Akkermansia muciniphila phospholipid induces homeostatic immune responses.

Multiple studies have established associations between human gut bacteria and host physiology, but determining the molecular mechanisms underlying these associations has been challenging1-3. Akkermansia muciniphila has been robustly associated with positive systemic effects on host metabolism, favourable outcomes to checkpoint blockade in cancer immunotherapy and homeostatic immunity4-7. Here we report the identification of a lipid from A. muciniphila's cell membrane that recapitulates the immunomodulatory activity of A. muciniphila in cell-based assays8. The isolated immunogen, a diacyl phosphatidylethanolamine with two branched chains (a15:0-i15:0 PE), was characterized through both spectroscopic analysis and chemical synthesis. The immunogenic activity of a15:0-i15:0 PE has a highly restricted structure-activity relationship, and its immune signalling requires an unexpected toll-like receptor TLR2-TLR1 heterodimer9,10. Certain features of the phospholipid's activity are worth noting: it is significantly less potent than known natural and synthetic TLR2 agonists; it preferentially induces some inflammatory cytokines but not others; and, at low doses (1% of EC50) it resets activation thresholds and responses for immune signalling. Identifying both the molecule and an equipotent synthetic analogue, its non-canonical TLR2-TLR1 signalling pathway, its immunomodulatory selectivity and its low-dose immunoregulatory effects provide a molecular mechanism for a model of A. muciniphila's ability to set immunological tone and its varied roles in health and disease.

Collinsella aerofaciens Produces a pH-Responsive Lipid Immunogen.

Some members of the human gut microbiota profoundly influence their host's physiology, health, and therapeutic responses, but the responsible molecules and mechanisms are largely unknown. As part of a project to identify immunomodulators produced by gut microbes, we analyzed the metabolome of Collinsella aerofaciens, an actinomycete that figures prominently in numerous association studies. The associations are typically positive correlations of C. aerofaciens with pro-inflammatory responses and undesirable outcomes, but an association with favorable responses to PD-1/PD-L1 cancer immunotherapy is a notable exception. A phenotypic assay-guided screen using dendritic cells (mBMDCs) and cytokine readouts identified the active compound, which was structurally characterized as a lysoglycoglycerolipid with an acetal-bearing ß-galactofuranose head group (CaLGL-1, 1). The structural assignment was confirmed through total synthesis. Assays with tlr2-/-, tlr4-/-, and wt mBMDCs revealed TLR2-dependent signaling. CaLGL-1 is produced by a conversion of a bacterially biosynthesized plasmalogen (CaPlsM, 3) to CaLGL-1 (1) in a low-pH environment.

BMI is Not Associated with Chest-Specific Body Image, Complications or Revisions in Gender-Affirming Mastectomy: A Single-Center Cross-Sectional Study.

OBJECTIVE: To analyze the impact of Body Mass Index (BMI) on clinical and patient-reported outcomes following gender-affirming mastectomy (GM). BACKGROUND: BMI is a barrier for obese patients seeking GM despite increasing evidence that it is safe in this population. Currently little is known about the impact of BMI on chest-specific body image and satisfaction following GM. METHODS: This single-center, cross-sectional study included individuals 18 years and older who underwent GM between 1990-2020 and were at least 2 years post-operative. Patient-reported chest-specific body image was measured using the BODY-Q and Gender Congruence and Life Satisfaction (GCLS) chest subscales. Satisfaction was measured using the Holmes-Rovner Satisfaction with Decision (SWD) scale. Clinical and demographic variables were identified from chart review. Bivariate analysis was performed to determine if BMI was associated with chest-specific body image, satisfaction, complications within 30 days or revisions in GM. RESULTS: Two hundred twenty-seven individuals meeting eligibility criteria were contacted to participate and one hundred thirty-seven responded (60.4% response rate). The mean age was 29.1 (SD=9.0) and mean BMI was 30.9 (SD=8.0), with 26.4% (N=60) of the cohort having a BMI>35. Chest-specific body image, and satisfaction with decision did not vary by BMI or breast resection weight. Complications and revisions were not associated with BMI. CONCLUSION: Individuals undergoing GM reported high rates of satisfaction following GM regardless of BMI. Complication and revision rates did not vary significantly by BMI or breast resection weight. Surgeons should re-evaluate the role BMI plays in patient selection and counseling for GM.

Long-Term Regret and Satisfaction With Decision Following Gender-Affirming Mastectomy.

