Chemosensory dysfunction as a marker of global disease: Investigating the role of taste and smell signalling in obesity and COVID-19

The work in this thesis examines chemosensory dysfunction related to obesity and COVID-19, two global pandemics markedly impacting on health. Following the COVID-19 outbreak, reports emerged that loss of smell and/or taste may be caused by SARS-CoV-2. The work in Chapter 2 was undertaken before loss of smell and/or taste were recognised COVID-19 symptoms and aimed to determine the seroprevalence of SARS-CoV-2 antibodies in people with acute taste and/or smell loss, characterise the loss of chemosensory function and identify factors affecting their recovery. Overall, 78% of people with taste and/or smell loss had positive SARS-CoV-2 IgG/IgM antibodies. Female sex and altered smell/taste perceptions were identified as predictors for persistent loss of sense of taste and/or smell and long COVID. Furthermore, objective smell testing and quantitative MRI brain imaging were undertaken to investigate the underlying pathophysiology. Early results suggest ongoing neuroinflammation in people with persistent smell loss. Obesity, a chronic disease with multiple associated co-morbidities, is associated with chemosensory dysfunction, particularly toward dietary fat. The obesity section of this thesis used different modalities, including functional taste assessment, salivary and circulating biomarkers and functional brain imaging to characterise chemosensory dysfunction in obesity. Findings from these studies demonstrated a reduced ability to taste fat in the fed state, as well as increased taste-stimulated activity in reward-related brain regions in people with obesity. Altered adipocytokines and inflammation are postulated to underlie the increased risk of critical illness from COVID-19 in people living with obesity. In Chapter 6 inflammatory adipocytokines and metabolomic markers were measured in people with obesity before and after bariatric surgery. A substantial inter-individual variability was identified in circulating levels of these markers, which may underlie some of the susceptibility to infection-induced critical illness. Importantly, the results indicated improvement in inflammation markers following bariatric surgery, suggesting the potential for reducing obesity-associated risks

Obesity, body weight regulation and the brain: Insights from fMRI

Obesity constitutes a major global health threat. Despite the success of bariatric surgery in delivering sustainable weight loss and improvement in obesity-related morbidity, effective non-surgical treatments are urgently needed, necessitating an increased understanding of body weight regulation. Neuroimaging studies undertaken in people with healthy weight, overweight, obesity and following bariatric surgery have contributed to identifying the neurophysiological changes seen in obesity and are increasing our understanding of the mechanisms driving the favourable eating behaviour changes and sustained weight loss engendered by bariatric surgery. These studies have revealed a key interplay between peripheral metabolic signals, homeostatic and hedonic brain regions and genetics. Findings from brain functional magnetic resonance imaging (fMRI) studies have consistently associated obesity with an increased motivational drive to eat, increased reward responses to food cues and impaired food-related self-control processes. Interestingly, new data link these obesity-associated changes with structural and connectivity changes within the central nervous system. Moreover, emerging data suggest that bariatric surgery leads to neuroplastic recovery. A greater understanding of the interactions between peripheral signals of energy balance, the neural substrates that regulate eating behaviour, the environment and genetics will be key for the development of novel therapeutic strategies for obesity. This review provides an overview of our current understanding of the pathoaetiology of obesity with a focus upon the role that fMRI studies have played in enhancing our understanding of central regulation of eating behaviour and energy homeostasis

Mechanisms of weight regain

Weight regain following weight loss is frequent problem that people with obesity face. This weight recidivism is often attributed to the lack of compliance with appropriate food habits and exercise. On the contrary, it is known that body weight and fat mass are regulated by numerous physiological mechanisms, far beyond voluntary food intake and physical exercise. Thus, the aim of this paper is to review the main peripheral and central mechanisms involved in weight regain. Gut hormone secretion profiles impact upon predisposition to weight regain according to an individual variability, although it is recognised a usual pattern of compensatory changes: a reduction in anorectic hormones secretion and an increase in orexigenic hormone. These changes lead to both increased appetite and reward value of food leading to increased energye intake. In addition, resting energy expenditure after weight loss is lower than expected according to body composition changes. This gap between observed and predicted energy expenditure following weight loss is named metabolic adaptation, which has been suggested to explain partly weight regain. This complicated scenario, beyond patient motivation, makes weight regain a challenge in long-term management interventions in patients with obesity

Metabolic and Bariatric Endoscopy: A Mini-Review

We are currently in a worldwide obesity pandemic, which is one of the most significant health problems of the 21st century. As the prevalence of obesity continues to rise, new and innovate treatments are becoming available. Metabolic and bariatric endoscopic procedures are exciting new areas of gastroenterology that have been developed as a direct response to the obesity crisis. These novel interventions offer a potentially reversible, less invasive, safer, and more cost-effective method of tackling obesity compared to traditional bariatric surgery. Minimally invasive endoscopic treatments are not entirely novel, but as technology has rapidly improved, many of the procedures have been proven to be extremely effective for weight loss and metabolic health, based on high-quality clinical trial data. This mini-review examines the existing evidence for the most prominent metabolic and bariatric procedures, followed by a discussion on the future trajectory of this emerging subspecialty

