A Randomized Trial Comparing the Specific Carbohydrate Diet to a Mediterranean Diet in Adults With Crohn's Disease.
Gastroenterology
BACKGROUND & AIMS:This study compared the effectiveness of the Specific Carbohydrate Diet (SCD) to the Mediterranean diet (MD) as treatment for Crohn's disease (CD) with mild to moderate symptoms. METHODS:Adult patients with CD and with mild-to-moderate symptoms were randomly assigned 1:1 to consume the MD or SCD for 12 weeks. For the first 6 weeks, participants received prepared meals and snacks according to their assigned diet. After 6 weeks, participants were instructed to follow the diet independently. The primary outcome was symptomatic remission at week 6. Key secondary outcomes at week 6 included fecal calprotectin (FC) response (FC <250 μg/g and reduction by >50% among those with baseline FC >250 μg/g) and C-reactive protein (CRP) response (high-sensitivity CRP <5 mg/L and >50% reduction from baseline among those with high-sensitivity CRP >5 mg/L). RESULTS:The study randomized 194 patients, and 191 were included in the efficacy analyses. The percentage of participants who achieved symptomatic remission at week 6 was not superior with the SCD (SCD, 46.5%; MD, 43.5%; P = .77). FC response was achieved in 8 of 23 participants (34.8%) with the SCD and in 4 of 13 participants (30.8%) with the MD (P = .83). CRP response was achieved in 2 of 37 participants (5.4%) with the SCD and in 1 of 28 participants (3.6%) with the MD (P = .68). CONCLUSIONS:The SCD was not superior to the MD to achieve symptomatic remission, FC response, and CRP response. CRP response was uncommon. Given these results, the greater ease of following the MD and other health benefits associated with the MD, the MD may be preferred to the SCD for most patients with CD with mild to moderate symptoms. ClinicalTrials.gov Identifier: NCT03058679.
10.1053/j.gastro.2021.05.047
Porphyromonas gingivalis and Alzheimer disease: Recent findings and potential therapies.
Ryder Mark I
Journal of periodontology
Epidemiological studies have identified an association between periodontitis and Alzheimer disease (AD); however, the nature of this association has been unclear. Recent work suggests that brain colonization by the periodontal pathogen Porphyromonas gingivalis may link these two inflammatory and degenerative conditions. Evidence of P. gingivalis infiltration has been detected in autopsy specimens from the brains of people with AD and in cerebrospinal fluid of individuals diagnosed with AD. Gingipains, a class of P. gingivalis proteases, are found in association with neurons, tau tangles, and beta-amyloid in specimens from the brains of individuals with AD. The brains of mice orally infected with P. gingivalis show evidence of P. gingivalis infiltration, along with various neuropathological hallmarks of AD. Oral administration of gingipain inhibitors to mice with established brain infections decreases the abundance of P. gingivalis DNA in brain and mitigates the neurotoxic effects of P. gingivalis infection. Thus, gingipain inhibition could provide a potential approach to the treatment of both periodontitis and AD.
10.1002/JPER.20-0104
Secreted gingipains from Porphyromonas gingivalis induce microglia migration through endosomal signaling by protease-activated receptor 2.
