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. 2025 Mar 2:42:101964.
doi: 10.1016/j.bbrep.2025.101964. eCollection 2025 Jun.

Intestinal antibody repertoire is altered by diabetes and varies depending on the pathogenesis

Miho Chikazawa  1 , Ken-Ichiro Minato  1
Affiliations

Intestinal antibody repertoire is altered by diabetes and varies depending on the pathogenesis

Miho Chikazawa et al. Biochem Biophys Rep. .

Abstract

Intestinal immunity is an important system for host defense and it is influenced by various factors such as diet and diseases. To elucidate the relationship between intestinal immunity and type 2 diabetes, we analyzed the effects of diabetes on intestinal antibody production and IgA repertoire using high-fat diet-fed mice and genetically diabetic KK-Ay mice model. The antibody level in the small intestine increased only in KK-Ay mice. We also confirmed that the IgA repertoire in both models experienced significant changes when compared to that in control mice, and no shared characteristics were observed between the two diabetic models. Antibody production in the intestine is influenced by stimuli associated with the onset of diabetes, and the types of induced IgA would differ depending on the process of disease onset.

Keywords: Antibody repertoire; Diabetes; IgA; Intestinal immunity.

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Conflict of interest statement

The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Miho Chikazawa reports financial support was provided by Government of Japan Ministry of Education Culture Sports Science and Technology. Miho Chikazawa reports financial support was provided by Public Interest Foundation 10.13039/501100011907Mishima Kaiun Memorial Foundation. Ken-Ichiro Minato reports financial support was provided by Research Institute of 10.13039/501100009380Meijo University. Miho Chikazawa reports writing assistance was provided by Enago.

Figures

Fig. 1
Fig. 1
Characteristics of HFD and KK-Aydiabetic mice. (A) Total body weight (n = 6–7). (B) Serum glucose and (C) urinary glucose levels of non-diabetic control mice, HFD, and KK-Ay mice (n = 5–7), respectively. Serum was collected at 17 weeks of age, and urine was collected at 14 weeks of age. Each symbol represents a mouse. Differences were analyzed by Dunnett's test (A) and Tukey's test (B and C). ∗, p < 0.05; ∗∗, p < 0.01; ∗∗∗, p < 0.001; versus control.
Fig. 2
Fig. 2
Determination of immunoglobulin levels in the small intestine. (A) Western blotting of intestinal fluid IgA (n = 4) at 17 weeks. Intestinal fluid was subjected to SDS–PAGE. Antibodies were visualized by Western blotting using anti-IgA antibodies. (B) Gut IgA and (C) IgG, and (D) fecal IgA levels at 17 weeks (gut) or 14 weeks (feces) were determined by ELISA. Each symbol represents a mouse. Differences were analyzed by Tukey's test. ∗∗, p < 0.01; ∗∗∗, p < 0.001; versus Control.
Fig. 3
Fig. 3
Clonal distributions of intestinal B-cell repertoires. The number of CDR3 sequences of (A) IgA heavy chain and (B) kappa light chain. Shannon's entropy of BCR repertoire in the (C) IgH region of IgA and (D) IgK region. (E) The distribution of CDR3 lengths of IgH in Control, HFD, and KK-Ay mice. Heatmaps were generated from sequences with ≥10 reads.
Fig. 4
Fig. 4
Clonal overlap of CDR3 sequences in small intestinal antibodies among the three groups. Number of overlapped sequences of (A) IgA heavy chain and (D) kappa light chain. Comparison of high-frequency CDR3 sequences of (B) IgH and (E) IgK in each group. Heat map indicates the distribution of highly read IgA IgH sequences. The y-axis shows each (B) 124 and (E) 334 sequences that were detected with ≥500 reads. Ten sequences each for (C) IgH and (F) IgK with the highest total number of reads.
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