R. Balfour Sartor’s research while affiliated with University of North Carolina at Chapel Hill and other places

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Publications (492)


Beyond Random Fecal Microbial Transplants
  • Article

December 2024

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8 Reads

Gastroenterology Clinics of North America

R. Balfour Sartor

Fig. 6 Integrative analysis of 16S microbiome and LC-MS metabolome. Integrative analysis of 16S microbiome and LC-MS metabolome was performed using a customized gene set enrichment analysis (GSEA) method. Metabolites obtained by LC-MS were significantly enriched in (a) amino acid biosynthesis and (b) aminoacyl-tRNA charging using the predicted metagenome of 16S rRNA gene dataset (P < 0.05). Peak intensity of metabolites involved in (c) amino acid biosynthesis and (d) aminoacyl-tRNA charging was log transformed and visualized by heatmap, with each row representing a unique sample and each column representing a LC-MS peak. For (c, d), *P < 0.05, **P < 0.01, ***P < 0.001. For LC-MS, 3-month, n = 5; 24-month, n = 5. For 16S, 3-month, n = 8; 24-month, n = 8
Fig. 7 Effect of colonization on bone phenotype of germ-free mice is independent of age of donor microbiome. Effect of colonization for 1 month on trabecular bone volume fraction (Tb. BV/TV), cortical thickness (Ct. Th), cortical area (Ct. Ar), serum P1NP and CTX-1 in young adult (2-monthold, a-e) and skeletal immature (1-month-old, f-j) females is shown. Consequences of 8 months colonization on Tb. BV/TV, Ct. Th, and Ct. Ar are shown for (k-m) female and (p-r) male mice. n, o Serum P1NP and CTX-1 is shown in female after 8 months colonization. s Representative 3D images of femur trabecular bone are shown. Data are represented as mean ± SEM. One-way ANOVA or Kruskal-Wallis test with Tukey post hoc was performed. *P < 0.05, **P < 0.01, ***P < 0.001, ns, not statistically significant. For (a-e): GF, n = 11; Col with 3-month, n = 14; Col with 24-month, n = 14. For (f-j): GF = 8; Col with 3-month, n = 9; Col with 24-month, n = 8. For (k-o): GF, n = 12; Col with 3-month, n = 7; Col with 24-month, n = 8. For (p-r): n = 8 per group. 4 data in (e) and 5 data in (n) and (o) were missing due to insufficient sample collection
Bone loss with aging is independent of gut microbiome in mice
  • Article
  • Full-text available

November 2024

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24 Reads

Bone Research

Xiaomeng You

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Jing Yan

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Julia F. Charles

Emerging evidence suggests a significant role of gut microbiome in bone health. Aging is well recognized as a crucial factor influencing the gut microbiome. In this study, we investigated whether age-dependent microbial change contributes to age-related bone loss in CB6F1 mice. The bone phenotype of 24-month-old germ-free (GF) mice was indistinguishable compared to their littermates colonized by fecal transplant at 1-month-old. Moreover, bone loss from 3 to 24-month-old was comparable between GF and specific pathogen-free (SPF) mice. Thus, GF mice were not protected from age-related bone loss. 16S rRNA gene sequencing of fecal samples from 3-month and 24-month-old SPF males indicated an age-dependent microbial shift with an alteration in energy and nutrient metabolism potential. An integrative analysis of 16S predicted metagenome function and LC-MS fecal metabolome revealed an enrichment of protein and amino acid biosynthesis pathways in aged mice. Microbial S-adenosyl methionine metabolism was increased in the aged mice, which has previously been associated with the host aging process. Collectively, aging caused microbial taxonomic and functional alteration in mice. To demonstrate the functional importance of young and old microbiome to bone, we colonized GF mice with fecal microbiome from 3-month or 24-month-old SPF donor mice for 1 and 8 months. The effect of microbial colonization on bone phenotypes was independent of the microbiome donors’ age. In conclusion, our study indicates age-related bone loss occurs independent of gut microbiome.

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Early subclinical stages of the inflammatory bowel diseases - insights from human and animal studies

November 2024

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14 Reads

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1 Citation

AJP Gastrointestinal and Liver Physiology

The inflammatory bowel diseases (IBD) occur in genetically susceptible individuals that mount inappropriate immune responses to their microbiota leading to chronic intestinal inflammation. The natural history of IBD progression begins with early subclinical stages of disease that occur before clinical diagnosis. Improved understanding of those early subclinical stages could lead to new or improved strategies for IBD diagnosis, prognostication or prevention. Here we review our current understanding of the early subclinical stages of IBD in humans including studies from first-degree relatives of IBD patients and members of the general population who go on to develop IBD. We also discuss representative mouse models of IBD that can be used to investigate disease dynamics and host-microbiota relationships during these early stages. In particular, we underscore how mouse models of IBD that develop disease later in life with variable penetrance may present valuable opportunities to discern early subclinical mechanisms of disease before histological inflammation and other severe symptoms become apparent.