Nonaka Saori,Nakanishi Hiroshi
Neurochemistry international
Much attention has been paid to the connection between periodontitis and Alzheimer's disease (AD). We previously showed that infection of P. gingivalis, one of major periodontal pathogen causing periodontitis, induced migration and inflammatory responses in murine microglia through gingipain-induced activation of protease-activated receptor 2 (PAR2). In this study, we have attempted to clarify effects of secreted gingipains on cell migration of human microglial cell line, cleavage sites of PAR2 by gingipains and subsequent signaling pathways. P. gingivalis culture supernatant induced migration and membrane ruffling, which is necessary for microglia migration, in human microglial cell line HMC3 cells through PAR2. These effects were mainly mediated by gingipains, because cell migration and membrane ruffling were dramatically inhibited by treatment with gingipain inhibitors. Furthermore, pharmacological and genetic inhibition of Src kinase and β-arrestin, which are important for the internalization of G protein-coupled receptors, significantly inhibited P. gingivavlis culture supernatant-induced membrane ruffling in HMC3 cells. After treatment with P. gingivalis culture supernatant in Flag-PAR2-HA transfected HEK293T cells, Flag was removed from the cell surface, and HA was detected in the cytosol, indicating the internalization of PAR2. Furthermore, the phosphorylation level of ERK1/2 increased in PAR2-transfected HEK293T cells after treatment with P. gingivalis culture supernatant. The gingipain inhibitors, Src kinase inhibitor and β-arrestin knockdown suppressed PAR2 internalization and ERK1/2 phosphorylation. These observations suggest that secreted gingipains from P. gingivalis induce Src- and β-arrestin-dependent internalization of PAR2 and further activate the ERK1/2 pathway to promote migration of microglia. PAR2 are activated by the tethered ligands exposed by cleavage of extracellular N-terminal of PAR2. We also estimated potential gingipain cleavage sites in PAR2 and exposed tethered ligands, which are required for PAR2 internalization and membrane ruffling. The identified mechanism in this study might contribute to the retrogression of sporadic AD in patients after infection with P. gingivalis.
10.1016/j.neuint.2020.104840
Effect of periodontal treatment on preclinical Alzheimer's disease-Results of a trial emulation approach.
Schwahn Christian,Frenzel Stefan,Holtfreter Birte,Van der Auwera Sandra,Pink Christiane,Bülow Robin,Friedrich Nele,Völzke Henry,Biffar Reiner,Kocher Thomas,Grabe Hans Jörgen,
Alzheimer's & dementia : the journal of the Alzheimer's Association
INTRODUCTION:We investigated the relationship between periodontal treatment and pre-clinical Alzheimer's disease (AD). METHODS:In this quasi-experimental design, 177 periodontally treated patients from the "Greifswald Approach to Individualized Medicine" cohort, which used the same protocols as the population-based Study of Health in Pomerania TREND (SHIP-TREND), and 409 untreated subjects from SHIP-TREND were analyzed. Subjects were younger than 60 years at the magnetic resonance imaging examination, with a median observation period of 7.3 years. Imaging markers for brain atrophy in late-onset AD and brain aging were used as the outcomes. RESULTS:Robust to sensitivity analyses, periodontal treatment had a favorable effect on AD-related brain atrophy (-0.41; 95% confidence interval: -0.70 to -0.12; P = .0051), which corresponds to a shift from the 50th to the 37th percentile of the outcome distribution. For brain aging, the treatment effect was uncertain. CONCLUSION:Periodontitis is related to pre-clinical AD in our population.
10.1002/alz.12378
The Oral Health Status of Chinese Elderly People with and without Dementia: A Cross-Sectional Study.
Gao Sherry Shiqian,Chen Kitty Jieyi,Duangthip Duangporn,Lo Edward Chin Man,Chu Chun Hung
International journal of environmental research and public health
OBJECTIVE:The objective of this study was to compare the caries, periodontal status, and toothbrushing practices of Chinese elderly people with and without dementia. METHODS:This cross-sectional study recruited Chinese people aged 65 years or over attending daycare centers in Hong Kong. The participants' dementia status was identified from their medical record. Their demographic information and toothbrushing practices were obtained through a questionnaire survey. Caries experience, periodontal status, and oral hygiene were measured using the Decayed, Missing, and Filled Teeth (DMFT) Index, Community Periodontal Index, and Visible Plaque Index (VPI), respectively. The case matching process, using the propensity score, was conducted to match the participants in dementia and nondementia groups. The chi-square test and t-test were conducted for analysis. RESULTS:A total of 341 elderly people participated in this study. After case matching by gender and age, 129 participants with dementia were matched with 99 participants without dementia. The mean age and mean DMFT of the dementia group versus the nondementia group were 80.9 ± 7.5 vs. 79.4 ± 6.7 ( = 0.428) and 22.5 ± 7.9 vs. 19.2 ± 9.3 ( = 0.041), respectively. There was no significant difference of periodontal status observed. The VPI of dementia and nondementia groups were 77% and 63%, respectively ( = 0.027). Though they had no difference in frequency of toothbrushing, more dementia participants encountered difficulties in toothbrushing than those without dementia (57% vs. 8%, < 0.001). CONCLUSION:Compared with elderly people without dementia, Chinese elderly people with dementia had more caries experience and poorer oral hygiene in Hong Kong. They were more likely to have difficulty in performing toothbrushing.
