Commensal Bacteria Modulate Immunoglobulin A Binding in Response to Host Nutrition

Huus, Kelsey E.; Bauer, Kylynda C.; Brown, Eric; Bozorgmehr, Tahereh; Woodward, Sarah E.; Serapio-Palacios, Antonio; Boutin, Rozlyn C.T.; Petersen, Charisse; Finlay, B. Brett

doi:10.1016/j.chom.2020.03.012

Cited by 71 publications

(79 citation statements)

References 61 publications

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“…Immunoglobulin (Ig) A regulates host-bacterial homeostasis in the mammalian gut [14,15]. Studies of IgAtargeted bacteria indicate that acute undernutrition and inflammatory bowel disease are both associated with altered interactions between IgA and the intestinal microbiota [16][17][18][19]. Acutely malnourished children had higher IgA-targeting of Bacteroidales and Escherichia coli, while patients with inflammatory bowel disease (IBD) had higher targeting of a variety of bacteria including Haemophilus and E. coli [16][17][18], and these IgA+ bacteria induced intestinal inflammation and disease when transferred into germ-free mice.…”

Section: Introductionmentioning

confidence: 99%

“…Acutely malnourished children had higher IgA-targeting of Bacteroidales and Escherichia coli, while patients with inflammatory bowel disease (IBD) had higher targeting of a variety of bacteria including Haemophilus and E. coli [16][17][18], and these IgA+ bacteria induced intestinal inflammation and disease when transferred into germ-free mice. Moreover, chronic undernutrition in mice directly alters IgA recognition of the microbiota, in part by driving bacterial dietary adaptation [19]. Here, we investigated whether chronic undernutrition and EED are also associated with altered Igrecognition of the microbiota in children, using two geographically distinct populations from the Afribiota study.…”

Section: Introductionmentioning

confidence: 99%

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Immunoglobulin recognition of fecal bacteria in stunted and non-stunted children: findings from the Afribiota study

et al. 2020

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Background: Child undernutrition is a global health issue that is associated with poor sanitation and an altered intestinal microbiota. Immunoglobulin (Ig) A mediates host-microbial homeostasis in the intestine, and acutely undernourished children have been shown to have altered IgA recognition of the fecal microbiota. We sought to determine whether chronic undernutrition (stunting) or intestinal inflammation were associated with antibody recognition of the microbiota using two geographically distinct populations from the Afribiota project. Fecal bacteria from 200 children between 2 and 5 years old in Antananarivo, Madagascar, and Bangui, Central African Republic (CAR), were sorted into IgA-positive (IgA+) and IgA-negative (IgA−) populations by flow cytometry and subsequently characterized by 16S rRNA gene sequencing to determine IgA-bacterial targeting. We additionally measured IgG+ fecal bacteria by flow cytometry in a subset of 75 children. Results: Stunted children (height-forage z-score ≤ −2) had a greater proportion of IgA+ bacteria in the fecal microbiota compared to non-stunted controls. This trend was consistent in both countries, despite the higher overall IgA-targeting of the microbiota in Madagascar, but lost significance in each country individually. Two of the most highly IgA-recognized bacteria regardless of nutritional status were Campylobacter (in CAR) and Haemophilus (in both countries), both of which were previously shown to be more abundant in stunted children; however, there was no association between IgA-targeting of these bacteria and either stunting or inflammatory markers. IgGbound intestinal bacteria were rare in both stunted and non-stunted children, similar to levels observed in healthy populations.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Immunoglobulin recognition of fecal bacteria in stunted and non-stunted children: findings from the Afribiota study

et al. 2020

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“…To select between using the IgA+ Probability or Probability Ratio: if the sole interest is to identify taxa most likely to bind IgA then the IgA+ Probability is sufficient and benefits from its direct interpretability as a probability of IgA binding (ranging from 0-1); otherwise the Probability Ratio provides a more generally applicable score that also provides better resolution of relative binding between taxa with lower IgA binding. For example, detecting the loss of Lactobacillus binding in undernourished mice detected in the Huus et al study [20]. The Probability Ratio additionally benefits from being centred on zero, so a positive or negative score indicates if the majority of a taxon's bacteria fall into the IgA+ or IgA-fraction respectively.…”

Section: Discussionmentioning

confidence: 99%

“…used FACS-based IgA-Seq to study bacterial binding of GI IgA in a mouse model of nutrient restriction [20]. Mice on a conventional (CON) or moderately malnourished diet (MAL) were tracked from weaning to adulthood.…”

