Stability and heterogeneity in the antimicrobiota reactivity of human milk-derived immunoglobulin A.

Immunoglobulin A (IgA) is secreted into breast milk and is critical for both protecting against enteric pathogens and shaping the infant intestinal microbiota. The efficacy of breast milk-derived maternal IgA (BrmIgA) is dependent upon its specificity; however, heterogeneity in BrmIgA binding ability to the infant microbiota is not known. Using a flow cytometric array, we analyzed the reactivity of BrmIgA against bacteria common to the infant microbiota and discovered substantial heterogeneity between all donors, independent of preterm or term delivery. Surprisingly, we also observed intradonor variability in the BrmIgA response to closely related bacterial isolates. Conversely, longitudinal analysis showed that the antibacterial BrmIgA reactivity was relatively stable through time, even between sequential infants, indicating that mammary gland IgA responses are durable. Together, our study demonstrates that the antibacterial BrmIgA reactivity displays interindividual heterogeneity but intraindividual stability. These findings have important implications for how breast milk shapes the development of the preterm infant microbiota and protects against necrotizing enterocolitis.

M cell maturation and cDC activation determine the onset of adaptive immune priming in the neonatal Peyer's patch.

Early-life immune development is critical to long-term host health. However, the mechanisms that determine the pace of postnatal immune maturation are not fully resolved. Here, we analyzed mononuclear phagocytes (MNPs) in small intestinal Peyer's patches (PPs), the primary inductive site of intestinal immunity. Conventional type 1 and 2 dendritic cells (cDC1 and cDC2) and RORgt+ antigen-presenting cells (RORgt+ APC) exhibited significant age-dependent changes in subset composition, tissue distribution, and reduced cell maturation, subsequently resulting in a lack in CD4+ T cell priming during the postnatal period. Microbial cues contributed but could not fully explain the discrepancies in MNP maturation. Type I interferon (IFN) accelerated MNP maturation but IFN signaling did not represent the physiological stimulus. Instead, follicle-associated epithelium (FAE) M cell differentiation was required and sufficient to drive postweaning PP MNP maturation. Together, our results highlight the role of FAE M cell differentiation and MNP maturation in postnatal immune development.

Magnetic-activated cell sorting identifies a unique lung microbiome community.

BACKGROUND: The advent of culture-independent, next-generation DNA sequencing has led to the discovery of distinct lung bacterial communities. Studies of lung microbiome taxonomy often reveal only subtle differences between health and disease, but host recognition and response may distinguish the members of similar bacterial communities in different populations. Magnetic-activated cell sorting has been applied to the gut microbiome to identify the numbers and types of bacteria eliciting a humoral response. We adapted this technique to examine the populations of immunoglobulin-bound bacteria in the lung. METHODS: Sixty-four individuals underwent bronchoalveolar lavage (BAL). We separated immunoglobulin G-bound bacteria using magnetic-activated cell sorting and sequenced the 16S rRNA gene on the Illumina MiSeq platform. We compared microbial sequencing data in IgG-bound bacterial communities compared to raw BAL then examined the differences in individuals with and without HIV as a representative disease state. RESULTS: Immunoglobulin G-bound bacteria were identified in all individuals. The community structure differed when compared to raw BAL, and there was a greater abundance of Pseudomonas and fewer oral bacteria in IgG-bound BAL. Examination of IgG-bound communities in individuals with HIV demonstrated the differences in Ig-bound bacteria by HIV status that were not seen in a comparison of raw BAL, and greater numbers of immunoglobulin-bound bacteria were associated with higher pulmonary cytokine levels. CONCLUSIONS: We report a novel application of magnetic-activated cell sorting to identify immunoglobulin G-bound bacteria in the lung. This technique identified distinct bacterial communities which differed in composition from raw bronchoalveolar lavage, revealing the differences not detected by traditional analyses. Cytokine response was also associated with differential immunoglobulin binding of lung bacteria, suggesting the functional importance of these communities. Video Abstract.

