Bacteroides thetaiotaomicron Ameliorates Colon Inflammation in Preclinical Models of
Crohn’s Disease.
characterized by inflammation along any part of the gastrointestinal (GI) tract which can lead to
fistulas, or abnormal passages that connect different hollow parts of organs to each other.
Although the exact causes of Crohn’s are not known, it is classified as an autoimmune disease because of
the overactivation and infiltration of immune cells to various areas of the GI tract
causing inflammation along the entire thickness.2 It is also known that there are genetic risk
factors, immunological risk factors, and microbiotic risk factors associated with the development
of the disease. Crohn’s disease affects approximately 700,000 people in the United States and can
range in severity from mild flare-ups causing discomfort to severe inflammation and fistulas in the
GI tract that can require surgical procedures.3
It is “widely” believed that Crohn’s is likely triggered by an improperly mounted response to a
shift in the microbiome of the intestinal mucosa.2 The microbiome consists of the various
microscopic organisms, both good and bad, that reside in the mucosa, the protective lining, of the
intestines. In this new preclinical model, Bacteroides thetaiotaomicron (BT) is shown to be a
helpful microorganism in reducing the inflammatory response of the immune system to flare-ups
of Crohn’s. Two different models of Crohn’s diseases were created in germ-free, or isolated, mice in order
to test the effectiveness of BT on alleviating symptoms of Crohn’s flare-ups. Mice were first dosed for 8
days with BT or culture medium (for DSS mice) and then both groups were exposed for 6 days to 3% concentration of dextran sodium sulphate (DSS), which has been established to mimic Crohn’s disease in mice.3 (One group of mice were pure controls and were not exposed to anything.) The researchers then evaluated the weight change, physical changes, and regulation of genes associated with inflammation. They found that mice dosed with BT had less weight loss and less enlargement of GI tissue,4 suggesting less disruption to their diet and lower levels of inflammation. Lower levels of inflammation were also confirmed by observing the decreased activation of pro-inflammatory genes.
Crohn’s Disease.
Recent discoveries in Crohn’s Disease research may give insight into developing future treatments
for people that are affected by the disease.1 Crohn’s disease is an autoimmune disease which is characterized by inflammation along any part of the gastrointestinal (GI) tract which can lead to
fistulas, or abnormal passages that connect different hollow parts of organs to each other.
Although the exact causes of Crohn’s are not known, it is classified as an autoimmune disease because of
the overactivation and infiltration of immune cells to various areas of the GI tract
causing inflammation along the entire thickness.2 It is also known that there are genetic risk
factors, immunological risk factors, and microbiotic risk factors associated with the development
of the disease. Crohn’s disease affects approximately 700,000 people in the United States and can
range in severity from mild flare-ups causing discomfort to severe inflammation and fistulas in the
GI tract that can require surgical procedures.3
It is “widely” believed that Crohn’s is likely triggered by an improperly mounted response to a
shift in the microbiome of the intestinal mucosa.2 The microbiome consists of the various
microscopic organisms, both good and bad, that reside in the mucosa, the protective lining, of the
intestines. In this new preclinical model, Bacteroides thetaiotaomicron (BT) is shown to be a
helpful microorganism in reducing the inflammatory response of the immune system to flare-ups
of Crohn’s. Two different models of Crohn’s diseases were created in germ-free, or isolated, mice in order
to test the effectiveness of BT on alleviating symptoms of Crohn’s flare-ups. Mice were first dosed for 8
days with BT or culture medium (for DSS mice) and then both groups were exposed for 6 days to 3% concentration of dextran sodium sulphate (DSS), which has been established to mimic Crohn’s disease in mice.3 (One group of mice were pure controls and were not exposed to anything.) The researchers then evaluated the weight change, physical changes, and regulation of genes associated with inflammation. They found that mice dosed with BT had less weight loss and less enlargement of GI tissue,4 suggesting less disruption to their diet and lower levels of inflammation. Lower levels of inflammation were also confirmed by observing the decreased activation of pro-inflammatory genes.
