Emerging evidence suggests that higher physical activity and physical fitness are associated with fewer decayed teeth (DT). This study investigates whether salivary immunoglobulin A (SIgA) mediates the association between physical activity or fitness and DT, and whether dentine caries is associated with salivary and systemic immunoglobulin levels in adults. Data were derived from the 46-year follow-up of the Northern Finland Birth Cohort 1966. Participants (N = 1,589) underwent clinical oral examinations using ICDAS criteria. SIgA and serum immunoglobulins (IgA, IgG, IgM) were analysed from saliva and fasting blood samples using a chemiluminescence immunoassay. Physical activity was measured objectively using wrist-worn accelerometers, and physical fitness by step testing and heart rate recovery. Mediation analyses examined whether SIgA mediated associations between physical activity or fitness and DT. Associations between immunoglobulins and DT were analysed using adjusted negative binomial regression. Descriptive analyses indicated higher SIgA levels among participants with greater dentine caries burden. No significant indirect effects of physical activity or fitness on caries through SIgA were observed. In adjusted models, higher SIgA concentrations were associated with increased DT (Exp(β) = 1.282, p = 0.001), whereas serum IgA, IgG, and IgM were not associated with caries. No evidence was found that SIgA statistically mediated the association between physical activity or fitness and dentine caries in this dataset. Higher SIgA levels are associated with greater caries burden, suggesting a reactive rather than protective role. Salivary SIgA may reflect immune activation in response to dentine caries rather than protection against disease, highlighting the potential role of local immunity in caries progression.

Salivary immunoglobulin A (IgA) is a key component of oral mucosal immunity, yet its relationships to systemic health are not well defined. We investigated whether salivary IgA relates to systemic immune responses, cardiometabolic risk, and oral microbial diversity and composition. In this cross-sectional study we analyzed adults from the Northern Finland Birth Cohort 1966 at age 46 years. Participants underwent standardized clinical and laboratory assessments and provided saliva and serum samples. The oral microbiome was characterized from salivary samples (n = 863) by 16S rRNA gene sequencing. Salivary IgA and circulating IgA/IgG/IgM were quantified by chemiluminescence immunoassay. Participants were categorized by salivary IgA levels, and immunological, anthropometric, metabolic, inflammatory, and microbiome measures were examined. Here we show that higher salivary IgA is associated with greater adiposity, including higher BMI (25.7 vs. 27.2 kg/m²; P = 0.001), percent body fat (27.3% vs. 29.6%; P = 0.031), body fat mass (20.7 vs. 24.0 kg; P = 0.00007), and visceral fat area (95.3 vs. 107.7 cm²; P = 0.002) across salivary IgA quartiles. Salivary IgA is associated with less favorable glycemic profiles: higher fasting glucose (P = 0.018), HbA1c (P = 0.014), and insulin (P = 0.006), and shows a positive association with serum IgA (P = 0.042) while serum IgG, IgM, and high-sensitivity C-reactive protein (hs-CRP) do not differ across salivary IgA quartiles (Kruskal–Wallis, Bonferroni post hoc). Oral microbial α-diversity is lower in the highest IgA quartile compared with the lowest, and specific shifts in the community structure and composition are observed. Oral microbiome α- or β-diversity is not associated with body fat mass. In this cross-sectional study, greater adiposity and higher glycemic indices are associated with higher salivary IgA, which in turn is associated with decreased oral microbiome diversity in the absence of overt oral inflammation. These findings are consistent with possible mucosal-metabolic crosstalk and motivate longitudinal and mechanistic studies to determine directionality and clinical implications.