Excess Dietary Sugar Alters Colonocyte Metabolism and Impairs the Proliferative Response to Damage.

BACKGROUND & AIMS: The colonic epithelium requires continuous renewal by crypt resident intestinal stem cells (ISCs) and transit-amplifying (TA) cells to maintain barrier integrity, especially after inflammatory damage. The diet of high-income countries contains increasing amounts of sugar, such as sucrose. ISCs and TA cells are sensitive to dietary metabolites, but whether excess sugar affects their function directly is unknown. METHODS: Here, we used a combination of 3-dimensional colonoids and a mouse model of colon damage/repair (dextran sodium sulfate colitis) to show the direct effect of sugar on the transcriptional, metabolic, and regenerative functions of crypt ISCs and TA cells. RESULTS: We show that high-sugar conditions directly limit murine and human colonoid development, which is associated with a reduction in the expression of proliferative genes, adenosine triphosphate levels, and the accumulation of pyruvate. Treatment of colonoids with dichloroacetate, which forces pyruvate into the tricarboxylic acid cycle, restored their growth. In concert, dextran sodium sulfate treatment of mice fed a high-sugar diet led to massive irreparable damage that was independent of the colonic microbiota and its metabolites. Analyses on crypt cells from high-sucrose-fed mice showed a reduction in the expression of ISC genes, impeded proliferative potential, and increased glycolytic potential without a commensurate increase in aerobic respiration. CONCLUSIONS: Taken together, our results indicate that short-term, excess dietary sucrose can directly modulate intestinal crypt cell metabolism and inhibit ISC/TA cell regenerative proliferation. This knowledge may inform diets that better support the treatment of acute intestinal injury.

Stability and heterogeneity in the anti-microbiota reactivity of human milk-derived Immunoglobulin A.

Immunoglobulin A (IgA) is secreted into breast milk and is critical to both protecting against enteric pathogens and shaping the infant intestinal microbiota. The efficacy of breast milk-derived maternal IgA (BrmIgA) is dependent upon its specificity, however heterogeneity in BrmIgA binding ability to the infant microbiota is not known. Using a flow cytometric array, we analyzed the reactivity of BrmIgA against bacteria common to the infant microbiota and discovered substantial heterogeneity between all donors, independent of preterm or term delivery. We also observed intra-donor variability in the BrmIgA response to closely related bacterial isolates. Conversely, longitudinal analysis showed that the anti-bacterial BrmIgA reactivity was relatively stable through time, even between sequential infants, indicating that mammary gland IgA responses are durable. Together, our study demonstrates that the anti-bacterial BrmIgA reactivity displays inter-individual heterogeneity but intra-individual stability. These findings have important implications for how breast milk shapes the development of the infant microbiota and protects against Necrotizing Enterocolitis. Summary: We analyze the ability of breast milk-derived Immunoglobulin A (IgA) antibodies to bind the infant intestinal microbiota. We discover that each mother secretes into their breast milk a distinct set of IgA antibodies that are stably maintained over time.

Programmed and environmental determinants driving neonatal mucosal immune development.

The mucosal immune system of neonates goes through successive, non-redundant phases that support the developmental needs of the infant and ultimately establish immune homeostasis. These phases are informed by environmental cues, including dietary and microbial stimuli, but also evolutionary developmental programming that functions independently of external stimuli. The immune response to exogenous stimuli is tightly regulated during early life; thresholds are set within this neonatal "window of opportunity" that govern how the immune system will respond to diet, the microbiota, and pathogenic microorganisms in the future. Thus, changes in early-life exposure, such as breastfeeding or environmental and microbial stimuli, influence immunological and metabolic homeostasis and the risk of developing diseases such as asthma/allergy and obesity.

Infection-elicited microbiota promotes host adaptation to nutrient restriction.

