeability of the gut rather the absolute number and the subsequent inactivation of digestive proteases.
of the bacteria in gut lumen that determined the level of Then these poorly inactivated proteases work synergisti-
exposure[133]. Therefore, the enhanced immune activities cally with the glycosides from the remaining bacteria
seen in these patients may just be a normal response to to cause an accelerated degradation of the mucus layer,
the increased infiltration of bacterial and dietary compo- resulting in damage of the gut barrier (the Bacteria-Pro-
nents from the gut lumen[133]. Then the key to the mystery tease-Mucus-Barrier hypothesis). This will further result
would be to know what caused the increased intestinal in infiltration of bacteria and their components (mainly
permeability in modern society. Here I propose a mecha- in the large intestine) and recruitment of neutrophils

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 Qin X. Etiology of IBD

[20] [21] [137,138] [20,141]

Saccharin , sucralose and some other dietary chemicals in modern society Impaired Inactivation of digestive proteases

[108,139]
Antibiotics → ← other agents? [20,141]
Increased protease activity in the gut lumen

[137]
Inhibition of certain kinds of gut flora Degradation of the
[144]
(-) Meat[145,146]
core peptide of mucin

(-) Failure of replenishment due to the [147]

[137,140]
(par) enteral nutrition
clean diet, water and air

Degradation of the oligosaccharide side chains of mucin

[20,141]
Less b-glucuronidase by excessive amounts of bacterial glycosidases
[144]

[144]
[142] (Mucus in germ-free animals is well preserved )
Probiotics
[20,141]
Impaired conversion of conjugated bilirubin to free bilirubin Loss of mucus layer
[144]

[20] [144]
Decrease bilirubin availability Exposure of epithelium
[143]
(e.g., primary sclerosing cholangitis )
[133,148]
Damage of the epithelium and increase in intestinal permeability ← Nonsteroidal antiinflammatory drugs, etc.

[20] [20,136]
(Mainly in the large intestine ) Inflammation of the gastrointestinal and (In small and large intestine )
Infiltration of bacteria and their components increased immune response of the body
[149]
Infiltration of antigens and particles
(lipopolysaccharide, etc. ) (Dietary, etc. )

Extra-intestinal symptomes
[20] [20]
Recruitment of neutrophils (liver, eye, skin, mouth, etc. )
[149] Recruitment of macrophages and lymphocytes

[20]
Crypt abscess Granuloma
[20]

(Feature of ulcerative colitis) (Feature of Crohn’s disease)

Further reduction in gut bacteria

Figure 5 An overall hypotheses for the cause and mechanism of inflammatory bowel disease (both Crohn’s disease and ulcerative colitis).

lead­ing to the formation of crypt abscess[20], the char- dance with many facts. Figure 6 further illustrated the
acteristic change of UC[134]; while at places or situations mechanism of IBD as well as the relationship between
being relative sterile, the increased infiltration of antigens UC and CD. It explained why gut damage and IBD start-
and particles from gut lumen would result in accumula- ed to appear and became more prevalent along with the
tion of macrophages and formation of inflammatory improved sanitary condition but failed to develop under
granulomas[20], the hallmark of CD[134] (Figure 5). This both conventional and germ-free condition[144], and pre-
would further induce enhanced immune response of dicted a shift of predominance from the bacteria-medi-
the body, leading to further damage of the gut as well as ated UC to antigen/particle-mediated CD along with the
extra-intestinal manifestations in the joints, skin, eyes and decrease in gut bacteria in modern society or other cir-
mouth, etc.[135,136]. More detailed descriptions regarding the cumstances (Figure 6B). It provided a simple explanation
proposed mechanism can be found in the corresponding for many big puzzles in IBD such as: (1) the discrepancy
references[20,21,108,133,136-151]. between the temporal changes of UC vs CD: Many stud-
ies had revealed a regular pattern that UC emerged first,
then reached a plateau or even started to decrease, while
ULCERATIVE COLITIS AND CROHN'S CD showed a delayed appearance but accelerated increase
DISEASE ARE LIKELY JUST TWO with an eventual tendency to pass UC[2]. This would be
just the pattern demonstrated in Figure 6B; (2) The in-
SYMPTOMS OF THE SAME MORBIDITY crease in colonic CD over time: Studies in Stockholm
RATHER THAN TWO DIFFERENT County, Sweden found that colonic CD increased from
15% during 1959-1964 to 32% during 1980-1989, and
DISEASES further to 52% during 1990-2001, while the ileocaecal
The Bacteria-Protease-Mucus-Barrier hypothesis and CD decreased from 58% during 1959-1964 to 41% dur-
mechanism of IBD as described above and illustrated ing 1980-1989, and to 28% during 1990-2001[86,93]. Similar
in Figure 5 suggest that UC and CD share virtually the changes were also observed in other long-term studies
same cause, thus UC and CD would be just two symp- such as the one conducted in Cardiff, United Kingdom[89].
toms of the same morbidity rather than two different Again, Figure 6B illustrated the anticipated shift of UC
diseases. This notion contradicts the current main stream to colonic CD over time; (3) the inverse relationship be-
of thoughts that are trying to dissect UC and CD into tween age and colonic CD in children: It is found that
multiple subtypes with different causes and diverse mech- the younger the children, the more likely they had colonic
anisms[152]. Nevertheless, this new perception is in accor­ CD[153]. This may be just due to the younger the children,

