Abnormalities in microbiota/butyrate/FFAR3 signaling in aging gut impair brain function.

Aging-related abnormalities in gut microbiota are associated with cognitive decline, depression, and anxiety, but underlying mechanisms remain unstudied. Here, our study demonstrated that transplanting old gut microbiota to young mice induced inflammation in the gut and brain coupled with cognitive decline, depression, and anxiety. We observed diminished mucin formation and increased gut permeability ("leaky gut") with a reduction in beneficial metabolites like butyrate because of decline in butyrate-producing bacteria in the aged gut microbiota. This led to suppressed expression of butyrate receptors, free fatty acid receptors 2 and 3 (FFAR2/3). Administering butyrate alleviated inflammation, restored mucin expression and gut barriers, and corrected brain dysfunction. Furthermore, young mice with intestine-specific loss of FFAR2/3 exhibited gut and brain abnormalities akin to those in older mice. Our results demonstrate that reduced butyrate-producing bacteria in aged gut microbiota result in low butyrate levels and reduced FFAR2/3 signaling, leading to suppressed mucin formation that increases gut permeability, inflammation, and brain abnormalities. These findings underscore the significance of butyrate-FFAR2/3 agonism as a potential strategy to mitigate aged gut microbiota-induced detrimental effects on gut and brain health in older adults.

Geroprotective potential of microbiome modulators in the Caenorhabditis elegans model.

Aging is associated with cellular and physiological changes, which significantly reduce the quality of life and increase the risk for disease. Geroprotectors improve lifespan and slow the progression of detrimental aging-related changes such as immune system senescence, mitochondrial dysfunction, and dysregulated nutrient sensing and metabolism. Emerging evidence suggests that gut microbiota dysbiosis is a hallmark of aging-related diseases and microbiome modulators, such as probiotics (live bacteria) or postbiotics (non-viable bacteria/bacterial byproducts) may be promising geroprotectors. However, because they are strain-specific, the geroprotective effects of probiotics and postbiotics remain poorly understood and understudied. Drosophila melanogaster, Caenorhabditis elegans, and rodents are well-validated preclinical models for studying lifespan and the role of probiotics and/or postbiotics, but each have their limitations, including cost and their translation to human aging biology. C. elegans is an excellent model for large-scale screening to determine the geroprotective potential of drugs or probiotics/postbiotics due to its short lifecycle, easy maintenance, low cost, and homology to humans. The purpose of this article is to review the geroprotective effects of microbiome modulators and their future scope, using C. elegans as a model. The proposed geroprotective mechanisms of these probiotics and postbiotics include delaying immune system senescence, preventing or reducing mitochondrial dysfunction, and regulating food intake (dietary restriction) and metabolism. More studies are warranted to understand the geroprotective potential of probiotics and postbiotics, as well as other microbiome modulators, like prebiotics and fermented foods, and use them to develop effective therapeutics to extend lifespan and reduce the risk of debilitating aging-related diseases.

Intestinal FFA2 promotes obesity by altering food intake in Western diet-fed mice.

Short-chain fatty acids (SCFAs) are key nutrients that play a diverse set of roles in physiological function, including regulating metabolic homeostasis. Generated through the fermentation of dietary fibers in the distal colon by the gut microbiome, SCFAs and their effects are partially mediated by their cognate receptors, including free fatty acid receptor 2 (FFA2). FFA2 is highly expressed in the intestinal epithelial cells, where its putative functions are controversial, with numerous in vivo studies relying on global knockout mouse models to characterize intestine-specific roles of the receptor. Here, we used the Villin-Cre mouse line to generate a novel, intestine-specific knockout mouse model for FFA2 (Vil-FFA2) to investigate receptor function within the intestine. Because dietary changes are known to affect the composition of the gut microbiome, and can thereby alter SCFA production, we performed an obesogenic challenge on male Vil-FFA2 mice and their littermate controls (FFA2-floxed, FFA2fl/fl) to identify physiological changes on a high-fat, high-sugar 'Western diet' (WD) compared to a low-fat control diet (CD). We found that the WD-fed Vil-FFA2 mice were transiently protected from the obesogenic effects of the WD and had lower fat mass and improved glucose homeostasis compared to the WD-fed FFA2fl/fl control group during the first half of the study. Additionally, major differences in respiratory exchange ratio and energy expenditure were observed in the WD-fed Vil-FFA2 mice, and food intake was found to be significantly reduced at multiple points in the study. Taken together, this study uncovers a novel role of intestinal FFA2 in mediating the development of obesity.

