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Impact of a Western-style diet on small-intestinal mucosal barrier function
Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). (Björn Schröder)ORCID iD: 0000-0003-4898-5673
2024 (English)Doctoral thesis, comprehensive summary (Other academic)Alternative title
Effekten av en västerländsk kost på tunntarmsslemhinnans barriärfunktion (Swedish)
Abstract [en]

Specialized defense mechanisms at mucosal barriers along the gastrointestinal tract constantly protect us against the trillions of microorganisms living inside the human body. These mechanisms include a mucus layer as a physical barrier that prevents bacteria from reaching the epithelium and the production of antimicrobial peptides (AMPs) as a chemical barrier that helps neutralize or lyse these bacteria. On the other hand, many intestinal bacteria benefit human health by providing colonization resistance against pathogenic bacteria, helping produce vitamins, aiding in the digestion of complex carbohydrates, and producing anti-inflammatory short-chain fatty acids. Therefore, the intestinal mucosal barrier has the challenging task of maintaining a homeostatic interaction between the host and the intestinal microbiota. 

Alterations in the integrity of the mucus barrier and the expression of AMPs have been associated with inflammatory bowel disease and obesity. This thesis investigates how the intake of a high-fat and low-fiber Western-style diet (WSD) as an exogenous factor can affect the protective function of the mucus barrier and intestinal AMPs in mice with or without modulation of the microbiota.

In paper 1 “Intestinal α-Defensins Play a Minor Role in Modulating the Small Intestinal Microbiota Composition as Compared to Diet” we fed wild-type and Mmp7-/- mice, which lack active a-defensins, the major family of AMPs in the small intestine, a control or a WSD.  We found that diet had a stronger impact on modulating small intestinal microbiota composition, while defensins only modulated the abundance of specific bacteria. In addition, defensins protected against metabolic dysfunction induced by the intake of a WSD.

In paper 2 “Investigating the link between antimicrobial defense, gut microbiota and metabolic dysfunction at the small intestinal mucosal barrier” we investigated the effect of obesogenic diets (Western diet or a high fat diet), obesity itself and other variables, including microbiota composition and sex, on small intestinal AMP expression. We observed that prolonged intake of a WSD had a stronger impact on AMP expression than genetic obesity, and determined that experimental set-up defined by mouse vendor and diet type, may have a larger influence than the specific dietary disturbances.

In paper 3 “Muc2-dependent microbial colonization of the jejunal mucus layer is diet sensitive and confers local resistance to enteric pathogen infection” we determined that the mucus layer of the jejunum formed aggregates and became more penetrable to bacteria-sized beads following the intake of a WSD. Both Muc2-/- and WSD-fed mice had an altered microbiota composition and increased susceptibility to enteric infection with Citrobacter rodentium in the jejunum, highlighting the role of the mucus layer as a microbiota- supporting niche that mediates colonization resistance against infection.

In summary, our work investigates the mechanisms by which a WSD changes the small intestinal microbiota composition at different intestinal sites while simultaneously disrupting mucus and AMP function. Our findings can aid the development of potential therapeutic avenues for addressing obesity and inflammatory bowel diseases through targeted modulation of mucus function, AMP expression or microbial composition.

Place, publisher, year, edition, pages
Umeå: Umeå University, 2024. , p. 42
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 2312
Keywords [en]
Western-style diet, High-fat diet, small intestine, microbiota, antimicrobial peptides, mucus layer, mucosal defense
National Category
Microbiology Immunology Nutrition and Dietetics
Research subject
Molecular Biology; Microbiology; Immunology; Nutrition
Identifiers
URN: urn:nbn:se:umu:diva-224480ISBN: 9789180704243 (electronic)ISBN: 9789180704236 (print)OAI: oai:DiVA.org:umu-224480DiVA, id: diva2:1858922
Public defence
2024-06-14, Stora hörsalen (KBE303), KBC-huset, Umeå, 09:00 (English)
Opponent
Supervisors
Available from: 2024-05-24 Created: 2024-05-20 Last updated: 2024-05-24Bibliographically approved
List of papers
1. Intestinal α-defensins play a minor role in modulating the small intestinal microbiota composition as compared to diet
Open this publication in new window or tab >>Intestinal α-defensins play a minor role in modulating the small intestinal microbiota composition as compared to diet
2023 (English)In: Microbiology Spectrum, E-ISSN 2165-0497, Vol. 11, no 3, article id e0056723Article in journal (Refereed) Published
Abstract [en]