Importance: There has been increasing legislative interest in regulating gender-affirming surgery, in part due to the concern about decisional regret. The regret rate following gender-affirming surgery is thought to be approximately 1%; however, previous studies relied heavily on ad hoc instruments. Objective: To evaluate long-term decisional regret and satisfaction with decision using validated instruments following gender-affirming mastectomy. Design, Setting, and Participants: For this cross-sectional study, a survey of patient-reported outcomes was sent between February 1 and July 31, 2022, to patients who had undergone gender-affirming mastectomy at a US tertiary referral center between January 1, 1990, and February 29, 2020. Exposure: Decisional regret and satisfaction with decision to undergo gender-affirming mastectomy. Main Outcomes and Measures: Long-term patient-reported outcomes, including the Holmes-Rovner Satisfaction With Decision scale, the Decision Regret Scale, and demographic characteristics, were collected. Additional information was collected via medical record review. Descriptive statistics and univariable analysis using Fisher exact and Wilcoxon rank sum tests were performed to compare responders and nonresponders. Results: A total of 235 patients were deemed eligible for the study, and 139 responded (59.1% response rate). Median age at the time of surgery was 27.1 (IQR, 23.0-33.4) years for responders and 26.4 (IQR, 23.1-32.7) years for nonresponders. Nonresponders (n = 96) had a longer postoperative follow-up period than responders (median follow-up, 4.6 [IQR, 3.1-8.6] vs 3.6 [IQR, 2.7-5.3] years, respectively; P = .002). Nonresponders vs responders also had lower rates of depression (42 [44%] vs 94 [68%]; P < .001) and anxiety (42 [44%] vs 97 [70%]; P < .001). No responders or nonresponders requested or underwent a reversal procedure. The median Satisfaction With Decision Scale score was 5.0 (IQR, 5.0-5.0) on a 5-point scale, with higher scores noting higher satisfaction. The median Decision Regret Scale score was 0.0 (IQR, 0.0-0.0) on a 100-point scale, with lower scores noting lower levels of regret. A univariable regression analysis could not be performed to identify characteristics associated with low satisfaction with decision or high decisional regret due to the lack of variation in these responses. Conclusions and Relevance: In this cross-sectional survey study, the results of validated survey instruments indicated low rates of decisional regret and high levels of satisfaction with decision following gender-affirming mastectomy. The lack of dissatisfaction and regret impeded the ability to perform a more complex statistical analysis, highlighting the need for condition-specific instruments to assess decisional regret and satisfaction with decision following gender-affirming surgery.

A Call to Action for Intermediate and Secondary School Lifestyle Medicine Education: Instating Healthy Teen Behaviors.

Chronic diseases, previously thought to require decades of risk factors, have become increasingly prevalent in America's youth. National Health Education Standards have been published since 1995, and yet nearly a fifth of schools fail to follow any state or national health education guidelines. Utilizing the phrase "lifestyle medicine" in childhood would elevate the importance and standardization of the core health guidelines. Several independent pilot programs taught by undergraduate and medical student volunteers have successfully demonstrated lifestyle medicine education models at intermediate and secondary schools. Preliminary feedback demonstrates that student interest in and consideration of behavioral change is possible within this age group. As with any life stage, significant behavior change in youth requires strategic planning of authentic learning practices and culturally competent lessons. We argue for the interdisciplinary development and implementation of community-engaged lifestyle medicine education for intermediate and secondary schools as a promising intervention to address and reverse the chronic disease trend in our youth.

Students Teaching Students: Bringing Lifestyle Medicine Education to Middle and High Schools Through Student-Led Community Outreach Programs.

Lifestyle medicine has the power to reverse the growing burden of chronic disease that now plagues our health care system. The World Health Organization, the Centers for Disease Control and Prevention, and the American College of Lifestyle Medicine have all independently recognized the need for community-centered lifestyle medicine education as a means of empowering individuals to take charge of their own health. Students in undergraduate, medical, and allied health schools may serve as mediators for these conversations. With guidance from faculty lifestyle medicine mentors, these students can operate as peer educators in primary and secondary schools to supplement current health teaching with the core tenants of lifestyle medicine: nutrition, exercise, sleep, mental and social well-being, and substance avoidance as strategies to prevent and treat chronic disease. We present models of two such student-led programs working with middle and high school students in Massachusetts and New Jersey. Both programs have found success by engaging middle and high school students in interactive workshops and by responding to their individual interests and community needs. We share our currently available resources and, moving forward, hope to publish a tested curriculum that students around the country can implement in their communities to promote lifestyle medicine.

Insights From a Short-Term Protein-Calorie Restriction Exploratory Trial in Elective Carotid Endarterectomy Patients.

BACKGROUND: Open vascular surgery interventions are not infrequently hampered by complication rates and durability. Preclinical surgical models show promising beneficial effects in modulating the host response to surgical injury via short-term dietary preconditioning. Here, we explore short-term protein-calorie restriction preconditioning in patients undergoing elective carotid endarterectomy to understand patient participation dynamics and practicalities of robust research approaches around nutritional/surgical interventions. METHODS: We designed a pilot prospective, multicenter, randomized controlled study in patients undergoing carotid endarterectomy. After a 3:2 randomization to a 3-day preoperative protein-calorie restriction regimen (30% calorie/70% protein restriction) or ad libitum group, blood, clinical parameters, and stool samples were collected at baseline, pre-op, and post-op days 1 and 30. Subcutaneous and perivascular adipose tissues were harvested periprocedurally. Samples were analyzed for standard chemistries and cell counts, adipokines. Bacterial DNA isolation and 16S rRNA sequencing were performed on stool samples and the relative abundance of bacterial species was measured. RESULTS: Fifty-one patients were screened, 9 patients consented to the study, 5 were randomized, and 4 completed the trial. The main reason for non-consent was a 3-day in-hospital stay. All 4 participants were randomized to the protein-calorie restriction group, underwent successful endarterectomy, reported no compliance difficulties, nor were there adverse events. Stool analysis trended toward increased abundance of the sulfide-producing bacterial species Bilophila wadsworthia after dietary intervention (P = .08). CONCLUSIONS: Although carotid endarterectomy patients held low enthusiasm for a 3-day preoperative inpatient stay, there were no adverse effects in this small cohort. Multidisciplinary longitudinal research processes were successfully executed throughout the nutritional/surgical intervention. Future translational endeavors into dietary preconditioning of vascular surgery patients should focus on outpatient approaches.