AIM:The humoral immune system is implicated in the link between periodontitis and atherosclerosis. This study aims to explore how interactions between the oral microbiota and humoral immune responses may contribute to this association. MATERIALS AND METHODS:We analysed data from the Northern Finland Birth Cohort 1966, which included 1560 participants who underwent comprehensive health and oral examinations. Serum antibodies against phosphorylcholine (PCho) and malondialdehyde acetaldehyde (MAA) adducts were measured using chemiluminescence immunoassays. In a sub-cohort (n = 868), the oral microbiome from saliva samples was characterised using 16S rRNA gene sequencing. RESULTS:Higher serum levels of IgA and IgG to PCho, as well as IgA to MAA, were associated with an increased number of teeth with probing pocket depths (PPD) ≥ 4 mm. Several oral bacterial species, including Prevotella dentalis , Filifactor alocis and Treponema denticola , correlated with both PPD ≥ 4 mm and IgA/IgG responses to PCho. Mediation analysis, adjusted for periodontitis risk factors, identified F. alocis as a mediator linking elevated plasma IgG to PCho with the number of teeth with PPD ≥ 4 mm. Additionally, individuals harbouring F. alocis exhibited increased carotid intima-media thickness. CONCLUSIONS:Our findings suggest that F. alocis may serve as a microbial link between periodontitis and atherosclerosis. Future mechanistic studies should investigate how F. alocis induces systemic IgG responses and contributes to atherosclerosis.

BACKGROUND:Bacterial DNA from the oral cavity, respiratory tract, gut, and skin has been detected in atherosclerotic plaques, suggesting a role in chronic inflammation linked to atherosclerosis. Chronic bacterial infections often form biofilms resistant to antibiotics and immune detection, giving rise to a new generation of virulent bacteria in suitable conditions. This study explores the role of the immune system in bacterial-induced inflammation of atherosclerotic plaques. METHODS:Coronary plaques from 121 sudden death victims and endarterectomy samples from 96 surgical patients were analyzed using bacterial real-time quantitative polymerase chain reaction, immunohistochemistry, and genome-wide expression analysis. TLR (toll-like receptor) signaling was examined in bacterial-activated TLR cell lines. RESULTS:Of the bacteria detected, oral viridans group streptococcal DNA was the most common, being found in 42.1% of coronary plaques and 42.9% of endarterectomies. Immunopositivity for viridans streptococci correlated with severe atherosclerosis (P<0.0001) in both series and death from coronary heart disease (P=0.021) or myocardial infarction (P=0.042). Viridans streptococci colonized the core of the atheroma as a biofilm unrecognized by macrophages of the innate immune system. In contrast, immunopositive streptococci that appeared to have originated from the biofilm infiltrated the ruptured fibrous cap of the atheroma in endarterectomy samples and coronary plaques and were detected by pattern-recognizing receptors and coexpressed with the adaptive immune response. Among the viridans streptococcal strains, TLR2 was the most activated bacterial-signaling pathway. Genome-wide expression analysis of endarterectomy samples showed upregulation of bacterial recognition pathways. CONCLUSIONS:Latent chronic bacterial inflammation evades immune detection and may contribute to the pathogenesis of complicated atherosclerotic plaques and fatal myocardial infarction.

BACKGROUND:Although there have been significant advancements in reducing the burden of cardiovascular disease (CVD) by modifying traditional CVD risk factors, substantial risks persist, particularly among male subjects who exhibit heightened susceptibility to atherosclerosis. In this context, we aim to study the link between oral microbiome and carotid intima media thickness (cIMT). METHODS:The Northern Finland Birth Cohort of 1966 (mean age 46 years, n = 869) underwent an extensive health examination, including the measurement of cIMT. The oral microbiome was also investigated using high-throughput 16S rRNA gene sequencing. RESULTS:Here we show that oral microbiome diversity links with atherosclerosis risk factors, namely smoking, glycemic balance, low-grade inflammation, and periodontitis. After excluding CVD-influencing factors (n = 339), oral microbiome genera (p = 0.030), Shannon index (p = 0.001), β-diversity Bray-Curtis (p < 0.001), and Jaccard (p < 0.001) are associated with cIMT in males, but not in the female sub-cohort. Furthermore, in the male sub-cohort (n = 131), the genera Prevotella, Megasphaera, and Veillonella associate positively with cIMT, while Absconditabacteria, Capnocytophaga, Gemella, Fusobacterium, Neisseria, Aggregatibacter, Tannerella, Treponema, Cardiobacterium, and Bacteroidales associate inversely with cIMT. We examine the involvement of serum total immunoglobulins and antibodies to phosphorylcholine (PCho) and malondialdehyde-acetaldehyde LDL (MAA-LDL) with cIMT. Subjects with high cIMT have lower levels of serum total IgA (p = 0.009), IgA to PCho (p = 0.017), and IgG to PCho (p = 0.008). The relative abundance of cIMT-associated genera correlates with serum IgA antibodies. CONCLUSIONS:This middle-aged birth cohort study shows that male oral microbiome diversity links to cIMT, suggesting a potential sex-specific interaction between the oral microbiome and atherosclerosis.