Poor Oral Health Linked with Higher Risk of Alzheimer's Disease.

Alzheimer's disease (AD) is a multifactorial neurodegenerative disease characterized by cognitive and behavioral changes in older adults. Emerging evidence suggests poor oral health is associated with AD, but there is a lack of large-scale clinical studies demonstrating this link. Herein, we used the TriNetX database to generate clinical cohorts and assess the risk of AD and survival among >30 million de-identified subjects with normal oral health (n = 31,418,814) and poor oral health (n = 1,232,751). There was a greater than two-fold increase in AD risk in the poor oral health cohort compared to the normal oral health group (risk ratio (RR): 2.363, (95% confidence interval: 2.326, 2.401)). To reduce potential bias, we performed retrospective propensity score matching for age, gender, and multiple laboratory measures. After matching, the cohorts had no significant differences in survival probability. Furthermore, when comparing multiple oral conditions, diseases related to tooth loss were the most significant risk factor for AD (RR: 3.186, (95% CI: 3.007, 3.376)). Our results suggest that oral health may be important in AD risk, regardless of age, gender, or laboratory measures. However, more large-scale cohort studies are necessary to validate these findings and further evaluate links between oral health and AD.

The Triple Alliance: Microbiome, Mitochondria, and Metabolites in the Context of Age-Related Cognitive Decline and Alzheimer's Disease.

Alzheimer's disease (AD) is a progressive, age-related neurodegenerative disorder that affects a large proportion of the older population. It currently lacks effective treatments, placing a heavy burden on patients, families, health care systems, and society. This is mainly due to our limited comprehension of the pathophysiology of AD progression, as well as the lack of effective drug targets and intervention timing to address the underlying pathology. AD is a multifactorial condition, and emerging evidence suggests that abnormalities in the gut microbiota play a significant role as environmental and multifaceted contributors to AD, although the exact mechanisms are yet to be fully explored. Changes in the composition of microbiota influence host neuronal health through their metabolites. These metabolites regulate intestinal epithelia, blood-brain barrier permeability, and neuroinflammation by affecting mitochondrial function. The decline in the proportion of beneficial microbes and their essential metabolites during aging and AD is directly linked to poor mitochondrial function, although the specific mechanisms remain unclear. In this review, we discuss recent developments in understanding the impact of the microbiome and its metabolites on various cell types, their influence on the integrity of the gut and blood-brain barriers, systemic and brain inflammation, and cell-specific effects in AD pathology. This information is expected to pave the way for a new understanding of the interactions between microbiota and mitochondria in AD, providing a foundation for the development of novel treatments for AD.

Treating Leaky Syndrome in the Over 65s: Progress and Challenges.

As we age, our organ functions gradually decline. Circulating factors in the blood and the integrity of organ barriers can become dysfunctional, resulting in a condition known as leaky syndrome. This condition involves the unregulated exchange or leakage of components between organs. However, the triggers of leaky syndrome, as well as its role in aging-related disorders and illnesses, remain largely unknown. In this editorial, we discuss potential mechanisms that originate from the gut and resident microbes (microbiome) to contribute in leaky syndrome. Furthermore, we explore how the food we consume can impact the development of leaky syndrome, potentially influencing the biology of aging and challenges to diagnose the leaky gut condition accurately and clinically.

A Comparative Study on Effectiveness of Parental Presence versus Sedative Premedication for Reducing Anxiety in Children Undergoing General Anesthesia.