Figure 1: Graphical representation of weight loss in DSS Crohn’s model of mice. In DSS exposed
mice, BT significantly decreased weight loss as compared with mice that were not administered any form
of treatment. Control = mice not exposed to DSS or BT. DSS = mice that were exposed to dextran sodiu
sulphate to induce Crohn's like symptoms. DSS/BT = mice exposed to DSS and treated with BT as a
treatment of the gastrointestinal inflammation.
The researchers went on to recreate this experiment in an additional mouse model of Crohn’s
disease. The researchers knocked out an anti-inflammatory molecule interleukin-10 (IL-10) in mice before
birth which causes them to spontaneously develop inflammation in their intestines around 2-4 months of
age.5,6 These mice were also treated with BT 3 times a week for 13-14 weeks. Although this is a slightly
different treatment plan, there were still significant results in the same categories as described above.
Additionally, freeze-dried BT was used in a different cohort of DSS mice to assess the effectiveness of the
organism in its less active form. The freeze-dried version gave nearly identical amelioratory effects as the
regular BT. These variations of administering BT demonstrate multiple prospective treatment options that
would be equally effective in ameliorating Crohn’s symptoms.
mice, BT significantly decreased weight loss as compared with mice that were not administered any form
of treatment. Control = mice not exposed to DSS or BT. DSS = mice that were exposed to dextran sodiu
sulphate to induce Crohn's like symptoms. DSS/BT = mice exposed to DSS and treated with BT as a
treatment of the gastrointestinal inflammation.
The researchers went on to recreate this experiment in an additional mouse model of Crohn’s
disease. The researchers knocked out an anti-inflammatory molecule interleukin-10 (IL-10) in mice before
birth which causes them to spontaneously develop inflammation in their intestines around 2-4 months of
age.5,6 These mice were also treated with BT 3 times a week for 13-14 weeks. Although this is a slightly
different treatment plan, there were still significant results in the same categories as described above.
Additionally, freeze-dried BT was used in a different cohort of DSS mice to assess the effectiveness of the
organism in its less active form. The freeze-dried version gave nearly identical amelioratory effects as the
regular BT. These variations of administering BT demonstrate multiple prospective treatment options that
would be equally effective in ameliorating Crohn’s symptoms.
Figure 2: Colons of IL10KO mice. The mice treated with BT have similar colon structure to the
wild-type mice which represent people without Crohn’s. The IL10KO mouse has significant levels of
inflammation and enlargement which are relieved with the BT treatment. WT=wildtype/control, IL10KO= IL-10 knockout, untreated, IL10KO/BT= IL-10 knockout treated with BT.
wild-type mice which represent people without Crohn’s. The IL10KO mouse has significant levels of
inflammation and enlargement which are relieved with the BT treatment. WT=wildtype/control, IL10KO= IL-10 knockout, untreated, IL10KO/BT= IL-10 knockout treated with BT.
Finally, the researchers synthesized a protein called pirin-like protein BT_0187, which is one of 43
proteins highly expressed by BT in epithelial cell cultures. Although this protein was able to alleviate
some inflammation in rat models of Crohn’s, it was nowhere near as effective as the BT or freeze-dried
BT. It is important to note that they performed this last part of the experiment in rats rather than mice.
Perhaps there would have been a greater effectiveness of the treatment in mice. Or perhaps both mice and
rats are too different than humans for any of these results to be clinically relevant, although hopefully not.