10.3390/ijerph17061913
in Alzheimer's disease brains: Evidence for disease causation and treatment with small-molecule inhibitors.
Dominy Stephen S,Lynch Casey,Ermini Florian,Benedyk Malgorzata,Marczyk Agata,Konradi Andrei,Nguyen Mai,Haditsch Ursula,Raha Debasish,Griffin Christina,Holsinger Leslie J,Arastu-Kapur Shirin,Kaba Samer,Lee Alexander,Ryder Mark I,Potempa Barbara,Mydel Piotr,Hellvard Annelie,Adamowicz Karina,Hasturk Hatice,Walker Glenn D,Reynolds Eric C,Faull Richard L M,Curtis Maurice A,Dragunow Mike,Potempa Jan
Science advances
, the keystone pathogen in chronic periodontitis, was identified in the brain of Alzheimer's disease patients. Toxic proteases from the bacterium called gingipains were also identified in the brain of Alzheimer's patients, and levels correlated with tau and ubiquitin pathology. Oral infection in mice resulted in brain colonization and increased production of Aβ, a component of amyloid plaques. Further, gingipains were neurotoxic in vivo and in vitro, exerting detrimental effects on tau, a protein needed for normal neuronal function. To block this neurotoxicity, we designed and synthesized small-molecule inhibitors targeting gingipains. Gingipain inhibition reduced the bacterial load of an established brain infection, blocked Aβ production, reduced neuroinflammation, and rescued neurons in the hippocampus. These data suggest that gingipain inhibitors could be valuable for treating brain colonization and neurodegeneration in Alzheimer's disease.
10.1126/sciadv.aau3333
Infection burden, periodontal pathogens, and their interactive association with incident all-cause and Alzheimer's disease dementia in a large national survey.
Alzheimer's & dementia : the journal of the Alzheimer's Association
INTRODUCTION:Relationships and interplay of an infection burden (IB) and periodontal pathogens or periodontal disease (Pd) markers with Alzheimer's disease (AD) and all-cause dementia among US adults were examined. METHODS:Less than or equal to 2997 participants from the National Health and Nutrition Survey III were linked to CMS-Medicare [≥45 years (1988-1994); ≤30 years follow-up]. RESULTS:Hepatitis C (hazard ratio = 3.33, p = 0.004) and herpes simplex virus 2 were strongly associated with greater all-cause dementia risk. Porphyromonas gingivalis and Streptococcus oralis were associated with greater AD risk at higher IB. The red-green periodontal pathogen cluster coupled with higher IB count increased the risk of all-cause dementia among minority racial groups. Pocket probing depth associated with dementia risk at lower IB in the overall sample. DISCUSSION:Select viruses and bacteria were associated with all-cause and AD dementia, while the IB interacted with Pd markers in relation to these outcomes. HIGHLIGHTS:Interplay of infection burden (IB) and periodontal disease with dementia was tested. ≤2997 participants from NHANES III were linked to Medicare. Hepatitis C and herpes simplex virus 2 strongly associated with dementia risk. Tetanus sero-positivity increased Alzheimer's disease (AD) risk. Porphyromonas gingivalis and Streptococcus oralis associated with AD at higher IB. Red-green periodontal cluster at high IB, increased dementia in racial minorities. Pocket probing depth associated with dementia risk at lower IB.
10.1002/alz.14141
Alzheimer's disease and symbiotic microbiota: an evolutionary medicine perspective.
