Early gut colonization and type 1 diabetes mellitus

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Caesarean section, commonly known as C-section, is a surgical procedure that allows pregnant women to deliver one or more babies through incisions made in the abdomen and uterus. In the case that vaginal delivery poses a serious threat to the health to either the mother or the child, C-section is a successful and often necessary alternative to vaginal delivery. From 1996 to 2009, the rate of C-section among all gestational age groups increased by more then 40 percent in the United States alone, a trend that has benefited from an increase in social tolerance of surgical intervention, from monetary incentives on the part of healthcare providers and from limited patient awareness of short and long-term risks associated with the procedure^1,2.

Recent medical interest in the human gut flora, or gut microbiotia, has yielded multiple studies that suggest that mode of delivery heavily impacts early colonization of the infant gut microbial community and potentially alters the long-term composition and diversity of the gut microbiotia. Furthermore, a growing body of evidence links both aberrance of the gut microbiotia and mode of delivery with increased risk for immune disorders including allergy, gastrointestinal disease, and type 1 diabetes mellitus³. Coincidently, the American Diabetes Association reported a 23 percent increase in the number of reported cases of type 1 diabetes from 2001 to 2009, a trend that may be driven by a variety of environmental factors⁴. As a potential risk factor for type 1 diabetes, C-section and consequent aberrance of the gut microbiotia have recently received scrutiny in the context of early and late immune health.

Modes of Delivery

Vaginal Delivery

When an infant passes through its mother’s birth canal during vaginal delivery, it is exposed to its first non-sterile environment outside the uterus via direct contact with the vagina and its own mucous membranes. The vagina is typically colonized by a wide variety of anaerobic bacteria and is dominated by several species of lactic acid bacteria^5,6. During delivery, infants also come into contact with the microbes that colonize their mothers’ feces as a result of the proximity of the birth canal and the anus⁵ Direct contact with the mother’s lower genital tract and anus initiates colonization of the infant’s skin and oral mucosa, and eventually of the infant’s intestinal tract, which is first dominated by facultative anaerobes including enterobacteria and lactobacilli, and then dominated by other anaerobes including Bifidobacteria, Bacteroides, Clostridia and Eubacteria⁷. Following expulsion from the birth canal, infants are continuously exposed to environmental, oral and cutaneous microbes through mother-infant contact and environmental exposure, and they continue to ingest gut-colonizing microbes during the breastfeeding process. By two years of age, most healthy infants show a gut microbial composition similar to that of a typical healthy adult⁵.

Caesarean Section

During delivery by C-section, the infant bypasses the birth canal and is directly removed from the mother’s body through incisions made in her abdomen and uterus⁸. As opposed to initial microbial exposure via direct vaginal and anal contact, infants delivered by C-section are initially exposed to microbial isolates from the medical and nursing staff, surgical equipment and other elements of the immediate external environment⁵. As a result, early microbial composition—including diversity and total cell count—of the skin and oral/nasal mucosa in infants delivered by C-section differs greatly from the early microbiotia of infants delivered vaginally. Directly following delivery, the skin and oral/nasal mucosa microbiotia of vaginally delivered infants resemble the mother’s vaginal microbiotia and are dominated by the Lactobacillus genus. The microbiotia of infants delivered by C-section closely resemble the microbiotia of skin surfaces and is dominated by Staphylococcus⁹.

Gut Microbiotia Aberrance

Initial colonization of the skin and mucous membranes is closely linked with the successive colonization of the infant intestinal tract, whose composition is highly affected by the initial composition of the mucosal microbiotia. During the first month of life, the infant gut microbiotia is composed predominantly of Bifidobacteria, a genus of Gram-positive anaerobes that are found in moderate numbers in the lower female genital tract. In a 2007 study that controlled for variant breastfeeding among test subjects, a group of researchers from Finland found that the number of bifidobacteria in vaginally delivered infants was 1,300-fold higher than in infants delivered by C-section at one month of age⁷. The same study reported significantly hampered mucosal immunity in C-section infants at 6 months of age, which suggests that early composition of the gut microbiotia may be related to immune health.

Type 1 diabetes

Type 1 diabetes mellitus (T1DM), commonly known as type 1 diabetes, is a metabolic autoimmune disease that develops in early childhood or adolescence. The disease is characterized by chronic hyperglycemia, which results from defects in insulin production due to autoimmune destruction of insulin-producing beta cells in the pancreas¹¹. The precise cause of T1DM is so far unknown, although individuals with a family history of the disease are known to be at higher risk for developing T1DM. Beyond genetic susceptibility, T1DM is currently thought to be triggered by one or more environmental factors¹².

Pathophysiology

Within the pancreas, regions of endocrine cells called the islets of Langerhans are responsible for producing hormones like glucagon, insulin and amylin. Beta cells, which are one of the five secretory cells located within the islets of Langerhans, are responsible for storing and secreting insulin and amylin directly into the bloodstream. When beta cells become damaged or undergo turnover, they release autoantigens which, in healthy individuals, are not recognized by the immune system¹⁶. However, when these autoantigens are received by antigen-presenting cells within the pancreas that recognize the autoantigens as foreign bodies, namely macrophages and dendritic cells, CD4+ T cells become activated by the signals secreted by the antigen-presenting cells. These activated CD4+ T cells induce the differentiation of CD8+ T cells into cytotoxic T cells, which are involved in the destruction of beta cells¹⁴.

