Microbial dysbiosis and inflammation are implicated in diet-induced obesity and insulin resistance. However, it is not known whether crosstalk between immunity and microbiota also regulates metabolic homeostasis in healthy animals. Here, we report that genetic deletion of tuberous sclerosis 1 (Tsc1) in CD11c⁺ myeloid cells (Tsc1^f/fCD11c^Cre mice) reduced food intake and body mass in the absence of metabolic disease. Co-housing and fecal transplant experiments revealed a dominant role for the healthy gut microbiota in regulation of body weight. 16S rRNA sequencing, selective culture, and reconstitution experiments further confirmed that selective deficiency of Lactobacillus johnsonii Q1-7 contributed to decreased food intake and body mass in Tsc1^f/fCD11c^Cre mice. Mechanistically, activation of mTORC1 signaling in CD11c cells regulated production of L. johnsonii Q1-7-specific IgA, allowing for its stable colonization in the gut. Together, our findings reveal an unexpected transkingdom immune-microbiota feedback loop for homeostatic regulation of food intake and body mass in mammals.

Background

Individuals with serious mental illness often do not receive guideline-concordant metabolic screening and human immunodeficiency virus (HIV) testing, contributing to increased morbidity and premature mortality. This study evaluates the effectiveness of CRANIUM (Cardiometabolic Risk Assessment and treatment through a Novel Integration model for Underserved populations with Mental illness), an intervention to increase metabolic screening and HIV testing among patients with serious mental illness in a community mental health clinic compared to usual care.

Methods

The study used a quasi-experimental design, prospectively comparing a preventive care screening intervention at one community mental health clinic (n = 536 patients) to usual care at the remaining clinics within an urban behavioural health system (n = 4,847 patients). Psychiatrists at the intervention site received training in preventive health screening and had access to a primary care consultant, screening and treatment algorithms, patient registries, and a peer support specialist. Outcomes were the change in screening rates of A1c, lipid, and HIV testing post-intervention at the intervention site compared to usual care sites.

Results

Rates of lipid screening and HIV testing increased significantly at the intervention site compared to usual care, with and without multivariable adjustment [Lipid: aOR 1.90, 95% CI 1.32-2.75, P = .001; HIV: aOR 23.42, 95% CI 5.94-92.41, P < .001]. While we observed a significant increase in A1c screening rates at the intervention site, this increase did not persist after multivariable adjustment (aOR 1.37, 95% CI .95-1.99, P = .09).

Conclusions

This low-cost, reverse integrated care model targeting community psychiatrist practices had modest effects on increasing preventive care screenings, with the biggest effect seen for HIV testing rates. Additional incentives and structural supports may be needed to further promote screening practices for individuals with serious mental illness.

Host defenses against pathogens are energetically expensive, leading ecological immunologists to postulate that they might participate in energetic trade-offs with other maintenance programs. However, the metabolic costs of immunity and the nature of physiologic trade-offs it engages are largely unknown. We report here that activation of immunity causes an energetic trade-off with the homeothermy (the stable maintenance of core temperature), resulting in hypometabolism and hypothermia. This immunity-induced physiologic trade-off was independent of sickness behaviors but required hematopoietic sensing of lipopolysaccharide (LPS) via the toll-like receptor 4 (TLR4). Metabolomics and genome-wide expression profiling revealed that distinct metabolic programs supported entry and recovery from the energy-conserving hypometabolic state. During bacterial infections, hypometabolic states, which could be elicited by competition for energy between maintenance programs or energy restriction, promoted disease tolerance. Together, our findings suggest that energy-conserving hypometabolic states, such as dormancy, might have evolved as a mechanism of tissue tolerance.