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A Carbohydrate side chains that can be
degraded by glycosidases enriched in gut bacteria
Core peptide that can be broken down by digestive proteases
Single mucin
molecule
Bundles of
mucins
Gut bacteria
Gut lumen
Mucus layer
Epithelial layer
Goblet cell
B
Max Bacterial glycosidases in lower intestine to break
down oligosaccharide side chains of mucin
Mucus degradation, Digestive proteases in
which would be lower intestine to break
parrallel to IBD down core peptide of mucin
CD
IBD
UC
0 in saccharin regulation and consumption among the dif-
0
Conventional Germ free
(Along with improved hygiene and increased intake of inhibitory agents)
Figure 6 Ulcerative colitis and Crohn’s disease are likely just two symp-
toms of the same morbidity rather than two different diseases. A: The
structure of mucin; B: Mechanistic sketch of the temporal changes of ulcerative
colitis (UC) and Crohn’s disease (CD) and their relationship. A reduction in
gut bacteria along with the improved hygiene and increased intake of dietary
chemicals like saccharin and sucralose will result in impairment in digestive
proteases inactivation. The poorly inactivated proteases will work together with
glycosidases from the gut bacteria to cause accelerated degradation of the
mucus layer that is proposed here paralleling the risk of developing inflamma-
tory bowel disease (IBD = UC + CD). UC and CD differ in that UC is caused by
the increased infiltration of bacteria and the resultant recruitment of neutrophils
and formation of crypt abscess, while CD is caused by increased infiltration of
luminal antigens and particles and the resultant recruitment of macrophages
and formation of granulomas. Thus the reduction in gut bacteria along with the
modernization or other factors will result in a shift of predominance from the
bacteria-meditated UC to antigen/particle-mediated CD. Max: Maximum.
the less population of bacteria in their gut; (4) the more
pronounced increase in the risk of CD than UC along
with the use of antibiotics[103]: again, this would be just
the result of shift from UC to colonic CD along with the
dramatic decrease in gut bacteria by the antibiotics; and
(5) the proposed mechanisms as demonstrated in Figure
5 and Figure 6 may even provide some explanation for
the similarities and discrepancies in the susceptible genes
between UC and CD: UC and CD as well as other disea­
ses like psoriasis and ankylosing spondylitis shared some
common genes related to chronic inflammation such as
interleukin-23 pathway, while CD being more associated
with genes related to the function of macrophages such
as NOD2 and autophage, but UC being more associated
WJG|www.wjgnet.com
Qin X. Etiology of IBD
with genes related to neutrophil extravasation and epithe-
lial defense such as LSP1[154].
CONCLUSION
Currently, tremendous efforts have been taking for re-
search on the genes, the microbiota and the immune
system: genome-wide association studies to find out the
susceptible loci among the tens of thousands of genes
in our body; metagenome, metaprotome, and metabo-
lome analyses of gut microbiota that contains more than
100 times of genes than our own genome[155] to find
out the bacteria responsible; and extensive studies on
the many cells, signal pathways, mediators and cytokines
of the immune system to find out aberrant immune re-
sponse[127,128,156-158]. IBD emerged and became epidemic
for about a century, suggesting the factors in environ-
ment rather than the gene or other factors within the
body would be the primary cause. Increased risk of IBD
in twins, families, or the same ethnic groups may attribute
to not only the gene, but also environmental factors they
shared such as the type of diet[159,160]. This article propos-
es saccharin being the key causative factor that contrib-
uted greatly to the emergence and epidemic of IBD in
last century. As described above, there were big variations
ferent countries and also in the different periods or even
different parts (such as the different states in the United
States[161]) within a country. This may explain the constant
temporal changes and big geographical variations in IBD,
and why similar changes were more likely seen within the
border of a country rather than the closeness between
cities[3,5]. In the developed countries, saccharin may be
more frequently used by white collars working in the of-
fice, while saccharin may be more likely consumed by
people in lower class in the developing countries due to
its cheapness. This may contributed to the high incidence
of IBD in high social, economical, educational status in
the developed countries[162], while some early study in In-
dia found almost all the patients belonged to the middle
and poorer classes under poor hygiene condition[163], in
accordance with a heavy saccharin consumption in that
country[164]. This would suggest improved hygiene itself
might facilitate but still not be sufficient, while some
dietary chemicals might be enough to cause significant
impact on gut bacteria and IBD. This notion is also in
accordance with the close relationship of IBD with west-
ernization rather industrialization, as demonstrated by the
much low incidence of IBD in the developed countries
like Japan, Singapore and Hong Kong[138,156]. The recent
increase again of IBD in the developed countries is also
unlikely attribute to a further improvement in hygiene
condition. At early times, saccharin was mainly used as a
tabletop sweetener in the restaurants, tea houses or coffee
shops, thus men may have more chance to consume than