The microbiota performs multiple functions vital to host fitness, including defense against pathogens and adaptation to dietary changes. Yet, how environmental challenges shape microbiota resilience to nutrient fluctuation remains largely unexplored. Here, we show that transient gut infection can optimize host metabolism toward the usage of carbohydrates. Following acute infection and clearance of the pathogen, mice gained more weight as a result of white adipose tissue expansion. Concomitantly, previously infected mice exhibited enhanced carbohydrate (glucose) disposal and insulin sensitivity. This metabolic remodeling depended on alterations to the gut microbiota, with infection-elicited Betaproteobacteria being sufficient to enhance host carbohydrate metabolism. Further, infection-induced metabolic alteration protected mice against stunting in the context of limited nutrient availability. Together, these results propose that alterations to the microbiota imposed by acute infection may enhance host fitness and survival in the face of nutrient restriction, a phenomenon that may be adaptive in settings where both infection burden and food precarity are prevalent.

Group 3 innate lymphoid cells require BATF to regulate gut homeostasis in mice.

Group 3 innate lymphoid cells (ILC3s) are crucial for the maintenance of host-microbiota homeostasis in gastrointestinal mucosal tissues. The mechanisms that maintain lineage identity of intestinal ILC3s and ILC3-mediated orchestration of microbiota and mucosal T cell immunity are elusive. Here, we identified BATF as a gatekeeper of ILC3 homeostasis in the gut. Depletion of BATF in ILC3s resulted in excessive interferon-γ production, dysbiosis, aberrant T cell immune responses, and spontaneous inflammatory bowel disease (IBD), which was considerably ameliorated by the removal of adaptive immunity, interferon-γ blockade, or antibiotic treatment. Mechanistically, BATF directly binds to the cis-regulatory elements of type 1 effector genes, restrains their chromatin accessibility, and inhibits their expression. Conversely, BATF promotes chromatin accessibility of genes involved in MHCII antigen processing and presentation pathways, which in turn directly promotes the transition of precursor ILC3s to MHCII+ ILC3s. Collectively, our findings reveal that BATF is a key transcription factor for maintaining ILC3 stability and coordinating ILC3-mediated control of intestinal homeostasis.

A gut-oral microbiome-driven axis controls oropharyngeal candidiasis through retinoic acid.

A side effect of antibiotics is outgrowth of the opportunistic fungus Candida albicans in the oropharynx (oropharyngeal candidiasis, OPC). IL-17 signaling is vital for immunity to OPC, but how the microbiome impacts antifungal immunity is not well understood. Mice in standard specific pathogen-free (SPF) conditions are resistant to OPC, whereas we show that germ-free (GF) or antibiotic-treated mice are susceptible. Oral type 17 cells and IL-17-dependent responses were impaired in antibiotic-treated and GF mice. Susceptibility could be rescued in GF mice by mono-colonization with segmented filamentous bacterium (SFB), an intestine-specific constituent of the microbiota. SFB protection was accompanied by restoration of oral IL-17+CD4+ T cells and gene signatures characteristic of IL-17 signaling. Additionally, RNA-Seq revealed induction of genes in the retinoic acid (RA) and RA receptor-α (RARα) pathway. Administration of RA rescued immunity to OPC in microbiome-depleted or GF mice, while RAR inhibition caused susceptibility in immunocompetent animals. Surprisingly, immunity to OPC was independent of serum amyloids. Moreover, RAR inhibition did not alter oral type 17 cytokine levels. Thus, mono-colonization with a component of the intestinal microflora confers protection against OPC by type 17 and RA/RARα, which act in parallel to promote antifungal immunity. In principle, manipulation of the microbiome could be harnessed to maintain antifungal immunity.

Human Milk Oligosaccharides Impact Cellular and Inflammatory Gene Expression and Immune Response.