Annals of the New York Academy of Sciences
Microorganisms resident in our bodies participate in a variety of regulatory and pathogenic processes. Here, we describe how etiological pathways implicated in Alzheimer's disease (AD) may be regulated or disturbed by symbiotic microbial activity. Furthermore, the composition of symbiotic microbes has changed dramatically across human history alongside the rise of agriculturalism, industrialization, and globalization. We postulate that each of these lifestyle transitions engendered progressive depletion of microbial diversity and enhancement of virulence, thereby enhancing AD risk pathways. It is likely that the human life span extended into the eighth decade tens of thousands of years ago, yet little is known about premodern geriatric epidemiology. We propose that microbiota of the gut, oral cavity, nasal cavity, and brain may modulate AD pathogenesis, and that changes in the microbial composition of these body regions across history suggest escalation of AD risk. Dysbiosis may promote immunoregulatory dysfunction due to inadequate education of the immune system, chronic inflammation, and epithelial barrier permeability. Subsequently, proinflammatory agents-and occasionally microbes-may infiltrate the brain and promote AD pathogenic processes. APOE genotypes appear to moderate the effect of dysbiosis on AD risk. Elucidating the effect of symbiotic microbiota on AD pathogenesis could contribute to basic and translational research.
10.1111/nyas.14129
Lipopolysaccharide alters the blood-brain barrier transport of amyloid beta protein: a mechanism for inflammation in the progression of Alzheimer's disease.
Brain, behavior, and immunity
Alzheimer's disease (AD) brains are characterized by accumulation of amyloid beta protein (Abeta) and neuroinflammation. Increased blood-to-brain influx and decreased brain-to-blood efflux across the blood-brain barrier (BBB) have been proposed as mechanisms for Abeta accumulation. Epidemiological studies suggest that the nonsteroidal anti-inflammatory drug (NSAID) indomethacin slows the progression of AD. We hypothesized that inflammation alters BBB handling of Abeta. Mice treated with lipopolysaccharide (LPS) had increased brain influx and decreased brain efflux of Abeta, recapitulating the findings in AD. Neither influx nor efflux was mediated by LPS acting directly on BBB cells. Increased influx was mediated by a blood-borne factor, indomethacin-independent, blocked by the triglyceride triolein, and not related to expression of the blood-to-brain transporter of Abeta, RAGE. Serum levels of IL-6, IL-10, IL-13, and MCP-1 mirrored changes in Abeta influx. Decreased efflux was blocked by indomethacin and accompanied by decreased protein expression of the brain-to-blood transporter of Abeta, LRP-1. LPS paradoxically increased expression of neuronal LRP-1, a major source of Abeta. Thus, inflammation potentially increases brain levels of Abeta by three mechanisms: increased influx, decreased efflux, and increased neuronal production.
10.1016/j.bbi.2009.01.017
Periodontitis promotes bacterial extracellular vesicle-induced neuroinflammation in the brain and trigeminal ganglion.
PLoS pathogens
Gram-negative bacteria derived extracellular vesicles (EVs), also known as outer membrane vesicles, have attracted significant attention due to their pathogenic roles in various inflammatory diseases. We recently demonstrated that EVs secreted by the periodontopathogen Aggregatibacter actinomycetemcomitans (Aa) can cross the blood-brain barrier (BBB) and that their extracellular RNA cargo can promote the secretion of proinflammatory cytokines, such as IL-6 and TNF-α, in the brain. To gain more insight into the relationship between periodontal disease (PD) and neuroinflammatory diseases, we investigated the effect of Aa EVs in a mouse model of ligature-induced PD. When EVs were administered through intragingival injection or EV-soaked gel, proinflammatory cytokines were strongly induced in the brains of PD mice. The use of TLR (Toll-like receptor)-reporter cell lines and MyD88 knockout mice confirmed that the increased release of cytokines was triggered by Aa EVs via TLR4 and TLR8 signaling pathways and their downstream MyD88 pathway. Furthermore, the injection of EVs through the epidermis and gingiva resulted in the direct retrograde transfer of Aa EVs from axon terminals to the cell bodies of trigeminal ganglion (TG) neurons and the subsequent activation of TG neurons. We also found that the Aa EVs changed the action potential of TG neurons. These findings suggest that EVs derived from periodontopathogens such as Aa might be involved in pathogenic pathways for neuroinflammatory diseases, neuropathic pain, and other systemic inflammatory symptoms as a comorbidity of periodontitis.
10.1371/journal.ppat.1011743