Background: Preoperative anxiety is an important, yet often unattended problem in children. Minimizing anxiety and distress at the time of anesthetic induction may reduce adverse psychological and physiological outcomes. Sedative premedication and parental presence during anesthesia induction are among the most commonly employed strategies for reducing child anxiety. Aims and Objective: The study aimed to compare the effectiveness of a pharmacological intervention (premedication with midazolam) versus behavioral intervention (parental presence) in reducing preoperative anxiety in children undergoing general anesthesia. Methodology: Sixty patients of age group of 4-12 years, of ASA Grade 1 and 2 and either sex posted for elective surgery under general anesthesia were divided into two groups of 30 each Group M (midazolam group) and Group P (parental presence). Group M received intravenous midazolam 0.03-0.05 mg/kg preoperatively and anxiety was measured in preoperative room, during separation from parents and during introduction of anesthesia mask, whereas in Group P, parents accompanied the child inside the operation theater and anxiety was measured at preoperative room and during introduction of mask. Parental anxiety was measured in both groups at preoperative room and waiting room. Modified Yale Preoperative Anxiety Scale (mYPAS) and State Trait Anxiety Inventory (STAI) tool was used to measure anxiety in children and parents, respectively. Results: The mean mYPAS score while the introduction of anesthesia mask in Group M was 31.30 ± 12.04 and in Group P was 63.19 ± 25.31, and the difference was found to be statistically significant (P = 0.001). In preoperative room, there was no significant difference in anxiety in the two study groups. The mean STAI score in Group P was 45.63 ± 1.45 and in Group M was 41.10 ± 1.69, and the difference was found to be statistically significant (P = 0.001). In preoperative room, parental anxiety was found to be comparable among the two groups. The mean duration of induction of anesthesia in Group M was 5.53 ± 1.01 min, and in Group P, it was 8.77 ± 2.03 min. The difference was found to be statistically significant (P = 0.001). Conclusion: Both interventions were effective in reducing anxiety in children, but midazolam was more effective compared to parental presence. Parents in Group M were less anxious in the waiting room than Group P. Children in Group M were more compliant during the induction of anesthesia, hence a lesser duration of induction than Group P.

Unique trans-kingdom microbiome structural and functional signatures predict cognitive decline in older adults.

The prevalence of age-related cognitive disorders/dementia is increasing, and effective prevention and treatment interventions are lacking due to an incomplete understanding of aging neuropathophysiology. Emerging evidence suggests that abnormalities in gut microbiome are linked with age-related cognitive decline and getting acceptance as one of the pillars of the Geroscience hypothesis. However, the potential clinical importance of gut microbiome abnormalities in predicting the risk of cognitive decline in older adults is unclear. Till now the majority of clinical studies were done using 16S rRNA sequencing which only accounts for analyzing bacterial abundance, while lacking an understanding of other crucial microbial kingdoms, such as viruses, fungi, archaea, and the functional profiling of the microbiome community. Utilizing data and samples of older adults with mild cognitive impairment (MCI; n = 23) and cognitively healthy controls (n = 25). Our whole-genome metagenomic sequencing revealed that the gut of older adults with MCI harbors a less diverse microbiome with a specific increase in total viruses and a decrease in bacterial abundance compared with controls. The virome, bacteriome, and microbial metabolic signatures were significantly distinct in subjects with MCI versus controls. Selected bacteriome signatures show high predictive potential of cognitive dysfunction than virome signatures while combining virome and metabolic signatures with bacteriome boosts the prediction power. Altogether, the results from our pilot study indicate that trans-kingdom microbiome signatures are significantly distinct in MCI gut compared with controls and may have utility for predicting the risk of developing cognitive decline and dementia- debilitating public health problems in older adults.

Sleep deprivation in obesogenic setting alters lipidome and microbiome toward suboptimal inflammation in acute heart failure.