Human milk harbors complex carbohydrates, including human milk oligosaccharides (HMOs), the third most abundant component after lactose and lipids. HMOs have been shown to impact intestinal microbiota, modulate the intestinal immune response, and prevent pathogenic bacterial binding by serving as decoy receptors. However, the direct effect of HMOs on intestinal function and immunity remains to be elucidated. To address this knowledge gap, 21-day-old germ-free mice (C57BI/6) were orally gavaged with 15 mg/day of pooled HMOs for 7 or 14 days and euthanized at day 28 or 35. A set of mice was maintained until day 50 to determine the persistent effects of HMOs. Control groups were maintained in the isolators for 28, 35, or 50 days of age. At the respective endpoints, intestinal tissues were subjected to histomorphometric and transcriptomic analyses, while the spleen and mesenteric lymph nodes (MLNs) were subjected to flow cytometric analysis. The small intestine (SI) crypt was reduced after HMO treatment relative to control at days 28 and 35, while the SI villus height and large intestine (LI) gland depth were decreased in the HMO-treated mice relative to the control at day 35. We report significant HMO-induced and location-specific gene expression changes in host intestinal tissues. HMO treatment significantly upregulated genes involved in extracellular matrix, protein ubiquitination, nuclear transport, and mononuclear cell differentiation. CD4+ T cells were increased in both MLNs and the spleen, while CD8+ T cells were increased in the spleen at day 50 in the HMO group in comparison to controls. In MLNs, plasma cells were increased in HMO group at days 28 and 35, while in the spleen, only at day 28 relative to controls. Macrophages/monocytes and neutrophils were lower in the spleen of the HMO group at days 28, 35, and 50, while in MLNs, only neutrophils were lower at day 50 in the 14-day HMO group. In addition, diphtheria toxoid and tetanus toxoid antibody-secreting cells were higher in HMO-supplemented group compared to controls. Our data suggest that HMOs have a direct effect on gastrointestinal tract metabolism and the immune system even in the absence of host microbiota.

Regulation of tissue-resident memory T cells by the Microbiota.

Resident memory T cells (Trms) predominantly reside within tissue and are critical for providing rapid protection against invasive viruses, fungi and bacteria. Given that tissues are heavily impacted and shaped by the microbiota, it stands to reason that Trms are also influenced by the microbiota that inhabits barrier sites. The influence of the microbiota is largely mediated by microbial production of metabolites which are crucial to the immune response to both viral infection and cancerous tumors. In addition to the effects of metabolites, antigens derived from the microbiota can activate T cell responses. While microbiota-specific T cells may assist in tissue repair, control of infection and anti-tumor immunity, the actual 'memory' potential of these cells remains unclear. Here, we hypothesize that memory responses to antigens from the microbiota must be 'licensed' by inflammatory signals activated by invasion of the host by microorganisms.

Mitigation of portal fibrosis and cholestatic liver disease in ANKS6-deficient livers by macrophage depletion.

Congenital hepatic fibrosis (CHF) is a developmental liver disease that is caused by mutations in genes that encode ciliary proteins and is characterized by bile duct dysplasia and portal fibrosis. Recent work has demonstrated that mutations in ANKS6 can cause CHF due to its role in bile duct development. Here, we report a novel ANKS6 mutation, which was identified in an infant presenting with neonatal jaundice due to underlying biliary abnormalities and liver fibrosis. Molecular analysis revealed that ANKS6 liver pathology is associated with the infiltration of inflammatory macrophages to the periportal fibrotic tissue and ductal epithelium. To further investigate the role of macrophages in CHF pathophysiology, we generated a novel liver-specific Anks6 knockout mouse model. The mutant mice develop biliary abnormalities and rapidly progressing periportal fibrosis reminiscent of human CHF. The development of portal fibrosis in Anks6 KO mice coincided with the accumulation of inflammatory monocytes and macrophages in the mutant liver. Gene expression and flow cytometric analysis demonstrated the preponderance of M1- over M2-like macrophages at the onset of fibrosis. A critical role for macrophages in promoting peribiliary fibrosis was demonstrated by depleting the macrophages with clodronate liposomes which effectively reduced inflammatory gene expression and fibrosis, and ameliorated tissue histology and biliary function in Anks6 KO livers. Together, this study demonstrates that macrophages play an important role in the initiation of liver fibrosis in ANKS6-deficient livers and their therapeutic elimination may provide an avenue to mitigate CHF in patients.

