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Evidence for the Role of the Cecal Microbiome in Maintenance of Immune Regulation and Homestasis.
Preeti Chhabra*1, Anthony Spano*1, Daniel Bowers*1, Tiantian Ren*1, Christopher Wilson*2, Andrew Marshall*3, Michael Timko*1, Martin Wu*1, Daniel Moore*1, Kenneth L. Brayman1

OBJECTIVE(S): Our objective was to investigate alterations in the cecal microbial composition during the development of Type 1 Diabetes (T1D) with or without IgM therapy, and correlate these alterations with the corresponding immune profile.
METHODS: 1) Female non-obese diabetic (NOD) mice treated with IgM or saline (n=20/grp) were divided into 5wks−old non-diabetic; 9-12wks−old prehyperglycemic stage-1; ≥13wks−old prehyperglycemic stage-2; and diabetic groups. 16S rRNA libraries were prepared from bacterial DNA and deep-sequenced. 2) New-onset diabetic mice were treated with IgM (100ug on Day1 and Day4) and their blood glucose monitored for two months.
RESULTS: Significant dysbiosis was observed in the cecal microbiome with the progression of T1D development. The alteration in microbiome composition was characterized by an increase in the bacteroidetes:firmicutes ratio. In contrast, IgM conserved normal bacteroidetes:firmicutes ratio and this effect was long-lasting. Furthermore, oral gavage using cecal content from IgM-treated mice significantly diminished the incidence of diabetes compared to controls. Also, regulatory immune cell populations (myeloid derived suppressor cells and regulatory Tcells) were expanded and insulin autoantibody production diminished in the IgM-treated mice. No significant difference was observed in the fecal microbial composition between IgM-treated and control groups over time, indicating that IgM may specifically affect mucosa-associated microbes, possibly in a manner involving mucosal immunity. Additionally, IgM therapy reversed hyperglycemia in 63% of new-onset diabetic mice (n=11) and the mice remained normoglycemic for the entire post-treatment observation period.
CONCLUSIONS: The cecal microbiome appears to be important in maintaining immune homeostasis and normal immune responses.

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