Sleep is a fundamental medicine for cardiac homeostasis, and sleep-deprived individuals are prone to higher incidences of heart attack. The lipid-dense diet (obesogenic diet-OBD) is a cumulative risk factor for chronic inflammation in cardiovascular disease; thus, understanding how sleep fragmentation (SF) in an obesity setting impacts immune and cardiac health is an unmet medical need. We hypothesized whether the co-existence of SF with OBD dysregulates gut homeostasis and leukocyte-derived reparative/resolution mediators, thereby impairing cardiac repair. Two-month-old male C57BL/6J mice were randomized first into two groups, then four groups; Control, control + SF, OBD, and OBD + SF mice subjected to myocardial infarction (MI). OBD mice had higher levels of plasma linolenic acid with a decrease in eicosapentaenoic and docosahexaenoic acid. The OBD mice had lower Lactobacillus johnsonii indicating a loss of probiotic microbiota. SF in OBD mice increased Firmicutes/Bacteroidetes ratio indicative of a detrimental change in SF-directed microbiome. OBD + SF group increased in the neutrophil: lymphocyte ratio suggestive of suboptimal inflammation. As a result of SF, resolution mediators (RvD2, RvD3, RvD5, LXA4 , PD1, and MaR1) decreased and inflammatory mediators (PGD2 , PGE2 , PGF2a , 6k-PGF1a ) were increased in OBD mice post-MI. At the site of infarction, the proinflammatory cytokines Ccl2, IL1ß, and IL-6 were amplified in OBD + SF indicating a robust proinflammatory milieu post-MI. Also, brain circadian genes (Bmal1, Clock) were downregulated in SF-subjected control mice, but remained elevated in OBD mice post-MI. SF superimposed on obesity dysregulated physiological inflammation and disrupted resolving response thereby impaired cardiac repair and signs of pathological inflammation.

The effects of prebiotics on gastrointestinal side effects of metformin in youth: A pilot randomized control trial in youth-onset type 2 diabetes.

Disclosure summary: Dr. Yadav is Chief Scientific Officer and Co-Founder of Postbiotics Inc and has no conflict of interest with this work. All other authors have no conflicts of interest to disclose. Background: Metformin is the only approved first-line oral glucose lowering agent for youth with type 2 diabetes mellitus (Y-T2DM) but often causes gastrointestinal (GI) side effects, which may contribute to reduced treatment adherence and efficacy. Prebiotic intake may reduce metformin's side effects by shifting microbiota composition and activity. Objective: The aims of this study were to determine the feasibility and tolerability of a prebiotic supplement to improve metformin-induced GI symptoms and explore the changes in glycemia and shifts in the microbiota diversity. Methods: In a two-phase pilot clinical trial, we compared, stool frequency and stool form every 1-2 days, and composite lower GI symptoms (weekly) at initiation of daily metformin combined with either a daily prebiotic or a placebo shake in a 1-week randomized double-blind crossover design (Phase 1), followed by a 1-month open-labeled extension (Phase 2). Plasma glycemic markers and stool samples were collected before and after each phase. Results: Six Y-T2DM (17.2 ± 1.7y (mean ± SD), 67% male, BMI (42 ± 9 kg/m2), HbA1c (6.4 ± 0.6%)) completed the intervention. Stool frequency, stool composition, and GI symptom scores did not differ by group or study phase. There were no serious or severe adverse events reported, and no differences in metabolic or glycemic markers. After one week Phase 1metformin/placebo Proteobacteria, Enterobacteriaceae, and Enterobacteriales were identified as candidate biomarkers of metformin effects. Principle coordinate analyses of beta diversity suggested that the metformin/prebiotic intervention was associated with distinct shifts in the microbiome signatures at one week and one month. Conclusion: Administration of a prebiotic fiber supplement during short-term metformin therapy was well tolerated in Y-T2DM and associated with modest shifts in microbial composition. This study provides a proof-of-concept for feasibility exploring prebiotic-metformin-microbiome interactions as a basis for adjunctive metformin therapy. Clinical trial registration: https://clinicaltrials.gov/, identifier NCT04209075.

Intermittent fasting with ketogenic diet: A combination approach for management of chronic diseases.