High Sugar-Sweetened Beverage Consumption Is Associated with Increased Health Care Utilization in Patients with Inflammatory Bowel Disease: A Multiyear, Prospective Analysis.

BACKGROUND: Dietary factors like sugar-sweetened beverage (SSB) consumption are known to influence disease course in a variety of illnesses; however, long-term outcomes are not well documented for inflammatory bowel disease. OBJECTIVE: Does high consumption of SSBs lead to high healthcare utilization (ie, hospitalizations and emergency department visits), inflammation, and disease severity in patients with inflammatory bowel disease? DESIGN: A prospective cohort study was conducted from 2015 to 2019. Patients enrolled in the discovery study cohort were followed for 3 years, whereas patients in the validation cohort were followed for 2 years. They underwent nutrition assessment and received routine care. Dietary intakes of SSBs and fiber were quantified by a validated, self-reported questionnaire. PARTICIPANTS/SETTING: For the discovery study cohort, 1133 adult patients were recruited from the University of Pittsburgh Medical Center Digestive Disease Clinic in Pittsburgh, PA. Eligible patients had a preexisting diagnosis of Crohn's disease or ulcerative colitis and had at least annual follow-up at this tertiary referral center. High SSB consumption was defined as 7 or more SSBs per week. Moderate was defined as > 2 but < 7 SSBs per week. Low SSB consumption was defined as 2 or fewer SSBs per week. MAIN OUTCOME MEASURES: Primary outcome was time to hospitalization and emergency department visits. Secondary outcomes assessed laboratory markers of disease severity and inflammation. Tertiary outcomes assessed time to hospitalization and emergency department visits in a subsequent independent cohort of patients. STATISTICAL ANALYSIS PERFORMED: Multivariable logistic regression, Kaplan-Meier, and Cox proportional hazards modeling RESULTS: The discovery cohort included of 1,133 adult patients with inflammatory bowel disease (58% women, 70% with Chron's disease, 30% with ulcerative colitis, median age 46 years). Low SSB consumption, moderate SSB consumption, and high SSB consumption occurred in 57%, 17%, and 26% in the discovery cohort, respectively. Among patients without active disease at enrollment, high SSB consumption was associated with decreased time to hospitalization and emergency department visits when compared with low SSB consumption (hazard ratio 1.55, 95% CI 1.06 to 2.27; and hazard ratio 1.53, 95% CI 1.10 to 2.13). In terms of disease severity and inflammatory biomarkers, high SSB consumption was associated with increase odds of elevated erythrocyte sedimentation rate (odds ratio 2.04, 95% CI 1.31 to 3.18), elevated C-reactive protein level (odds ratio 1.60, 95% CI, 1.07-2.37), eosinophilia (odds ratio 1.88, 95% CI 1.06 to 3.335), and monocytosis (odds ratio 1.81, 95% CI 1.18 to 2.79) when compared with low SSB consumption after adjusting for baseline differences. Lastly, the validation cohort produced similar results to our primary outcome (ie, high SSB consumption was associated with decreased time to hospitalization and emergency department visits when compared with low SSB consumption). CONCLUSIONS: High SSB consumption was associated with decreased time to hospitalization and emergency department visits. Furthermore, high SSB consumption is associated with disease severity biomarkers and inflammation. Prospective studies assessing the therapeutic influence of nutrition counseling and decreased SSB consumption on long-term inflammatory bowel disease clinical course are warranted.

Microbiota-specific T follicular helper cells drive tertiary lymphoid structures and anti-tumor immunity against colorectal cancer.