Mouse adaptation of human inflammatory bowel diseases microbiota enhances colonization efficiency and alters microbiome aggressiveness depending on the recipient colonic inflammatory environment

August 2024

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54 Reads

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5 Citations

Background Understanding the cause vs consequence relationship of gut inflammation and microbial dysbiosis in inflammatory bowel diseases (IBD) requires a reproducible mouse model of human-microbiota-driven experimental colitis. Results Our study demonstrated that human fecal microbiota transplant (FMT) transfer efficiency is an underappreciated source of experimental variability in human microbiota-associated (HMA) mice. Pooled human IBD patient fecal microbiota engrafted germ-free (GF) mice with low amplicon sequence variant (ASV)-level transfer efficiency, resulting in high recipient-to-recipient variation of microbiota composition and colitis severity in HMA Il-10−/− mice. In contrast, mouse-to-mouse transfer of mouse-adapted human IBD patient microbiota transferred with high efficiency and low compositional variability resulting in highly consistent and reproducible colitis phenotypes in recipient Il-10−/− mice. Engraftment of human-to-mouse FMT stochastically varied with individual transplantation events more than mouse-adapted FMT. Human-to-mouse FMT caused a population bottleneck with reassembly of microbiota composition that was host inflammatory environment specific. Mouse-adaptation in the inflamed Il-10−/− host reassembled a more aggressive microbiota that induced more severe colitis in serial transplant to Il-10−/− mice than the distinct microbiota reassembled in non-inflamed WT hosts. Conclusions Our findings support a model of IBD pathogenesis in which host inflammation promotes aggressive resident bacteria, which further drives a feed-forward process of dysbiosis exacerbated by gut inflammation. This model implies that effective management of IBD requires treating both the dysregulated host immune response and aggressive inflammation-driven microbiota. We propose that our mouse-adapted human microbiota model is an optimized, reproducible, and rigorous system to study human microbiome-driven disease phenotypes, which may be generalized to mouse models of other human microbiota-modulated diseases, including metabolic syndrome/obesity, diabetes, autoimmune diseases, and cancer. 9-8iLEe2BorBmu_z2q_8UWVideo Abstract








Citations (55)


... It is also possible that host inflammation arising independent of the microbiome could lead to changes in microbiome composition. For example, the microbiome of IL-10-deficient mice is altered as colitis develops, becoming more colitogenic when transferred to new recipients (67). ...

Reference:

Inflammatory disease microbiomes share a functional pathogenicity predicted by C-reactive protein
Mouse adaptation of human inflammatory bowel diseases microbiota enhances colonization efficiency and alters microbiome aggressiveness depending on the recipient colonic inflammatory environment

... Greenstein et al [54] , who conducted a study involving 700 patients with IBD to assess the relative incidence and distinguishing characteristics of EIM, reported that ocular EIM occured more frequently in patients with CD compared to UC. This finding aligns with the observations made in other studies [55][56][57] . In this MR analysis, we aimed to assess the causal relationship between IBD, including UC and CD, and ocular inflammation. ...

Comprehensive Association Analyses of Extraintestinal Manifestations in Inflammatory Bowel Disease
  • Citing Article
  • March 2024

Gastroenterology

... Actually, germ-free mice, which was depleted of their resident microbiota, was considered as the gold standard for exploring the role of the microbiome in health and disease. However, germ-free mice got limited value in the study of human-specific pathogens because they do not support their replication (Wahl et al., 2023). In our studies, we just provided some evidence of gut microbiota alteration, including but not limited to enrichment of Alistipes onderdonkii, Lachnospiraceae bacterium 1_7_58FAA, Clostridium aspaaragiforme, reduction of Akkermansiaceae, Paraprevotell xylaniphila, and Prevotella copri in GDM patients, along with enrichment of Alistipes sp. ...