Background The Roux-en-Y gastric bypass (RYGB) is a common bariatric surgery to treat obesity. Its metabolic consequences are favourable and long-term clinical corollaries beneficial. However, detailed assessments of various affected metabolic pathways and their mediating physiological factors are scarce. Methods We performed a clinical study with 30 RYGB patients in preoperative and 6-month postoperative visits. NMR metabolomics was applied to profiling of systemic metabolism via 80 molecular traits, representing core cardiometabolic pathways. Glucose, glycated haemoglobin (HbA1c), insulin, and apolipoprotein B-48 were measured with standard assays. Logistic regression models of the surgery effect were used for each metabolic measure and assessed individually for multiple mediating physiological factors. Results Changes in insulin concentrations reflected those of BMI with robust decreases due to the surgery. Six months after the surgery, triglycerides, remnant cholesterol, and apolipoprotein B-100 were decreased −24%, −18%, and −14%, respectively. Lactate and glycoprotein acetyls, a systemic inflammation biomarker, decreased −16% and −9%, respectively. The concentrations of branched-chain (BCAA; leucine, isoleucine, and valine) and aromatic (phenylalanine and tyrosine) amino acids decreased after the surgery between −17% for tyrosine and −23% for leucine. Except for the most prominent metabolic changes observed for the BCAAs, all changes were almost completely mediated by weight change and insulin. Glucose and type 2 diabetes had clearly weaker effects on the metabolic changes. Conclusions The comprehensive metabolic analyses indicate that weight loss and improved insulin sensitivity during the 6 months after the RYGB surgery are the key physiological outcomes mediating the short-term advantageous metabolic effects of RYGB. The clinical study was registered at ClinicalTrials.gov as NCT01330251. Graphical Abstract

We aimed to study levels of natural antibodies in plasma, and their associations to clinical and fecal biomarkers, before and 6 months after Roux-en-Y gastric bypass (RYGB) surgery. Thirty individuals with obesity [16 type 2 diabetic, 14 non-diabetic (ND)] had RYGB surgery. Total plasma IgA, IgG and IgM antibody levels and specific antibodies to oxidized low-density lipoprotein (oxLDL), malondialdehyde-acetaldehyde adducts, Porphyromonas gingivalis gingipain A hemagglutinin domain (Rgp44), and phosphocholine were measured using chemiluminescence immunoassay. Associations between plasma and fecal antibodies as well as clinical markers were analyzed. RYGB surgery reduced blood pressure, and the glycemic state was improved. A higher level of diastolic blood pressure was associated with lower plasma antibodies to oxLDL after surgery. Also, lower level of glucose markers associated with lower level of plasma antibodies to bacterial virulence factors. Antibodies to oxLDL decreased after surgery, and positive association between active serum lipopolysaccharide and specific oxLDL antibodies was detected. Total IgG levels decreased after surgery, but only in ND individuals. Reduced level of total plasma IgG, improved state of hypertension and hyperglycemia and their associations with decreased levels of specific antibodies in plasma, suggest an improved state of systemic inflammation after RYGB surgery.

Inorganic polyphosphates are evolutionarily conserved bioactive phosphate polymers found as various chain lengths in all living organisms. In mammals, polyphosphates play a vital role in the regulation of cellular metabolism, coagulation, and inflammation. Long-chain polyphosphates are found along with endotoxins in pathogenic gram-negative bacteria and can participate in bacterial virulence. We aimed to investigate whether exogenously administered polyphosphates modulate human leukocyte function in vitro by treating the cells with 3 different chain lengths of polyphosphates (P14, P100, and P700). The long-chain polyphosphates, P700, had a remarkable capacity to downregulate type I interferon signaling dose dependently in THP1-Dual cells while only a slight elevation could be observed in the NF-κB pathway with the highest dose of P700. P700 treatment decreased lipopolysaccharide-induced IFNβ transcription and secretion, reduced STAT1 phosphorylation, and downregulated subsequent interferon-stimulated gene expression in primary human peripheral blood mononuclear cells. P700 also augmented lipopolysaccharide-induced secretion of IL-1α, IL-1β, IL-4, IL-5, IL-10, and IFNγ. Furthermore, P700 has previously been reported to increase the phosphorylation of several intracellular signaling mediators, such as AKT, mTOR, ERK, p38, GSK3α/β, HSP27, and JNK pathway components, which was supported by our findings. Taken together, these observations demonstrate the extensive modulatory effects P700 has on cytokine signaling and the inhibitory effects specifically targeted to type I interferon signaling in human leukocytes.