The composition of the intestinal microbiota is associated with both the development of tumors and the efficacy of anti-tumor immunity. Here, we examined the impact of microbiota-specific T cells in anti-colorectal cancer (CRC) immunity. Introduction of Helicobacter hepaticus (Hhep) in a mouse model of CRC did not alter the microbial landscape but increased tumor infiltration by cytotoxic lymphocytes and inhibited tumor growth. Anti-tumor immunity was independent of CD8+ T cells but dependent upon CD4+ T cells, B cells, and natural killer (NK) cells. Hhep colonization induced Hhep-specific T follicular helper (Tfh) cells, increased the number of colon Tfh cells, and supported the maturation of Hhep+ tumor-adjacent tertiary lymphoid structures. Tfh cells were necessary for Hhep-mediated tumor control and immune infiltration, and adoptive transfer of Hhep-specific CD4+ T cells to Tfh cell-deficient Bcl6fl/flCd4Cre mice restored anti-tumor immunity. Thus, introduction of immunogenic intestinal bacteria can promote Tfh-associated anti-tumor immunity in the colon, suggesting therapeutic approaches for the treatment of CRC.

Environmental enteric dysfunction induces regulatory T cells that inhibit local CD4+ T cell responses and impair oral vaccine efficacy.

Environmental enteric dysfunction (EED) is a gastrointestinal inflammatory disease caused by malnutrition and chronic infection. EED is associated with stunting in children and reduced efficacy of oral vaccines. To study the mechanisms of oral vaccine failure during EED, we developed a microbiota- and diet-dependent mouse EED model. Analysis of E. coli-labile toxin vaccine-specific CD4+ T cells in these mice revealed impaired CD4+ T cell responses in the small intestine and but not the lymph nodes. EED mice exhibited increased frequencies of small intestine-resident RORγT+FOXP3+ regulatory T (Treg) cells. Targeted deletion of RORγT from Treg cells restored small intestinal vaccine-specific CD4 T cell responses and vaccine-mediated protection upon challenge. However, ablation of RORγT+FOXP3+ Treg cells made mice more susceptible to EED-induced stunting. Our findings provide insight into the poor efficacy of oral vaccines in EED and highlight how RORγT+FOXP3+ Treg cells can regulate intestinal immunity while leaving systemic responses intact.

Production and Function of Immunoglobulin A.

Among antibodies, IgA is unique because it has evolved to be secreted onto mucosal surfaces. The structure of IgA and the associated secretory component allow IgA to survive the highly proteolytic environment of mucosal surfaces but also substantially limit IgA's ability to activate effector functions on immune cells. Despite these characteristics, IgA is critical for both preventing enteric infections and shaping the local microbiome. IgA's function is determined by a distinct antigen-binding repertoire, composed of antibodies with a variety of specificities, from permissive polyspecificity to cross-reactivity to exquisite specificity to a single epitope, which act together to regulate intestinal bacteria. Development of the unique function and specificities of IgA is shaped by local cues provided by the gut-associated lymphoid tissue, driven by the constantly changing environment of the intestine and microbiota.

Metabolic support of tumour-infiltrating regulatory T cells by lactic acid.

Regulatory T (Treg) cells, although vital for immune homeostasis, also represent a major barrier to anti-cancer immunity, as the tumour microenvironment (TME) promotes the recruitment, differentiation and activity of these cells1,2. Tumour cells show deregulated metabolism, leading to a metabolite-depleted, hypoxic and acidic TME3, which places infiltrating effector T cells in competition with the tumour for metabolites and impairs their function4-6. At the same time, Treg cells maintain a strong suppression of effector T cells within the TME7,8. As previous studies suggested that Treg cells possess a distinct metabolic profile from effector T cells9-11, we hypothesized that the altered metabolic landscape of the TME and increased activity of intratumoral Treg cells are linked. Here we show that Treg cells display broad heterogeneity in their metabolism of glucose within normal and transformed tissues, and can engage an alternative metabolic pathway to maintain suppressive function and proliferation. Glucose uptake correlates with poorer suppressive function and long-term instability, and high-glucose conditions impair the function and stability of Treg cells in vitro. Treg cells instead upregulate pathways involved in the metabolism of the glycolytic by-product lactic acid. Treg cells withstand high-lactate conditions, and treatment with lactate prevents the destabilizing effects of high-glucose conditions, generating intermediates necessary for proliferation. Deletion of MCT1-a lactate transporter-in Treg cells reveals that lactate uptake is dispensable for the function of peripheral Treg cells but required intratumorally, resulting in slowed tumour growth and an increased response to immunotherapy. Thus, Treg cells are metabolically flexible: they can use 'alternative' metabolites in the TME to maintain their suppressive identity. Further, our results suggest that tumours avoid destruction by not only depriving effector T cells of nutrients, but also metabolically supporting regulatory populations.

