Influence of Bariatric Surgery on Gut Microbiota Composition and Its Implication on Brain and Peripheral Targets.

Obesity remains a significant global health challenge, with bariatric surgery remaining as one of the most effective treatments for severe obesity and its related comorbidities. This review highlights the multifaceted impact of bariatric surgery beyond mere physical restriction or nutrient malabsorption, underscoring the importance of the gut microbiome and neurohormonal signals in mediating the profound effects on weight loss and behavior modification. The various bariatric surgery procedures, such as Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy (SG), act through distinct mechanisms to alter the gut microbiome, subsequently impacting metabolic health, energy balance, and food reward behaviors. Emerging evidence has shown that bariatric surgery induces profound changes in the composition of the gut microbiome, notably altering the Firmicutes/Bacteroidetes ratio and enhancing populations of beneficial bacteria such as Akkermansia. These microbiota shifts have far-reaching effects beyond gut health, influencing dopamine-mediated reward pathways in the brain and modulating the secretion and action of key gut hormones including ghrelin, leptin, GLP-1, PYY, and CCK. The resultant changes in dopamine signaling and hormone levels contribute to reduced hedonic eating, enhanced satiety, and improved metabolic outcomes. Further, post-bariatric surgical effects on satiation targets are in part mediated by metabolic byproducts of gut microbiota like short-chain fatty acids (SCFAs) and bile acids, which play a pivotal role in modulating metabolism and energy expenditure and reducing obesity-associated inflammation, as well as influencing food reward pathways, potentially contributing to the regulation of body weight and reduction in hedonic eating behaviors. Overall, a better understanding of these mechanisms opens the door to developing non-surgical interventions that replicate the beneficial effects of bariatric surgery on the gut microbiome, dopamine signaling, and gut hormone regulation, offering new avenues for obesity treatment.

Nutrition at the Intersection between Gut Microbiota Eubiosis and Effective Management of Type 2 Diabetes.

Nutrition is one of the most influential environmental factors in both taxonomical shifts in gut microbiota as well as in the development of type 2 diabetes mellitus (T2DM). Emerging evidence has shown that the effects of nutrition on both these parameters is not mutually exclusive and that changes in gut microbiota and related metabolites such as short-chain fatty acids (SCFAs) and branched-chain amino acids (BCAAs) may influence systemic inflammation and signaling pathways that contribute to pathophysiological processes associated with T2DM. With this background, our review highlights the effects of macronutrients, carbohydrates, proteins, and lipids, as well as micronutrients, vitamins, and minerals, on T2DM, specifically through their alterations in gut microbiota and the metabolites they produce. Additionally, we describe the influences of common food groups, which incorporate varying combinations of these macronutrients and micronutrients, on both microbiota and metabolic parameters in the context of diabetes mellitus. Overall, nutrition is one of the first line modifiable therapies in the management of T2DM and a better understanding of the mechanisms by which gut microbiota influence its pathophysiology provides opportunities for optimizing dietary interventions.

"Knee-Ding" a Diagnosis: A Case of Nail Patella Syndrome.

Nail Patella Syndrome (NPS) is a rare genetic disorder with pathognomonic signs including dystrophic fingernails, iliac horns, and limb abnormalities, which commonly include hypoplastic development of the patellae, causing patients to experience patellar instability. This resulting patellar instability increases susceptibility to recurrent subluxations or dislocations in NPS patients. Since these anatomical abnormalities are present at birth or in childhood, early recognition may prevent the need for surgical intervention if appropriate preventive measures are taken. This case report describes a 54-year-old woman with a history of NPS, diagnosed later in adulthood, with a prior patellectomy at age 18 secondary to an unspecified left knee injury that occurred at age 4. A combination of radiographic and clinical findings are presented, which support the diagnosis of NPS, including dystrophic nails, left knee x-ray consistent with prior patellectomy, and right knee x-ray showing inferolateral subluxation of a hypoplastic patella. Additional signs associated with NPS are also discussed, including mood disorders, Raynaud's, and a high hairline which may assist in early diagnosis. This case report emphasizes earlier identification of NPS by clinicians through recognition of signs and symptoms while also considering proactive measures to lessen recurrent subluxations or dislocations to preserve patellar integrity and reduce the need for surgical intervention.