We aimed to study levels of natural antibodies in plasma, and their associations to clinical and fecal biomarkers, before and 6 months after Roux‐en‐Y gastric bypass (RYGB) surgery. Thirty individuals with obesity [16 type 2 diabetic, 14 non‐diabetic (ND)] had RYGB surgery. Total plasma IgA, IgG and IgM antibody levels and specific antibodies to oxidized low‐density lipoprotein (oxLDL), malondialdehyde‐acetaldehyde adducts, Porphyromonas gingivalis gingipain A hemagglutinin domain (Rgp44), and phosphocholine were measured using chemiluminescence immunoassay. Associations between plasma and fecal antibodies as well as clinical markers were analyzed. RYGB surgery reduced blood pressure, and the glycemic state was improved. A higher level of diastolic blood pressure was associated with lower plasma antibodies to oxLDL after surgery. Also, lower level of glucose markers associated with lower level of plasma antibodies to bacterial virulence factors. Antibodies to oxLDL decreased after surgery, and positive association between active serum lipopolysaccharide and specific oxLDL antibodies was detected. Total IgG levels decreased after surgery, but only in ND individuals. Reduced level of total plasma IgG, improved state of hypertension and hyperglycemia and their associations with decreased levels of specific antibodies in plasma, suggest an improved state of systemic inflammation after RYGB surgery.

Vibrational spectroscopic techniques, namely Fourier transform infrared (FTIR) and Raman spectroscopy, are based on the study of molecular vibrations, and they are complementary techniques to each other. This review provides an overview of the vibrational spectroscopic techniques applied in microbiology during the past decade. In addition, future applications of the elaborated spectroscopic techniques will be highlighted. The results of this review show that both FTIR and Raman spectroscopy are promising alternatives to conventional diagnostic approaches because they provide label-free and noninvasive bacterial detection, identification, and antibiotic susceptibility testing in a single step. Cost-effective, accurate, and rapid tests are needed in order to improve diagnostics and patient care, to decrease the use of unnecessary antimicrobial agents, to prevent resistant microbials, and to decrease the overall burden of outbreaks. Prior to that, however, the presented approaches need to be validated in a clinical workflow against the conventional diagnostic approaches.

Obesity is associated with low‐grade inflammation and increased systemic oxidative stress. Roux‐en‐Y gastric bypass (RYGB) surgery is known to ameliorate the obesity‐induced metabolic dysfunctions. We aimed to study the levels of natural antibodies in feces, before and 6 months after RYGB surgery in obese individuals with and without type 2 diabetes (T2D). Sixteen individuals with T2D and 14 non‐diabetic (ND) individuals were operated. Total IgA, IgG and IgM antibody levels and specific antibodies to oxidized low‐density lipoprotein (oxLDL), malondialdehyde‐acetaldehyde adducts (MAA adducts), Porphyromonas gingivalis gingipain A hemagglutinin domain (Rgp44) and phosphocholine (PCho) were measured using chemiluminescence immunoassay. Total fecal IgA was elevated, while total IgM and IgG were not affected by the surgery. Fecal natural IgM specific to oxLDL decreased significantly in both T2D and ND individuals, while fecal IgM to Rgp44 and PCho decreased significantly in T2D individuals. A decrease in IgG to MAA‐LDL, Rgp44 and PCho was detected. RYGB surgery increases the levels of total fecal IgA and decreases fecal natural IgG and IgM antibodies specific to oxLDL. Natural antibodies and IgA are important in maintaining the normal gut homeostasis and first‐line defense against microbes, and their production is markedly altered with RYGB surgery.