Although the pirin-like protein was ineffective in ameliorating the DSS induced pathology in rats,
it is still important to recognize the accomplishments made in the rest of the article. Bacteroides
thetaiotaomicron would be an easy supplement to treat patients with Crohn’s disease as bacteria
proliferate at exponentially fast levels. Further studies must be conducted in animal models using BT
before starting experimental treatment or supplements in human patients with Crohn’s. The next step
would be to increase the levels of BT in mice that are not “germ-free” in order to evaluate the effects of
the bacteria in conjunction with other microorganisms. Additionally, it would be interesting if research is
done with the other 42 upregulated genes produced by BT that the researchers mentioned but did not name
or evaluate specifically. Perhaps a different protein would have greater effectiveness in humans than it
does in rodent models and be used as an additional treatment. All-in-all, if future trials with BT provide
good results, it could potentially be used as to replace or reduce doses of immunosuppressive drugs which
many Crohn’s patients currently use to treat their disease.3 Immunosuppressants are drugs that cause an
overall decrease in activation of immune cells; this global decrease can leave Crohn’s patients more
susceptible to getting other illnesses. It is important to continue research of BT and other microorganisms
that may ameliorate Crohn’s inflammation because they would be inexpensive, mass producible, and
natural alternatives to medicating patients for any type of relief and comfort. BT could also be used in
addition to common treatments in order to hasten relief or shorten hospital time. This paper effectively
convinces the reader that Bacteroides thetaiotaomicron just may become a treatment of Crohn's disease in the future, so keep your eye out for more!
If you, or someone you know, is struggling with Crohn’s disease, try visiting these websites to get
more information.
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1Delday, Margaret, Imke Mulder, Elizabeth T. Logan, and George Grant. "Bacteroides Thetaiotaomicron
Ameliorates Colon Inflammation in Preclinical Models of Crohn’s Disease." Inflammatory Bowel
Diseases 24, no. 9 (September 12, 2018). doi:10.1093/ibd/izy281.
Ameliorates Colon Inflammation in Preclinical Models of Crohn’s Disease." Inflammatory Bowel
Diseases 24, no. 9 (September 12, 2018). doi:10.1093/ibd/izy281.
2Boyapati, R., Satsangi, J., & Ho, G.-T. (2015). Pathogenesis of Crohn’s disease. F1000Prime Reports, 7,
44. http://doi.org/10.12703/P7-44
44. http://doi.org/10.12703/P7-44
3"Understanding Crohn's Disease." Crohn's and Colitis. Accessed September 27, 2018.
https://www.crohnsandcolitis.com/crohns/disease-treatment.
https://www.crohnsandcolitis.com/crohns/disease-treatment.
4Kiesler, P., Fuss, I. J., & Strober, W. (2015). Experimental Models of Inflammatory Bowel Diseases.
Cellular and Molecular Gastroenterology and Hepatology, 1(2), 154–170.
Cellular and Molecular Gastroenterology and Hepatology, 1(2), 154–170.
5Berg, D. J., Davidson, N., Kühn, R., Müller, W., Menon, S., Holland, G., … Rennick, D. (1996).
Enterocolitis and colon cancer in interleukin-10-deficient mice are associated with aberrant cytokine
production and CD4(+) TH1-like responses. Journal of Clinical Investigation, 98(4), 1010–1020.
Enterocolitis and colon cancer in interleukin-10-deficient mice are associated with aberrant cytokine
production and CD4(+) TH1-like responses. Journal of Clinical Investigation, 98(4), 1010–1020.
6Wang, Honggang, Peiliang Shi, Lugen Zuo, Jianning Dong, Jie Zhao, Qinghong Liu, and Weiming Zhu.
"Dietary Non-digestible Polysaccharides Ameliorate Intestinal Epithelial Barrier Dysfunction in IL-10
Knockout Mice." Journal of Crohns and Colitis 10, no. 9 (2016): 1076-086. doi:10.1093/ecco-jcc/jjw065.
"Dietary Non-digestible Polysaccharides Ameliorate Intestinal Epithelial Barrier Dysfunction in IL-10
Knockout Mice." Journal of Crohns and Colitis 10, no. 9 (2016): 1076-086. doi:10.1093/ecco-jcc/jjw065.
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