Dietary Fat Modulation of Gut Microbiota and Impact on Regulatory Pathways Controlling Food Intake.

Obesity is a multifactorial disease that continues to increase in prevalence worldwide. Emerging evidence has shown that the development of obesity may be influenced by taxonomic shifts in gut microbiota in response to the consumption of dietary fats. Further, these alterations in gut microbiota have been shown to promote important changes in satiation signals including gut hormones (leptin, ghrelin, GLP-1, peptide YY and CCK) and orexigenic and anorexigenic neuropeptides (AgRP, NPY, POMC, CART) that influence hyperphagia and therefore obesity. In this review, we highlight mechanisms by which gut microbiota can influence these satiation signals both locally in the gastrointestinal tract and via microbiota-gut-brain communication. Then, we describe the effects of dietary interventions and associated changes in gut microbiota on satiety signals through microbiota-dependent mechanisms. Lastly, we present microbiota optimizing therapies including prebiotics, probiotics, synbiotics and weight loss surgery that can help restore beneficial gut microbiota by enhancing satiety signals to reduce hyperphagia and subsequent obesity. Overall, a better understanding of the mechanisms by which dietary fats induce taxonomical shifts in gut microbiota and their impact on satiation signaling pathways will help develop more targeted therapeutic interventions in delaying the onset of obesity and in furthering its treatment.

Reduced Striatal Dopamine Transporter Availability and Heightened Response to Natural and Pharmacological Stimulation in CCK-1R-Deficient Obese Rats.

Alterations in dopamine neurotransmission are associated with obesity and food preferences. Otsuka Long-Evans Tokushima Fatty (OLETF) rats that lack functional cholecystokinin receptor type-1 (CCK-1R), due to a natural mutation, exhibit impaired satiation, are hyperphagic, and become obese. In addition, compared to lean control Long-Evans Tokushima (LETO) rats, OLETF rats have pronounced avidity for over-consuming palatable sweet solutions, have greater dopamine release to psychostimulants, reduced dopamine 2 receptor (D2R) binding, and exhibit increased sensitivity to sucrose reward. This supports altered dopamine function in this strain and its general preference for palatable solutions such as sucrose. In this study, we examined the relationship between OLETF's hyperphagic behavior and striatal dopamine signaling by investigating basal and amphetamine stimulated motor activity in prediabetic OLETF rats before and after access to sucrose solution (0.3 M) compared to non-mutant control LETO rats, as well as availability of dopamine transporter (DAT) using autoradiography. In the sucrose tests, one group of OLETF rats received ad libitum access to sucrose while the other group received an amount of sucrose equal to that consumed by the LETO. OLETFs with ad libitum access consumed significantly more sucrose than LETOs. Sucrose exerted a biphasic effect on basal activity in both strains, i.e., reduced activity for 1 week followed by increased activity in weeks 2 and 3. Basal locomotor activity was reduced (-17%) in OLETFs prior to sucrose, compared to LETOs. Withdrawal of sucrose resulted in increased locomotor activity in both strains. The magnitude of this effect was greater in OLETFs and the activity was increased in restricted compared to ad-libitum-access OLETFs. Sucrose access augmented AMPH-responses in both strains with a greater sensitization to AMPH during week 1, an effect that was a function of the amount of sucrose consumed. One week of sucrose withdrawal sensitized AMPH-induced ambulatory activity in both strains. In OLETF with restricted access to sucrose, withdrawal resulted in no further sensitization to AMPH. DAT availability in the nucleus accumbens shell was significantly reduced in OLETF compared with aged-matched LETO. Together, these findings show that OLETF rats have reduced basal DA transmission and a heightened response to natural and pharmacological stimulation.

Treatment of Dyslipidemia through Targeted Therapy of Gut Microbiota.