Background and Aims : Development of atherosclerosis shares features of chronic inflammation. Most chronic infections are considered to be due to biofilms. We have shown that coronary atheromas and thrombosis aspirates harbor DNA from several oral bacteria among which DNA from viridans group streptococci was the most common. In the oral cavity viridans streptococci act as early colonizers in the formation of dental biofilm which calcifies into dental plaque. Here we studied whether viridans streptococcal immunopositivity correlates with coronary calcification and stenosis percentage.Methods: The surface areas of atherosclerosis lesion types (fatty, fibrous, calcified, complicated) and stenosis percentage were measured in the left anterior descending (LAD) coronary artery of 121 victims of sudden out-of-hospital death in the Tampere Sudden Death Study (TSDS). Coronary sections were stained immunohistochemically with a pool of antibodies raised against 3 most common viridans streptococcal strains. The strength of the immunopositivity was scored into no positivity (-), slight (+), moderate (++) or severe (+++).Conclusions: Viridans streptococcal immunopositivity of coronary atheromas was linked with coronary atheroma calcification and stenosis but not with other atherosclerosis lesion types. This suggests a new mechanism involved in the calcification of coronary atheroma. Background and Aims : Development of atherosclerosis shares features of chronic inflammation. Most chronic infections are considered to be due to biofilms. We have shown that coronary atheromas and thrombosis aspirates harbor DNA from several oral bacteria among which DNA from viridans group streptococci was the most common. In the oral cavity viridans streptococci act as early colonizers in the formation of dental biofilm which calcifies into dental plaque. Here we studied whether viridans streptococcal immunopositivity correlates with coronary calcification and stenosis percentage. Methods: The surface areas of atherosclerosis lesion types (fatty, fibrous, calcified, complicated) and stenosis percentage were measured in the left anterior descending (LAD) coronary artery of 121 victims of sudden out-of-hospital death in the Tampere Sudden Death Study (TSDS). Coronary sections were stained immunohistochemically with a pool of antibodies raised against 3 most common viridans streptococcal strains. The strength of the immunopositivity was scored into no positivity (-), slight (+), moderate (++) or severe (+++). Conclusions: Viridans streptococcal immunopositivity of coronary atheromas was linked with coronary atheroma calcification and stenosis but not with other atherosclerosis lesion types. This suggests a new mechanism involved in the calcification of coronary atheroma.

Type 1 diabetes is associated with increased intestinal inflammation and decreased abundance of butyrate-producing bacteria. We investigated the effect of butyrate on inflammation, kidney parameters, HbA1c, serum metabolites and gastrointestinal symptoms in persons with type 1 diabetes, albuminuria and intestinal inflammation. We conducted a randomized placebo-controlled, double-blind, parallel clinical study involving 53 participants randomized to 3.6 g sodium butyrate daily or placebo for 12 weeks. The primary endpoint was the change in fecal calprotectin. Additional endpoints were the change in fecal short chain fatty acids, intestinal alkaline phosphatase activity and immunoglobulins, serum lipopolysaccharide, CRP, albuminuria, kidney function, HbA1c, metabolites and gastrointestinal symptoms. The mean age was 54 ± 13 years, and the median [Q1:Q3] urinary albumin excretion was 46 [14:121] mg/g. The median fecal calprotectin in the butyrate group was 48 [26:100] μg/g at baseline, and the change was −1.0 [−20:10] μg/g; the median in the placebo group was 61 [25:139] μg/g at baseline, and the change was −12 [−95:1] μg/g. The difference between the groups was not significant (p = 0.24); neither did we find an effect of butyrate compared to placebo on the other inflammatory markers, kidney parameters, HbA1c, metabolites nor gastrointestinal symptoms. Twelve weeks of butyrate supplementation did not reduce intestinal inflammation in persons with type 1 diabetes, albuminuria and intestinal inflammation.