Section: The Probability Ratio Increases Power To Detect Differences mentioning

confidence: 99%

“…IgA-Seq is additionally limited to scoring relative, overall, IgA binding between taxa. Understanding what drives the observed differences, such as alterations in the spatial distribution of bacteria or changes in the affinities of host IgA, requires additional targeted experiments, such as fluorescence in situ hybridisation and enzyme-linked immunosorbent assays[10,20].We have developed an optimised experimental protocol and novel scoring methodologies for IgA-Seq. These enable robust and accurate identification of commensal bacteria targeted by the host immune response.…”

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Accurate identification and quantification of commensal microbiota bound by host immunoglobulins

Jackson

Pearson

Ilott

et al. 2020

Preprint

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Background: Identifying which taxa are targeted by immunoglobulins can uncover important host-microbe interactions. Immunoglobulin binding of commensal taxa can be assayed by sorting bound bacteria from samples and using amplicon sequencing to determine their taxonomy, a technique most widely applied to study Immunoglobulin A (IgA-Seq). Previous experiments have scored taxon binding in IgA-Seq datasets by comparing abundances in the IgA bound and unbound sorted fractions. However, as these are relative abundances, such scores are influenced by the levels of the other taxa present and represent an abstract combination of these effects. Diversity in the practical approaches of prior studies also warrants benchmarking of the individual stages involved. Here, we provide a detailed description of the design strategy for an optimised IgA-Seq protocol. Combined with a novel scoring method for IgA-Seq datasets that accounts for the aforementioned effects, this platform enables accurate identification and quantification of commensal gut microbiota targeted by host immunoglobulins. Results: Using germ-free and Rag1-/- mice as negative controls, and a strain-specific IgA antibody as a positive control, we determine optimal reagents and fluorescence activated cell sorting (FACS) parameters for IgA-Seq. Using simulated IgA-Seq data, we show that existing IgA-Seq scoring methods are influenced by pre-sort relative abundances. This has consequences for the interpretation of case-control studies where there are inherent differences in microbiota composition between groups. We show that these effects can be addressed using a novel scoring approach based on posterior probabilities. Finally, we demonstrate the utility of both the IgA-Seq protocol and probability-based scores by examining both novel and published data from in vivo disease models. Conclusions: We provide a detailed IgA-Seq protocol to accurately isolate IgA-bound taxa from intestinal samples. Using simulated and experimental data, we demonstrate novel probability-based scores that adjust for the compositional nature of relative abundance data to accurately quantify taxon-level IgA binding. All scoring approaches are made available in the IgAScores R package. These methods should improve the generation and interpretation of IgA-Seq datasets and could be applied to study other immunoglobulins and sample types.

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Gut microbes shape microglia and cognitive function during malnutrition

Bauer

York

Cirstea

et al. 2022

Glia

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Fecal-oral contamination promotes malnutrition pathology. Lasting consequences of early life malnutrition include cognitive impairment, but the underlying pathology and influence of gut microbes remain largely unknown. Here, we utilize an established murine model combining malnutrition and iterative exposure to fecal commensals (MAL-BG). The MAL-BG model was analyzed in comparison to malnourished (MAL mice) and healthy (CON mice) controls. Malnourished mice display poor spatial memory and learning plasticity, as well as altered microglia, non-neuronal CNS cells that regulate neuroimmune responses and brain plasticity. Chronic fecal-oral exposures shaped microglial morphology and transcriptional profile, promoting phagocytic features in MAL-BG mice. Unexpectedly, these changes occurred independently from significant cytokine-induced inflammation or blood-brain barrier (BBB) disruption, key gut-brain pathways. Metabolomic profiling of the MAL-BG cortex revealed altered polyunsaturated fatty acid (PUFA) profiles and systemic lipoxidative stress. In contrast, supplementation with an ω3 PUFA/antioxidant-associated diet (PAO) mitigated cognitive deficits within the MAL-BG model. These findings provide valued insight into the malnourished gut microbiota-brain axis, highlighting PUFA metabolism as a potential therapeutic target.

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Commensal Bacteria Modulate Immunoglobulin A Binding in Response to Host Nutrition

Abstract: Highlights d Dietary undernutrition in mice abolishes IgA targeting of intestinal Lactobacillus d Loss of this targeting is the result of bacterial adaptations to nutrient limitation d Lactobacillus-IgA interactions are glycan mediated and linked to sugar metabolism genes

Cited by 71 publications

References 61 publications

Immunoglobulin recognition of fecal bacteria in stunted and non-stunted children: findings from the Afribiota study

Immunoglobulin recognition of fecal bacteria in stunted and non-stunted children: findings from the Afribiota study

Accurate identification and quantification of commensal microbiota bound by host immunoglobulins

Gut microbes shape microglia and cognitive function during malnutrition

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