Intermittent Fasting (IF) is the consumption of food and drinks within a defined time, while the ketogenic diet (KD) switches the metabolism from glucose to fats. Continuation of intermittent fasting leads to the generation of ketones, the exact mechanism for a ketogenic diet. This article discusses the types of IF and KD, the monitoring required, and the mechanisms underlying IF and KD, followed by disorders in which the combination strategy could be applied. The strategies for successfully applying combination therapy are included, along with recommendations for the primary care physicians (PCP) which could serve as a handy guide for patient management. This opinion article could serve as the baseline for future clinical studies since there is an utmost need for developing new wholesome strategies for managing chronic disorders.

A mechanism by which gut microbiota elevates permeability and inflammation in obese/diabetic mice and human gut.

OBJECTIVE: Ample evidence exists for the role of abnormal gut microbiota composition and increased gut permeability ('leaky gut') in chronic inflammation that commonly co-occurs in the gut in both obesity and diabetes, yet the detailed mechanisms involved in this process have remained elusive. DESIGN: In this study, we substantiate the causal role of the gut microbiota by use of faecal conditioned media along with faecal microbiota transplantation. Using untargeted and comprehensive approaches, we discovered the mechanism by which the obese microbiota instigates gut permeability, inflammation and abnormalities in glucose metabolism. RESULTS: We demonstrated that the reduced capacity of the microbiota from both obese mice and humans to metabolise ethanolamine results in ethanolamine accumulation in the gut, accounting for induction of intestinal permeability. Elevated ethanolamine increased the expression of microRNA-miR-101a-3p by enhancing ARID3a binding on the miR promoter. Increased miR-101a-3p decreased the stability of zona occludens-1 (Zo1) mRNA, which in turn, weakened intestinal barriers and induced gut permeability, inflammation and abnormalities in glucose metabolism. Importantly, restoring ethanolamine-metabolising activity in gut microbiota using a novel probiotic therapy reduced elevated gut permeability, inflammation and abnormalities in glucose metabolism by correcting the ARID3a/miR-101a/Zo1 axis. CONCLUSION: Overall, we discovered that the reduced capacity of obese microbiota to metabolise ethanolamine instigates gut permeability, inflammation and glucose metabolic dysfunctions, and restoring ethanolamine-metabolising capacity by a novel probiotic therapy reverses these abnormalities. TRIAL REGISTRATION NUMBER: NCT02869659 and NCT03269032.

Sustaining Livelihoods or Saving Lives? Economic System Justification in the Time of COVID-19.

An ongoing debate in the United States relating to COVID-19 features the purported tension between containing the coronavirus to save lives or opening the economy to sustain livelihoods, with ethical overtones on both sides. Proponents of opening the economy argue that sustaining livelihoods should be prioritized over virus containment, with ethicists asking, "What about the risk to human life?" Defendants of restricting the spread of the virus endorse saving lives through virus containment but contend with the ethical concern "What about people's livelihoods and individual freedoms?" A commonly held belief is that political ideology drives these differential preferences: liberals are more focused on saving lives, whereas conservatives favor sustaining livelihoods with no additional government intervention in the free-market economy. We examine these lay beliefs among US residents in four studies and find that economic system justification (ESJ), an ideology that defends the prevailing economic system when under threat, is a reliable psychological predictor beyond political ideology. Specifically, compared to those who scored low on ESJ, people who scored high on ESJ judged China as more justified in downplaying the spread of virus to protect its interest in the global free-market economy, supported in-person over online learning, viewed shelter in place as less desirable, and perceived the opening of the Texas economy as more legitimate. We also find that multiple psychological mechanisms might be at work-resistance to market interventions, perceived legitimacy of opening the economy, perceived seriousness of the health crisis, and violation of human rights. Supplementary Information: The online version contains supplementary material available at 10.1007/s10551-022-05091-4.

Impact of FESS on the Pulmonary Function of Patients with Chronic Rhinosinusitis.