Background and aims Subjects with congenital chloride diarrhea (CLD; a defect in solute carrier family 26 member 3 (SLC26A3)) are prone to inflammatory bowel disease (IBD). We investigated fecal microbiota in CLD and CLD-associated IBD. We also tested whether microbiota is modulated by supplementation with the short-chain fatty acid butyrate. Subjects and methods We recruited 30 patients with CLD for an observational 3-week follow-up study. Thereafter, 16 consented to oral butyrate substitution for a 3-week observational period. Fecal samples, collected once a week, were assayed for calprotectin and potential markers of inflammation, and studied by 16S ribosomal ribonucleic acid (rRNA) gene amplicon sequencing and compared to that of 19 healthy controls and 43 controls with Crohn’s disease. Data on intestinal symptoms, diet and quality of life were collected. Results Patients with CLD had increased abundances of Proteobacteria, Veillonella, and Prevotella, and lower abundances of normally dominant taxa Ruminococcaceae and Lachnospiraceae when compared with healthy controls and Crohn´s disease. No major differences in fecal microbiota were found between CLD and CLD-associated IBD (including two with yet untreated IBD). Butyrate was poorly tolerated and showed no major effects on fecal microbiota or biomarkers in CLD. Conclusions Fecal microbiota in CLD is different from that of healthy subjects or Crohn´s disease. Unexpectedly, no changes in the microbiota or fecal markers characterized CLD-associated IBD, an entity with high frequency among patients with CLD.

Obesity is associated with low-grade inflammation and increased systemic oxidative stress. Roux-en-Y gastric bypass (RYGB) surgery is known to ameliorate the obesity-induced metabolic dysfunctions. We aimed to study the levels of natural antibodies in feces, before and 6 months after RYGB surgery in obese individuals with and without type 2 diabetes (T2D). Sixteen individuals with T2D and 14 non-diabetic (ND) individuals were operated. Total IgA, IgG and IgM antibody levels and specific antibodies to oxidized low-density lipoprotein (oxLDL), malondialdehyde-acetaldehyde adducts (MAA adducts), Porphyromonas gingivalis gingipain A hemagglutinin domain (Rgp44) and phosphocholine (PCho) were measured using chemiluminescence immunoassay. Total fecal IgA was elevated, while total IgM and IgG were not affected by the surgery. Fecal natural IgM specific to oxLDL decreased significantly in both T2D and ND individuals, while fecal IgM to Rgp44 and PCho decreased significantly in T2D individuals. A decrease in IgG to MAA-LDL, Rgp44 and PCho was detected. RYGB surgery increases the levels of total fecal IgA and decreases fecal natural IgG and IgM antibodies specific to oxLDL. Natural antibodies and IgA are important in maintaining the normal gut homeostasis and first-line defense against microbes, and their production is markedly altered with RYGB surgery.

OBJECTIVEOxidized epitopes such as malondialdehyde-acetaldehyde (MAA) play a crucial role in the progression of atherosclerosis through activation of the humoral immune response. The exact mechanism of the association between atherosclerosis and periodontal diseases is not fully understood. The aim of the current study is to evaluate the association of oral humoral immune response to oxidized epitopes with parameters of periodontal disease.MATERIALS AND METHODSThe Parogene cohort consist of patients who have undergone coronary angiography due to cardiac symptoms. In this study, 423 patients were randomly selected for an extensive oral examination. Salivary Immunoglobulin A to oxidized epitopes and bacterial antigens was determined by chemiluminescence immunoassay.RESULTSIn a binary logistic regression model adjusted with periodontal disease confounders, periodontal pocket depth (PPD) 4-5 mm associated with salivary IgA antibodies to MAA-LDL (p = 0.034), heat shock protein 60 of Aggregatibacter actinomycetemcomitans (p = 0.045), Porphyromonas gingivalis (p = 0.045), A. actinomycetemcomitans (p = 0.005), P. intermedia (p = 0.020), and total IgA (p = 0.003).CONCLUSIONSThe current study shows the association of salivary IgA to MAA-LDL with PPD 4-5 mm in a cohort of patients with chronic coronary artery disease. Humoral immune cross-reactivation to oxidized epitopes such MAA-LDL could partly explain the link of periodontitis with systemic diseases.

