# Primordially conserved principles governing mucosal immune responses to microbiota

> **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 2022 · $343,986

## Abstract

Throughout evolutionary time, specific immunoglobulin (Ig) isotypes have become specialized in the maintenance
of MB homeostasis. In mammals, secretory IgA (sIgA), plays the predominant role in MB regulation. We have
demonstrated that sIgT acts as the functional analog of sIgA in fish. Thus, the primordially conserved functions of
sIgA and sIgT strongly support the use of fish as an alternative vertebrate model for the study of mucosal
immunity.
 While the current dogma indicates that sIgA is the predominant isotype regulating MB homeostasis, it has
recently been shown that sIgM recognizes and coats a large percentage of the luminal MB in humans and may
assist sIgA in anchoring a highly diverse MB to mucus in the human gut. Intriguingly, sIgM does not coat gut
MB in mice, thus precluding further investigation of the specific contributions of sIgA and sIgM in the
maintenance of MB homeostasis in this experimental system. Critically, we have shown that as in humans, fish
sIgM targets a significant portion of the gut MB. Thus, fish provide a unique tractable vertebrate model to address
the role of IgM in the regulation of gut MB. Using this system, we provide the first demonstration that distinct
immunoglobulins (IgT and IgM) primarily recognize different gut bacterial taxa in a non-mammalian species. This
finding leads us to hypothesize unique and complementary roles for sIgT and sIgM in the recognition,
regulation and control of gut MB.
 Several recent studies in mammals suggest that MB-specific IgA and IgG in the serum play an important
role in the resolution of MB-induced sepsis. However, the involvement of serum IgM in these systemic
responses, and the nature of the microbial taxa inducing such responses, are still ill-defined. Here, we show that
fish serum contains very high levels of MB-specific-IgM, whereas those of IgT are negligible. These data lead us
to hypothesize that serum IgM plays a critical role in the recognition and control of systemically
translocated dysbiotic MB. Moreover, following colitis-induced dysbiosis, we primarily find phagocytic IgT+ B
cells with internalized dysbiotic MB in the gut, while phagocytic IgM+ B cells predominate in the spleen. These
results lead us to hypothesize that IgT+ and IgM+ B cells play distinct but complementary roles in the
control of dysbiotic MB.
 To test the above mentioned hypotheses, we will use our newly developed fish models that lack IgT, IgM
or both, in combination with our novel DSS-induced colitis fish model. We predict that our studies with fish will
provide a unique phylogenetic dimension to the field.
 Thus, the aims of this proposal are: AIM 1. Specific contributions of sIgT and sIgM in the maintenance of
MB homeostasis; AIM 2. MB taxa recognition and protective roles of sIgT and sIgM in MB-induced sepsis; AIM
3. Contributions of IgT+ and IgM+ B cells in the recognition and control of dysbiotic MB.

## Key facts

- **NIH application ID:** 10322114
- **Project number:** 5R01GM085207-12
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** J. ORIOL SUNYER
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $343,986
- **Award type:** 5
- **Project period:** 2010-09-01 → 2023-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10322114

## Citation

> US National Institutes of Health, RePORTER application 10322114, Primordially conserved principles governing mucosal immune responses to microbiota (5R01GM085207-12). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10322114. Licensed CC0.

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