Dyslipidemia is a multifaceted condition with various genetic and environmental factors contributing to its pathogenesis. Further, this condition represents an important risk factor for its related sequalae including cardiovascular diseases (CVD) such as coronary artery disease (CAD) and stroke. Emerging evidence has shown that gut microbiota and their metabolites can worsen or protect against the development of dyslipidemia. Although there are currently numerous treatment modalities available including lifestyle modification and pharmacologic interventions, there has been promising research on dyslipidemia that involves the benefits of modulating gut microbiota in treating alterations in lipid metabolism. In this review, we examine the relationship between gut microbiota and dyslipidemia, the impact of gut microbiota metabolites on the development of dyslipidemia, and the current research on dietary interventions, prebiotics, probiotics, synbiotics and microbiota transplant as therapeutic modalities in prevention of cardiovascular disease. Overall, understanding the mechanisms by which gut microbiota and their metabolites affect dyslipidemia progression will help develop more precise therapeutic targets to optimize lipid metabolism.

Fecal microbiota transplantation in non-communicable diseases: Recent advances and protocols.

Fecal microbiota transplant (FMT) is a therapeutic method that aims to restore normal gut microbial composition in recipients. Currently, FMT is approved in the USA to treat recurrent and refractory Clostridioides difficile infection and has been shown to have great efficacy. As such, significant research has been directed toward understanding the potential role of FMT in other conditions associated with gut microbiota dysbiosis such as obesity, type 2 diabetes mellitus, metabolic syndrome, neuropsychiatric disorders, inflammatory bowel disease, irritable bowel syndrome, decompensated cirrhosis, cancers and graft-versus-host disease. This review examines current updates and efficacy of FMT in treating conditions other than Clostridioides difficile infection. Further, protocols for administration of FMT are also discussed including storage of fecal samples in stool banks, inclusion/exclusion criteria for donors, fecal sample preparation and methods of treatment administration. Overall, understanding the mechanisms by which FMT can manipulate gut microbiota to provide therapeutic benefit as well as identifying potential adverse effects is an important step in clarifying its long-term safety and efficacy in treating multiple conditions in the future.

Gut Microbiota Restores Central Neuropeptide Deficits in Germ-Free Mice.

Recent work has demonstrated the ability of the gut microbiota (GM) to alter the expression and release of gut peptides that control appetite and regulate energy homeostasis. However, little is known about the neuronal response of these hormones in germ-free (GF) animals, especially leptin, which is strikingly low in these animals. Therefore, we aimed to determine the response to exogenous leptin in GF mice as compared to conventionally raised (CONV-R) mice. Specifically, we injected and measured serum leptin in both GF and CONV-R mice and measured expression of orexigenic and anorexigenic peptides NPY, AgRP, POMC, and CART in the hypothalamus and hindbrain to examine whether the GM has an impact on central nervous system regulation of energy homeostasis. We found that GF mice had a significant increase in hypothalamic NPY and AgRP mRNA expression and a decrease in hindbrain NPY and AgRP mRNA, while mRNA expression of POMC and CART remained unchanged. Administration of leptin normalized circulating levels of leptin, GLP-1, PYY, and ghrelin, all of which were significantly decreased in GF mice. Finally, brief conventionalization of GF mice for 10 days restored the deficits in hypothalamic and hindbrain neuropeptides present in GF animals. Taken together, these results show that the GM regulates hypothalamic and hindbrain orexigenic/anorexigenic neuropeptide expression. This is in line with the role of gut microbiota in lipid metabolism and fat deposition that may contribute to excess fat in conventionalized animals under high feeding condition.

Impact of Nutrition, Microbiota Transplant and Weight Loss Surgery on Dopaminergic Alterations in Parkinson's Disease and Obesity.