Background and Aims: There is interdependence between the upper and lower airway has led to the concept of a unified airway. Here we aim to study the impact of functional endoscopic sinus surgery (FESS) on the pulmonary function (PFT) of patients with chronic rhinosinusitis (CRS). Methods: The proposed study is undertaken in the department of ENT, PGIMER & Dr. RML Hospital, New Delhi. It is a prospective study of 34 patients fulfilling the clinical criteria for (CRS) from the study period of Oct 2015 to Dec 2017 not responding to medical management and taken up for fess and follow up done with (PFT). Results: The maximum incidence of cases was seen in the age group > 40 years. Chronic rhinosinusitis predominantly affected the male population. Nasal discharge was the commonest presenting complaint. A marked reduction is seen in the frequency of symptoms post-surgery. Conclusion: CRS affected persons of adult age with maximum number in the age group of > 40 years, with a male:female ratio of approximately 2:1. Percentage improvement in FEV1 and FVC is more in age group > 40 years while percentage improvement in FEV1/FVC ratio is more in age group 31-40 years. Percentage increase in FEV1 and FVC is more in males while percentage increase in FEV1/FVC is more in females. Percentage increase in FEV1 and FVC is more in males and FEV1/FVC is more in females. Percentage increase in FEV1, FVC and FEV1/FVC ratio is more in cases of bilateral diseases then those with unilateral disease.

Expression of Vascular Endothelial Growth Factor in Patients With Premalignant Lesions and Squamous Cell Carcinoma of Oral Cavity.

To evaluate and compare expression of VEGF in patients of premalignant lesions and squamous cell carcinoma of oral cavity. The cross sectional observational study is undertaken at the department of otorhionolaryngology and pathology, PGIMER and Dr RML Hospital, New Delhi,from 1st Nov 2017 to 31st March 2019,with a sample size of 30 cases each of premalignant lesions and oral squamous cell carcinoma immunohistochemistry by polymer method. In the participants with oral SCC, VEGF expression of Score 1 was observed in verrucous and well differentiated tumor, Score 2 in moderately differentiated SCC & Score 3 in poorly differentiated SCC with a p value of 0.0001. The observed difference and value of proportion p, is statically significant. In this study we concluded that VEGF expression increases as the lesion progresses from premalignant lesions to oral squamous cell carcinoma and is strongly associated with lymph node status (N-staging). Thus, VEGF can be a target in chemotherapy and its therapeutic implications in the HNSCC needs further research. Levels of Evidence 1A: Systematic review of randomized control trials.

Clinical Presentation and Microbiological Profile of Deep Neck Space Infections in Different Age Groups.

Deep neck space infection (DNI), is defined as infections in the deep fascia enclosing potential spaces of the neck. In the past the diagnosis and treatment of DNI have challenged. The health care personnel at all levels. The complex anatomy and the deep location of this region remains a big problem with significant risks of morbidity and mortality. The aim of this study is to analyse the difference in clinical presentation and microbiology of DNI in different age groups. Eighty two patients with DNI which were managed at the Department of Otorhinolaryngology, ABVIMS and Dr. Ram Manohar Lohia Hospital New Delhi, between November 2017 and March 2019 formed the basis of our prospective cross sectional observational study. We observed that DNI is a frequent and potentially life threatening condition in children and adults despite the use of antibiotics. For appropriate surgical management knowledge of complex spaces of the neck and their communication with the other spaces is necessary.

Diet-microbiome-gut-brain nexus in acute and chronic brain injury.

In recent years, appreciation for the gut microbiome and its relationship to human health has emerged as a facilitator of maintaining healthy physiology and a contributor to numerous human diseases. The contribution of the microbiome in modulating the gut-brain axis has gained significant attention in recent years, extensively studied in chronic brain injuries such as Epilepsy and Alzheimer's Disease. Furthermore, there is growing evidence that gut microbiome also contributes to acute brain injuries like stroke(s) and traumatic brain injury. Microbiome-gut-brain communications are bidirectional and involve metabolite production and modulation of immune and neuronal functions. The microbiome plays two distinct roles: it beneficially modulates immune system and neuronal functions; however, abnormalities in the host's microbiome also exacerbates neuronal damage or delays the recovery from acute injuries. After brain injury, several inflammatory changes, such as the necrosis and apoptosis of neuronal tissue, propagates downward inflammatory signals to disrupt the microbiome homeostasis; however, microbiome dysbiosis impacts the upward signaling to the brain and interferes with recovery in neuronal functions and brain health. Diet is a superlative modulator of microbiome and is known to impact the gut-brain axis, including its influence on acute and neuronal injuries. In this review, we discussed the differential microbiome changes in both acute and chronic brain injuries, as well as the therapeutic importance of modulation by diets and probiotics. We emphasize the mechanistic studies based on animal models and their translational or clinical relationship by reviewing human studies.