Loss of Fibroblast Growth Factor Receptor 2 (FGFR2) Leads to Defective Bladder Urothelial Regeneration after Cyclophosphamide Injury.

Cyclophosphamide may cause hemorrhagic cystitis and eventually bladder urothelial cancer. Genetic determinants for poor outcomes are unknown. We assessed actions of fibroblast growth factor receptor (FGFR) 2 in urothelium after cyclophosphamide exposure. Conditional urothelial deletion of Fgfr2 (Fgfr2KO) did not affect injury severity or proliferation of keratin 14+ (KRT14+) basal progenitors or other urothelial cells 1 day after cyclophosphamide exposure. Three days after cyclophosphamide exposure, Fgfr2KO urothelium had defective regeneration, fewer cells, larger basal cell bodies and nuclei, paradoxical increases in proliferation markers, and excessive replication stress versus controls. Fgfr2KO mice had evidence of pathologic basal cell endoreplication associated with absent phosphorylated ERK staining and decreased p53 expression versus controls. Mice with conditional deletion of Fgfr2 in urothelium enriched for KRT14+ cells reproduced Fgfr2KO abnormalities after cyclophosphamide exposure. Fgfr2KO urothelium had defects up to 6 months after injury versus controls, including larger basal cells and nuclei, more persistent basal and ectopic lumenal KRT14+ cells, and signs of metaplasia (attenuated E-cadherin staining). Mice missing one allele of Fgfr2 also had (less severe) regeneration defects and basal cell endoreplication 3 days after cyclophosphamide exposure versus controls. Thus, reduced FGFR2/ERK signaling apparently leads to abnormal urothelial repair after cyclophosphamide exposure from pathologic basal cell endoreplication. Patients with genetic variants in FGFR2 or its ligands may have increased risks of hemorrhagic cystitis or urothelial cancer from persistent and ectopic KRT14+ cells.

Nutritional Modulation of the Microbiome and Immune Response.

The evolution of the immune system, diet, and the microbiome are interconnected. Dietary metabolites modulate the cells of the immune system both directly and indirectly via shifts in the composition of the intestinal microbiota and its products. As a result, overconsumption and malnutrition can have substantial effects on immune responses and inflammation. In resource-rich nations, diets high in processed foods, fat, and sugar can contribute to chronic inflammatory conditions, which are on the rise worldwide. Conversely, in resource-poor countries, malnutrition associated with food insecurity can lead to immunodeficiencies and shifts in the microbiome that drive intestinal inflammation. Developing a deeper understanding of the relationship between diet, microbiota, and the immune system is of huge importance, given its impact on inflammatory diseases and its potential as an easily modifiable mediator of immunomodulation.

Influence of Maternal Milk on the Neonatal Intestinal Microbiome.

The intestinal microbiome plays an important role in maintaining health throughout life. The microbiota develops progressively after birth and is influenced by many factors, including the mode of delivery, antibiotics, and diet. Maternal milk is critically important to the development of the neonatal intestinal microbiota. Different bioactive components of milk, such as human milk oligosaccharides, lactoferrin, and secretory immunoglobulins, modify the composition of the neonatal microbiota. In this article, we review the role of each of these maternal milk-derived bioactive factors on the microbiota and how this modulation of intestinal bacteria shapes health, and disease.