Parkinson's disease (PD), the second most common neurodegenerative disorder worldwide, is characterized by dopaminergic neuron degeneration and α-synuclein aggregation in the substantia nigra pars compacta of the midbrain. Emerging evidence has shown that dietary intake affects the microbial composition in the gut, which in turn contributes to, or protects against, the degeneration of dopaminergic neurons in affected regions of the brain. More specifically, the Mediterranean diet and Western diet, composed of varying amounts of proteins, carbohydrates, and fats, exert contrasting effects on PD pathophysiology via alterations in the gut microbiota and dopamine levels. Interestingly, the negative changes in the gut microbiota of patients with PD parallel changes that are seen in individuals that consume a Western diet, and are opposite to those that adhere to a Mediterranean diet. In this review, we first examine the role of prominent food groups on dopamine bioavailability, how they modulate the composition and function of the gut microbiota and the subsequent effects on PD and obesity pathophysiology. We then highlight evidence on how microbiota transplant and weight loss surgery can be used as therapeutic tools to restore dopaminergic deficits through optimizing gut microbial composition. In the process, we revisit dietary metabolites and their role in therapeutic approaches involving dopaminergic pathways. Overall, understanding the role of nutrition on dopamine bioavailability and gut microbiota in dopamine-related pathologies such as PD will help develop more precise therapeutic targets to rescue dopaminergic deficits in neurologic and metabolic disorders.

Role of Microbiota-Gut-Brain Axis in Regulating Dopaminergic Signaling.

Dopamine is a neurotransmitter that plays a critical role both peripherally and centrally in vital functions such as cognition, reward, satiety, voluntary motor movements, pleasure, and motivation. Optimal dopamine bioavailability is essential for normal brain functioning and protection against the development of neurological diseases. Emerging evidence shows that gut microbiota have significant roles in maintaining adequate concentrations of dopamine via intricate, bidirectional communication known as the microbiota-gut-brain axis. The vagus nerve, immune system, hypothalamus-pituitary-adrenal axis, and microbial metabolites serve as important mediators of the reciprocal microbiota-gut-brain signaling. Furthermore, gut microbiota contain intrinsic enzymatic activity that is highly involved in dopamine metabolism, facilitating dopamine synthesis as well as its metabolite breakdown. This review examines the relationship between key genera of gut microbiota such as Prevotella, Bacteroides, Lactobacillus, Bifidobacterium, Clostridium,Enterococcus, and Ruminococcus and their effects on dopamine. The effects of gut dysbiosis on dopamine bioavailability and the subsequent impact on dopamine-related pathological conditions such as Parkinson's disease are also discussed. Understanding the role of gut microbiota in modulating dopamine activity and bioavailability both in the periphery and in the central nervous system can help identify new therapeutic targets as well as optimize available methods to prevent, delay, or restore dopaminergic deficits in neurologic and metabolic disorders.

Avian Primordial Germ Cells Contribute to and Interact With the Extracellular Matrix During Early Migration.

During early avian development, primordial germ cells (PGC) are highly migratory, moving from the central area pellucida of the blastoderm to the anterior extra-embryonic germinal crescent. The PGCs soon move into the forming blood vessels by intravasation and travel in the circulatory system to the genital ridges where they participate in the organogenesis of the gonads. This complex cellular migration takes place in close association with a nascent extracellular matrix that matures in a precise spatio-temporal pattern. We first compiled a list of quail matrisome genes by bioinformatic screening of human matrisome orthologs. Next, we used single cell RNA-seq analysis (scRNAseq) to determine that PGCs express numerous ECM and ECM-associated genes in early embryos. The expression of select ECM transcripts and proteins in PGCs were verified by fluorescent in situ hybridization (FISH) and immunofluorescence (IF). Live imaging of transgenic quail embryos injected with fluorescent antibodies against fibronectin and laminin, showed that germinal crescent PGCs display rapid shape changes and morphological properties such as blebbing and filopodia while surrounded by, or in close contact with, an ECM fibril meshwork that is itself in constant motion. Injection of anti-ß1 integrin CSAT antibodies resulted in a reduction of mature fibronectin and laminin fibril meshwork in the germinal crescent at HH4-5 but did not alter the active motility of the PGCs or their ability to populate the germinal crescent. These results suggest that integrin ß1 receptors are important, but not required, for PGCs to successfully migrate during embryonic development, but instead play a vital role in ECM fibrillogenesis and assembly.