IgA is the most abundant Ab in the human body. However, most patients with selective IgA deficiency (SIgAD) are asymptomatic. IgM, and to lesser extent IgG Abs, are generally presumed to compensate for the lack of IgA in SIgAD by multiplying and adopting functions of IgA. We used data from the Northern Finland Birth Cohort 1966 to investigate whether SIgAD patients have differences in levels of natural Abs to oxidized epitopes compared with 20 randomly selected healthy controls. First, we screened the saliva and serum samples from the Northern Finland Birth Cohort 1966 cohort (n = 1610) for IgA concentration. We detected five IgA-deficient subjects, yielding a prevalence of 0.3%, which is consistent with the general prevalence of 0.25% in the Finnish population. To detect natural Abs, we used malondialdehyde acetaldehyde-low-density lipoprotein (MAA-LDL), an Ag known to bind natural Abs. In this study, we show that natural secretory IgM and IgG Abs to MAA-DL were significantly increased in subjects with SIgAD. Given that secretory IgA is an important part of mucosal immune defense and that, in the gut microbiota, dysbiosis with SIgAD patients has been observed, we characterized the oral bacterial microbiota of the subjects with and without SIgAD using high-throughput 16S rRNA gene sequencing. We found no significant alterations in diversity and composition of the oral microbiota in subjects with SIgAD. Our data suggest that increased levels of secretory natural Abs in patients with SIgAD could be a compensatory mechanism, providing alternative first-line defense against infections and adjusting mucosal milieu to maintain a healthy oral microbiota.

Gastrointestinal dysbiosis is common among persons with type 1 diabetes (T1D), but its potential impact on diabetic nephropathy (DN) remains obscure. We examined whether faecal biomarkers, previously associated with low-grade gastrointestinal inflammation, differ between healthy controls and T1D subjects with and without DN. Faecal samples were analyzed for levels of calprotectin, intestinal alkaline phosphatase (IAP), short-chain fatty acids (SCFA) and immunoglobulins in subjects with T1D (n = 159) and healthy controls (NDC; n = 50). The subjects with T1D were stratified based on albuminuria: normoalbuminuria (< 30 mg/g; n = 49), microalbuminuria (30–299 mg/g; n = 50) and macroalbuminuria (≥ 300 mg/g; n = 60). aecal calprotectin, IAP and immunoglobulin levels did not differ between the T1D albuminuria groups. However, when subjects were stratified based on faecal calprotectin cut-off level (50 µg/g), macroalbuminuric T1D subjects exceeded the threshold more frequently than NDC ( p = 0.02). Concentrations of faecal propionate and butyrate were lower in T1D subjects compared with NDC ( p = 0.04 and p = 0.03, respectively). Among T1D subjects, levels of branched SCFA (BCFA) correlated positively with current albuminuria level (isobutyrate, p = 0.03; isovalerate, p = 0.005). In our study cohort, fatty acid metabolism seemed to be altered among T1D subjects and those with albuminuria compared to NDC. This may reflect gastrointestinal imbalances associated with T1D and renal complications.

Objective: Atherosclerosis is a key component of cardiovascular diseases. We set out to study here whether genetic ablation of P4H-TM (transmembrane prolyl 4-hydroxylase) could protect against atherosclerosis as does inhibition of the other 3 classical HIF-P4Hs (hypoxia-inducible factor prolyl 4-hydroxylases). Approach and Results: We generated a double knockout mouse line deficient in P4H-TM and LDL (low-density lipoprotein) receptor ( P4h-tm −/− /Ldlr −/− ) and subjected these mice to a high-fat diet for 13 weeks. The double knockout mice had less atherosclerotic plaques in their full-length aorta than their P4h-tm +/+ /Ldlr −/− counterparts and also had lower serum triglyceride levels on standard laboratory diet and high-fat diet, higher levels of IgM autoantibodies against Ox-LDL (oxidized LDL), and significantly higher LPL (lipoprotein lipase) protein levels in white adipose tissue and sera. RNA-sequencing analysis revealed changes in expression of mRNAs in multiple pathways including lipid metabolism and immunologic response in the P4h-tm −/− / Ldlr −/− livers as compared with P4h-tm +/+ / Ldlr −/− . Conclusions: Our data identify P4H-TM inhibition as a potential novel immuno-metabolic mechanism for intervening in the pathology of atherosclerosis, as hypertriglyceridemia is an individual risk factor for atherosclerosis, and IgM antibodies to Ox-LDL and increased lipoprotein lipase have been associated with protection against it.