housewives. However, in modern society, dietary drinks
or foods may be more consumed by young ladies for
concerns on their body weight. This may account for the
1717 April 21, 2012|Volume 18|Issue 15|
 Qin X. Etiology of IBD
changes and variations in gender and age of IBD over
time[3,5,6]. The recent finding of the even stronger impact
of sucralose on gut bacteria further provided a possible
explanation for the record high IBD observed recently in
multiple countries[21,114], as well as the remarkable increase
of IBD in children[122]. Epidemiological study revealed
spotted areas with high IBD[165]. Probably we should add
another thing to the checklist: to see if there is any fa-
mous bakery, restaurant, or bar where foods or drinks are
sweetened heavily by these artificial sweeteners.
Although it is proposed here that saccharin and sucra-
lose might be the key causative factors for IBD, it does
not mean to rule out that some other genetic or environ-
mental factors may also be capable of affecting or con-
tributing to IBD one way or the other.
However, the peculiar changes of IBD such as the
recent worldwide increase of IBD, especially in the devel-
oped countries in children, seems unlikely to be explained
by any of the currently suspected factors like the genes,
smoking, NSAIDs, conceptive, appendectomy, sunshine
and vitamin D, refrigeration, reduced exposure to bacte-
ria, virus or worms, etc. Therefore, a fundamental break-
ing through in IBD would largely depend on finding out
the key causative factors in the environment and thus the
root mechanism of IBD. This paper proposed that im-
paired inactivation of digestive proteases due to the inhi-
bition of gut bacteria by dietary chemicals like saccharin
and sucralose being the primary mechanism. This would
suggest it is not any pathogen but the digestive proteases
produced by our body to digest the food for survival
being the principal culprit for IBD. Under conventional
conditions, the commensal bacteria (the microbiota)
would be a valuable partner of our body by helping prom­
ptly inactivating these destructive proteases, probably by
simply providing their enriched β-glucuronidase needed
for deconjugation of biliary bilirubin. Thus the gut mi-
crobiota should be treated as an ‘‘microbial organ” of
the body and taken into consideration when assessing the
toxicity of chemicals or the adverse effects and efficacy
of drugs[150]. However, the microbiota could be benefi-
cial and also could be detrimental. Once there were not
enough gut bacteria to help maintaining the function of
gut barrier, they would start to leak into the body and be-
come the driving force for the chronic inflammation seen
in IBD. Once getting into the body, none of the com-
mensal bacteria will remain our friend and our body will
fight desperately against it. It seems unlikely and might
also be unnecessary to pin down to one or a couples
strains of bacteria exclusively responsible for IBD by
screening the tens of thousands of species of bacteria in
gut microbiota[149]. The enhanced immune activity in IBD
would be just the normal reaction to the infiltrated bacte-
rial and dietary components from gut lumen rather than
an unbalanced or aberrant immune response, which may
explain the remarkable increase of both the Th1-medi-
cated CD and Th2-mediated UC in modern society[133]. It
is proposed here that UC and CD are just two symptoms
of the same morbidity rather than two different diseases.
Some recent studies revealed that colonic CD had be-
WJG|www.wjgnet.com
come the main form of CD[166-168]. Apparently, the CD we
are talking about today is no more the “regional ileitis”
when this disease was defined by Crohn et al[169] in 1932.
These CD cases are also no more the resemblance of
Johne’s disease in cattle, but rather IBD frequently seen
in dogs and cats[146]. Many of the colonic CD diagnosed
today would be just UC cases early. On the other hand,
the advance in endoscopies and other technologies led
to reveal that a substantial portion of UC patients have
ileitis (backwash ileitis) and the prevalence of inflamma-
tion seen in the esophagus, stomach, and duodenum is
comparable among CD and UC[170], further suggesting
the intimate similarities between UC and CD. As stated
above, the discrepancy between the temporal changes of
UC vs CD would actually reflect their intimate connec-
tion. Elucidating the true relationship between UC and
CD would be the crucial step for a full understanding of
IBD.
This paper proposed a unified hypothesis regarding
the etiology for IBD, including the cause and mechanism
of IBD as well as the relationship between UC and CD.
It provides a simple explanation for many puzzles of
IBD. However, just like all other hypothesis and even ex-
isting theories well written in textbooks, it must be tested
against facts. In the last decade, I have contacted multiple
national and international organizations and IBD profes-
sionals suggesting checking out the possible link between
saccharin and IBD, but failed to raise any action. I have
also tried multiple times to apply grants from different
agents, but remain unsuccessful. Hope this article may
draw more attention and efforts. IBD just emerged and
became epidemic for about a century and would be pre-
ventable and also likely curable, but first we may need to
find out the key causative factors and thus the primary
and fundamental mechanism[171].
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S- Editor Gou SX L- Editor A E- Editor Xiong L
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