Correction: Bioactive peptides derived from milk proteins and their health beneficial potentials: an update.

Correction for 'Bioactive peptides derived from milk proteins and their health beneficial potentials: an update' by Ravinder Nagpal et al., Food Funct., 2011, 2, 18-27, DOI: 10.1039/C0FO00016G.

Evaluation of Contralateral Ear in Unilateral Chronic Otitis Media: Necessary or Not?

Eustachian tube appears to be central to the pathogenesis of all forms of otitis media. The reported frequency of bilateral disease ranges from 27 to 55%. The affected ear may well be the end point of the pathology in the contra lateral ear (CLE). Cross sectional observational study. One hundred patients who had unilateral chronic otitis media (COM) were enrolled in the study. Diseased ear was divided into either mucosal or squamosal type. Otoendoscopy, pure tone audiometry, impedance audiometry and X-ray mastoid (Schuller's view) findings of CLE were noted. Considering all the changes including tympanic membrane, X-ray mastoid, hearing assessment and tympanometry, we found that 70% of patients had alterations in the CLE. Our study was consistent with many previous studies that there was an increased risk of COM in the CLE of unilateral COM.

Intestinal FFA3 mediates obesogenic effects in mice on a Western diet.

Free fatty acid receptor 3 (FFA3) is a recently-deorphanized G-protein-coupled receptor. Its ligands are short-chain fatty acids (SCFAs), which are key nutrients derived from the gut microbiome fermentation process that play diverse roles in the regulation of metabolic homeostasis and glycemic control. FFA3 is highly expressed within the intestine, where its role and its effects on physiology and metabolism are unclear. Previous in vivo studies involving this receptor have relied on global knockout mouse models, making it difficult to isolate intestine-specific roles of FFA3. To overcome this challenge, we generated an intestine-specific knockout mouse model for FFA3, Villin-Cre-FFA3 (Vil-FFA3). Model validation and general metabolic assessment of male mice fed a standard chow diet revealed no major congenital defects. Because dietary changes are known to alter gut microbial composition, and thereby SCFA production, an obesogenic challenge was performed on male Vil-FFA3 mice and their littermate controls to probe for a phenotype on a high-fat, high-sugar "Western diet" (WD) compared with a low-fat control diet (CD). Vil-FFA3 mice versus FFA3fl/fl controls on WD, but not CD, were protected from the development of diet-induced obesity and exhibited significantly less fat mass as well as smaller adipose depositions and adipocytes. Although overall glycemic control was unchanged in the WD-fed Vil-FFA3 group, fasted glucose levels trended lower. Intestinal inflammation was significantly reduced in the WD-fed Vil-FFA3 mice, supporting protection from obesogenic effects. Furthermore, we observed lower levels of gastric inhibitory protein (GIP) in the WD-fed Vil-FFA3 mice, which may contribute to phenotypic changes. Our findings suggest a novel role of intestinal FFA3 in promoting the metabolic consequences of a WD, including the development of obesity and inflammation. Moreover, these data support an intestine-specific role of FFA3 in whole body metabolic homeostasis and in the development of adiposity.NEW & NOTEWORTHY Here, we generated a novel intestine-specific knockout mouse model for FFA3 (Vil-FFA3) and performed a comprehensive metabolic characterization of mice in response to an obesogenic challenge. We found that Vil-FFA3 mice fed with a Western diet were largely protected from obesity, exhibiting significantly lower levels of fat mass, lower intestinal inflammation, and altered expression of intestinal incretin hormones. Results support an important role of intestinal FFA3 in contributing to metabolism and in the development of diet-induced obesity.