Animal Models

Recent studies of type 1 diabetes in animal models suggest that the composition of the gut microbiotia is closely linked with autoimmune diabetes. In a 2009 study that compared the bacterial genera in the guts of diabetes resistant (BB-DR) and diabetes-prone (BB-DP) biobreeding rats, researchers found a higher abundance of the probiotic Lactobacillus and Bifidobacterium genera in BB-DR rats, suggesting that a lack of these bacteria in the rodent gut microbiotia is associated with the onset of type 1 diabetes¹³. As the most likely culprit of beta cell autoimmunity, antigen-specific T cell activation in diabetic individuals may be induced by the presence and/or absence of specific bacteria within the gut, which may determine an individual’s risk for developing autoimmune diabetes.

Immunomudulatory effect of Bifidobacteria

Microscope image of Gram-stained B. adolescentis, magnification 1000x. By Y tambe. http://upload.wikimedia.org/wikipedia/commons/3/35/Bifidobacterium_adolescentis_Gram.jpg

References

1. Osterman MJK, Martin JA. Changes in cesarean delivery rates by gestational age: United States, 1996–2011. NCHS data brief, no 124. Hyattsville, MD: National Center for Health Statistics. 2013. http://www.cdc.gov/nchs/data/databriefs/db124.htm#x2013;2011</a

2. "Why Is the National U.S. Cesarean Section Rate So High?" Why the National U.S. C-Section Rate Is So High. N.p., n.d. Web. http://www.childbirthconnection.org/article.asp?ck=10456

3. Cho, C. E., & Norman, M. “Cesarean section and development of the immune system in the offspring.” American Journal of Obstetrics and Gynecology 208.4 (2013): 249–54. Web. http://www.ncbi.nlm.nih.gov/pubmed/22939691

4. "Growing Number of Autoimmune Disease Cases Reported." Newswise. American Autoimmune Related Diseases Association, 21 June 2012. Web. http://www.newswise.com/articles/growing-number-of-autoimmune-disease-cases-reported

5. Mackie RI, Sghir A, Gaskins HR. Developmental microbial ecology of the neonatal gastrointestinal tract. Am J Clin Nutr 1999; 69: 1035S–1045S. http://ajcn.nutrition.org/content/69/5/1035s.short

6. Vásquez, Alejandra et al. “Vaginal Lactobacillus Flora of Healthy Swedish Women.” Journal of Clinical Microbiology 40.8 (2002): 2746–2749. PMC. Web. 20 Mar. 2015. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC120688/

7. Huurre, Anu, et al. "Mode of delivery-effects on gut microbiota and humoral immunity." Neonatology 93.4 (2008): 236. Web. http://www.ncbi.nlm.nih.gov/pubmed/18025796

8. "C-Section: What Can You Expect for Recovery?" MedicineNet. N.p., n.d. Web. http://www.medicinenet.com/c-section_cesarean_birth/article.htm

9. Dominguez-Bello MG, Costello EK, Contreras M, Magris M, Hidalgo G, Fierer N & Knight R. “Delivery mode shapes the acquisition and structure of the initial microbiota across multiple body habitats in newborns.” PNAS 107 (2010): 11971–11975. http://www.pnas.org/content/107/26/11971.full

11. "About diabetes". World Health Organization. http://www.who.int/diabetes/action_online/basics/en/

12. Belle, T. L. Van, K. T. Coppieters, and M. G. Von Herrath. "Type 1 Diabetes: Etiology, Immunology, and Therapeutic Strategies." Physiological Reviews 91.1 (2011): 79-118. Web. http://www.ncbi.nlm.nih.gov/pubmed/21248163

13. Roesch, Luiz Fw, Graciela L. Lorca, George Casella, Adriana Giongo, Andres Naranjo, Arianna M. Pionzio, Nan Li, Volker Mai, Clive H. Wasserfall, Desmond Schatz, Mark A. Atkinson, Josef Neu, and Eric W. Triplett. "Culture-independent Identification of Gut Bacteria Correlated with the Onset of Diabetes in a Rat Model." The ISME Journal 3.5 (2009): 536-48. Web. http://www.ncbi.nlm.nih.gov/pubmed/19225551

14. Yoon J.-W., Jun H.-S. Autoimmune destruction of pancreatic β cells. American Journal of Therapeutics. 2005;12(6):580–591. http://www.ncbi.nlm.nih.gov/pubmed/16280652

16. Poletaev AB, Churilov LP, Stroev YI, Agapov MM. (2012). "Immunophysiology versus immunopathology: Natural autoimmunity in human health and disease." Pathophysiology. http://www.pathophysiologyjournal.com/article/S0928-4680(12)00081-8/abstract

Edited by Kathleen Muenzen, a student of Nora Sullivan in BIOL168L (Microbiology) in The Keck Science Department of the Claremont Colleges Spring 2014.