The intestinal microbiota is at the interface between the host and its environment and thus under constant exposure to host-derived and external modulators. While diet is considered to be an important external factor modulating microbiota composition, intestinal defensins, one of the major classes of antimicrobial peptides, have been described as key host effectors that shape the gut microbial community. However, since dietary compounds can affect defensin expression, thereby indirectly modulating the intestinal microbiota, their individual contribution to shaping gut microbiota composition remains to be defined. To disentangle the complex interaction among diet, defensins, and small-intestinal microbiota, we fed wild-type (WT) mice and mice lacking functionally active α-defensins (Mmp7-/- mice) either a control diet or a Western-style diet (WSD) that is rich in saturated fat and simple carbohydrates but low in dietary fiber. 16S rDNA sequencing and robust statistical analyses identified that bacterial composition was strongly affected by diet while defensins had only a minor impact. These findings were independent of sample location, with consistent results between the lumen and mucosa of the jejunum and ileum, in both mouse genotypes. However, distinct microbial taxa were also modulated by α-defensins, which was supported by differential antimicrobial activity of ileal protein extracts. As the combination of WSD and defensin deficiency exacerbated glucose metabolism, we conclude that defensins only have a fine-tuning role in shaping the small-intestinal bacterial composition and might instead be important in protecting the host against the development of diet-induced metabolic dysfunction.

IMPORTANCE: Alterations in the gut microbial community composition are associated with many diseases, and therefore identifying factors that shape the microbial community under homeostatic and diseased conditions may contribute to the development of strategies to correct a dysbiotic microbiota. Here, we demonstrate that a Western-style diet, as an extrinsic parameter, had a stronger impact on shaping the small intestinal bacterial composition than intestinal defensins, as an intrinsic parameter. While defensins have been previously shown to modulate bacterial composition in young mice, our study supplements these findings by showing that defensins may be less important in adult mice that harbor a mature microbial community. Nevertheless, we observed that defensins did affect the abundance of distinct bacterial taxa in adult mice and protected the host from aggravated diet-induced glucose impairments. Consequently, our study uncovers a new angle on the role of intestinal defensins in the development of metabolic diseases in adult mice.

Place, publisher, year, edition, pages
American Society for Microbiology, 2023
Keywords
antimicrobial peptides, defensins, gut microbiota, metabolic disease, mucosal barrier, Western diet
National Category
Immunology
Identifiers
urn:nbn:se:umu:diva-212045 (URN)10.1128/spectrum.00567-23 (DOI)000969398400001 ()37039638 (PubMedID)2-s2.0-85163914021 (Scopus ID)
Funder
Swedish Research Council, 2018-02095Swedish Research Council, 2021-06602
Available from: 2023-07-18 Created: 2023-07-18 Last updated: 2024-05-20Bibliographically approved
2. Investigating the link between antimicrobial defense, gut microbiota and metabolic dysfunction at the small intestinal mucosal barrier
Open this publication in new window or tab >>Investigating the link between antimicrobial defense, gut microbiota and metabolic dysfunction at the small intestinal mucosal barrier
(English)Manuscript (preprint) (Other academic)
National Category
Biochemistry and Molecular Biology Immunology Microbiology
Research subject
Molecular Biology; Microbiology; Immunology
Identifiers
urn:nbn:se:umu:diva-224557 (URN)
Available from: 2024-05-20 Created: 2024-05-20 Last updated: 2024-05-20
3. Muc2-dependent microbial colonization of the jejunal mucus layer is diet sensitive and confers local resistance to enteric pathogen infection
Open this publication in new window or tab >>Muc2-dependent microbial colonization of the jejunal mucus layer is diet sensitive and confers local resistance to enteric pathogen infection
Show others...
2023 (English)In: Cell Reports, E-ISSN 2211-1247, Vol. 42, no 2, article id 112084Article in journal (Refereed) Published
Abstract [en]

Intestinal mucus barriers normally prevent microbial infections but are sensitive to diet-dependent changes in the luminal environment. Here we demonstrate that mice fed a Western-style diet (WSD) suffer regiospecific failure of the mucus barrier in the small intestinal jejunum caused by diet-induced mucus aggregation. Mucus barrier disruption due to either WSD exposure or chromosomal Muc2 deletion results in collapse of the commensal jejunal microbiota, which in turn sensitizes mice to atypical jejunal colonization by the enteric pathogen Citrobacter rodentium. We illustrate the jejunal mucus layer as a microbial habitat, and link the regiospecific mucus dependency of the microbiota to distinctive properties of the jejunal niche. Together, our data demonstrate a symbiotic mucus-microbiota relationship that normally prevents jejunal pathogen colonization, but is highly sensitive to disruption by exposure to a WSD.

Place, publisher, year, edition, pages
Cambridge: Cell Press, 2023
Keywords
Citrobacter rodentium, colonization resistance, CP: Immunology, CP: Microbiology, jejunum, mucus, small intestine, western-style diet
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-205507 (URN)10.1016/j.celrep.2023.112084 (DOI)000933530100001 ()36753416 (PubMedID)2-s2.0-85148954357 (Scopus ID)
Funder
Swedish Research Council, 2018-02278Swedish Research Council, 2018- 02095Swedish Research Council, 2019-01152Swedish Cancer Society, 19 0301 P
Available from: 2023-03-13 Created: 2023-03-13 Last updated: 2024-05-20Bibliographically approved

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Puértolas Balint, Fabiola

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