A germ-free humanized mouse model shows the contribution of resident microbiota to human-specific pathogen infection

Nature Biotechnology

... In a mouse model of early-stage IBD (deletion of the transcription factor Hnf4a in intestinal epithelial cells), spikes in Akkermansia levels were associated with spontaneous episodes of colitis and elevated intestinal inflammation. 5 However, the strain in these mice represented a new Akkermansia species, A. ignis. 6 NLRP6 (NOD-like receptor family pyrin domain containing 6) restricts A. muciniphila colonization. ...

Spontaneous episodic inflammation in the intestines of mice lacking HNF4A is driven by microbiota and associated with early life microbiota alterations

... In sub-Saharan African and southeast Asian countries, the Global Enteric Multicenter Study (GEMS) has identified cryptosporidiosis as the second cause of childhood mortality after rotaviral infection, and amoebiasis as an increased risk of death in infants and toddlers with moderateto-severe diarrhoea [1]. Similarly, the Malnutrition and Enteric Diseases (MAL-ED) multicenter study has linked giardiasis with malnutrition, growth retardation, and impaired cognitive development during early childhood [2,3]. On the other hand, the stramenopile Blastocystis sp. ...

Giardia hinders growth by disrupting nutrient metabolism independent of inflammatory enteropathy

... CFB is a part of the complement system and is involved in immune response and inflammation by activating the complement cascade. Studies have shown that CFB plays a crucial role in Crohn's disease [52], RA [53], and lupus nephritis [54], suggesting that CFB may drive the inflammatory process in AS. On the other hand, the negative correlation of CERT and ERGIC-3 with AS may suggest their roles in inhibiting inflammation or regulating immune cell functions. ...

Genetic coding variant in complement factor B (CFB) is associated with increased risk for perianal Crohn's disease and leads to impaired CFB cleavage and phagocytosis
  • Citing Article
  • April 2023

Gut

... Preclinical and clinical studies have investigated the preventive and curative effects of a mixture of bacteria, probiotics, single species/strains, bacterial component, metabolites, and different dosage regimens on the radioprotective potential of bacterial supplements (Tables 1 and 2). Bacterial metabolites have been proven to provide a long-term radioprotection that becomes beneficial compared to conventional pharmaceutical approaches that cause adverse effects upon long-term use, even when intestinal inflammation is present, thus meeting the standards of being an ideal radioprotector [86,101,111,112]. Also, conventional radioprotective agents like Amifostine show rapid drug clearance, thus ineffective in protecting the gut [113,114]. ...

Multi-omics analyses of radiation survivors identify radioprotective microbes and metabolites
  • Citing Article
  • May 2021

The Journal of Immunology

... In response to ER stress, the deregulation of ER homeostasis can trigger the unfolded protein response (UPR) pathways to restore homeostasis by activating genes involved in protein folding (Yu et al., 2023). For example, the anterior gradient 2 (AGR2) gene has recently been determined to be an important regulator of ER stress (Viladomiu et al., 2022). Therefore, it is not surprising that ER stress and UPR signaling are essential for shaping intestinal homeostasis and maintaining intestinal barrier function. ...

Agr2-associated ER stress promotes adherent-invasive E. coli dysbiosis and triggers CD103+ dendritic cell IL-23-dependent ileocolitis

Cell Reports

... Notwithstanding these limitations, the majority of metabolomic features present in donor samples are successfully recapitulated in colonized gnotobiotic mice, suggesting that the functional properties of the gut microbiota can be effectively replicated in this model [134]. And indeed, germ-free mice colonized with microbiota from humans with cirrhosis and AUD who showed improved clinical outcomes following FMT exhibited reduced alcohol consumption and preference, suggesting that AUD-related microbiome alterations are transmissible to a gnotobiotic mouse model and can be utilized to investigate the therapeutic effects of microbiome modulation [135]. ...

Reduced alcohol preference and intake after fecal transplant in patients with alcohol use disorder is transmissible to germ-free mice

... However, rare and highly penetrant variations identified through population-specific cohorts or family-focused research have immense potential to catch the variants with high effect sizes on complex diseases such as IBD [17,26]. Many large-scale sporadic case-control studies on WES-based rare variant burden analysis (RVB) have previously identified several strong risk loci for complex diseases, such as schizophrenia [27], Alzheimer's disease [28], autism [29], and CD [30]. According to a recent systemic review and meta-analysis of IBD in the Arab world, the consanguinity rate in Saudi Arabian IBD patients is high, 57.6%, which is similar to that in the general population as well [4,31]. ...

Large-scale sequencing identifies multiple genes and rare variants associated with Crohn’s disease susceptibility

Nature Genetics