Background and Aims: For women with inflammatory bowel disease [IBD], it is not very well known how IBD or IBD treatment affects their breast milk components. We aimed to investigate whether breast milk composition differs in healthy control [HC] versus IBD mothers in terms of antibodies, cytokines, and metabolite,s to identify potential impact of IBD breast milk on neonatal immune system. Methods: Breast milk specimens from HC [n = 17] and IBD [n = 31 for Crohn's disease [CD]; and n = 41 for ulcerative colitis [UC]; were collected at 3 and 6 months postpartum [PP3] and [PP6], respectively. Faecal samples were also collected. Cytokines and immunoglobulins [IgA/IgG/IgE] were analysed by multiplex Meso Scale Discovery [MSD] and commercial kits. Moreover, breast milk metabolites were analysed by 1 H nuclear magnetic resonance [NMR]. Results: We found that breast milk from IBD mothers showed significantly lower levels of IgA, sugar metabolite [lactose], and 2-aminobutyrate. In contrast, we observed that breast milk from mothers with IBD had increased levels of pro-inflammatory cytokines and higher energy metabolites [lactate and succinate] than milk from healthy mothers. In addition, we noticed that the type of treatment [5-aminosalicylic acid versus biologics] influenced the milk cytokines and metabolites profile. Conclusions: The reduction in immunoprotective components of IBD breast milk such as sIgA and lactose theoretically may modulate the potential protective effects of breastfeeding. On the other hand, presence of higher levels of pro-inflammatory cytokines, lactate, and succinate may predispose the offspring to an inflammatory condition or impact on the gut microbiome. Better understanding of the role of succinate in infants and its potential effects on microbiome or mucosal immunity merits further investigations.

The mammalian Na/H exchanger isoform 1 (NHE1) is an integral membrane protein that regulates intracellular pH (pH) by removing a single intracellular proton in exchange for one extracellular sodium ion. It is involved in cardiac hypertrophy and ischemia reperfusion damage to the heart and elevation of its activity is a trigger for breast cancer metastasis. NHE1 has an extensive 500 amino acid N-terminal membrane domain that mediates transport and consists of 12 transmembrane segments connected by intracellular and extracellular loops. Intracellular loops are hypothesized to modulate the sensitivity to pH. In this study, we characterized the structure and function of intracellular loop 5 (IL5), specifically amino acids 431-443. Mutation of eleven residues to alanine caused partial or nearly complete inhibition of transport; notably, mutation of residues L432, T433, I436, N437, R440 and K443 demonstrated these residues had critical roles in NHE1 function independent of effects on targeting or expression. The nuclear magnetic resonance (NMR) solution spectra of the IL5 peptide in a membrane mimetic sodium dodecyl sulfate solution revealed that IL5 has a stable three-dimensional structure with substantial alpha helical character. NMR chemical shifts indicated that K438 was in close proximity with W434. Overall, our results show that IL5 is a critical, intracellular loop with a propensity to form an alpha helix, and many residues of this intracellular loop are critical to proton sensing and ion transport.

Inflammatory bowel diseases (IBD), including Ulcerative Colitis (UC) and Crohn’s disease (CD), are inflammatory conditions of the intestinal tract that affect women in their reproductive years. Pregnancy affects Th1- and Th2-cytokines, but how these changes occur during pregnancy in IBD is unclear. We performed a longitudinal profiling of serum cytokines in a cohort of 11 healthy pregnant women and 76 pregnant women with IBD from the first trimester of pregnancy to the first 12 months post-partum. Participants were monitored for biochemical disease activity (C-reactive protein [CRP] and fecal calprotectin [FCP]) and clinical activities. Maternal cytokines were measured using ELISA. We identified changes in Th1 and Th17 cytokines throughout pregnancy in healthy pregnant women. During pregnancy, maternal serum cytokine expressions were influenced by IBD, disease activity, and medications. Active UC was associated with an elevation in IL-21, whereas active CD was associated with elevated IFN-γ, IL-6, and IL-21. Interestingly, T1 serum cytokine levels of IL-22 (>0.624 pg/mL) and IL-6 (>0.648 pg/mL) were associated with worse IBD disease activity throughout pregnancy in women with UC and CD, respectively. This shows serum cytokines in pregnancy differ by IBD, disease activity, and medications. We show for the first time that T1 IL-22 and IL-6 correlate with IBD disease course throughout pregnancy.

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