Seroprevalence of SARS-CoV-2 antibodies in people with an acute loss in their sense of smell and/or taste in a community-based population in London, UK: An observational cohort study

BACKGROUND: Loss of smell and taste are commonly reported symptoms associated with coronavirus disease 2019 (COVID-19); however, the seroprevalence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibodies in people with acute loss of smell and/or taste is unknown. The study aimed to determine the seroprevalence of SARS-CoV-2 antibodies in a community-based population with acute loss of smell and/or taste and to compare the frequency of COVID-19 associated symptoms in participants with and without SARS-CoV-2 antibodies. It also evaluated whether smell or taste loss are indicative of COVID-19 infection. METHODS AND FINDINGS: Text messages, sent via primary care centers in London, United Kingdom, invited people with loss of smell and/or taste in the preceding month, to participate. Recruitment took place between 23 April 2020 and 14 May 2020. A total of 590 participants enrolled via a web-based platform and responded to questions about loss of smell and taste and other COVID-19-related symptoms. Mean age was 39.4 years (SD ± 12.0) and 69.1% (n = 392) of participants were female. A total of 567 (96.1%) had a telemedicine consultation during which their COVID-19-related symptoms were verified and a lateral flow immunoassay test that detected SARS-CoV-2 immunoglobulin G (IgG) and immunoglobulin M (IgM) antibodies was undertaken under medical supervision. A total of 77.6% of 567 participants with acute smell and/or taste loss had SARS-CoV-2 antibodies; of these, 39.8% (n = 175) had neither cough nor fever. New loss of smell was more prevalent in participants with SARS-CoV-2 antibodies, compared with those without antibodies (93.4% versus 78.7%, p < 0.001), whereas taste loss was equally prevalent (90.2% versus 89.0%, p = 0.738). Seropositivity for SARS-CoV-2 was 3 times more likely in participants with smell loss (OR 2.86; 95% CI 1.27-6.36; p < 0.001) compared with those with taste loss. The limitations of this study are the lack of a general population control group, the self-reported nature of the smell and taste changes, and the fact our methodology does not take into account the possibility that a population subset may not seroconvert to develop SARS-CoV-2 antibodies post-COVID-19. CONCLUSIONS: Our findings suggest that recent loss of smell is a highly specific COVID-19 symptom and should be considered more generally in guiding case isolation, testing, and treatment of COVID-19. TRIALS REGISTRATION: ClinicalTrials.gov NCT04377815

Distorted chemosensory perception and female sex associate with persistent smell and/or taste loss in people with SARS-CoV-2 antibodies: a community based cohort study investigating clinical course and resolution of acute smell and/or taste loss in people with and without SARS-CoV-2 antibodies in London, UK

BACKGROUND: Loss of smell and/or taste are cardinal symptoms of COVID-19. 'Long-COVID', persistence of symptoms, affects around one fifth of people. However, data regarding the clinical resolution of loss of smell and/or taste are lacking. In this study we assess smell and taste loss resolution at 4-6 week follow-up, aim to identify risk factors for persistent smell loss and describe smell loss as a feature of long-COVID in a community cohort in London with known SARS-CoV-2 IgG/IgM antibody status. We also compare subjective and objective smell assessments in a subset of participants. METHODS: Four hundred sixty-seven participants with acute loss of smell and/or taste who had undergone SARS-CoV-2 IgG/IgM antibody testing 4-6 weeks earlier completed a follow-up questionnaire about resolution of their symptoms. A subsample of 50 participants completed an objective olfactory test and results were compared to subjective smell evaluations. RESULTS: People with SARS-CoV-2 antibodies with an acute loss of sense of smell and taste were significantly less likely to recover their sense of smell/taste than people who were seronegative (smell recovery: 57.7% vs. 72.1%, p = 0.027. taste recovery 66.2% vs. 80.3%, p = 0.017). In SARS-CoV-2 positive participants, a higher percentage of male participants reported full resolution of smell loss (72.8% vs. 51.4%; p  40 years) than those who reported full resolution. Participants who experienced parosmia reported lower smell recovery rates and participants with distorted taste perception lower taste recovery rates. Parosmia had a significant association to unresolved smell loss (OR 2.47, 95%CI 1.54-4.00, p  40 years) and people with a distorted perception of their sense of smell/taste are likely to benefit from prioritised early therapeutic interventions. TRIALS REGISTRATION: ClinicalTrials.gov NCT04377815 Date of registration: 23/04/2020

Impact of sleeve gastrectomy compared to Roux-en-y gastric bypass upon hedonic hunger and the relationship to post-operative weight loss

'Hedonic hunger' indicates the desire to consume food in the absence of an energy requirement. Hedonic hunger can be investigated using the validated Power of Food Scale (PFS). Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy (SG) are currently the most effective treatment options for severe obesity. Following RYGB, hedonic hunger diminishes, which may contribute to sustained weight loss. There are no data examining the effect of SG on hedonic hunger. We prospectively evaluated hedonic hunger using PFS in patients with severe obesity prior to and 6 months after SG (n = 95) or RYGB (n = 44) and investigated the procedure-specific relationship between percentage weight loss (%WL) and hedonic hunger. Anthropometric data were collected at baseline after 6 months, 12 months and 24 months post-operatively. PFS contains 15 items grouped into 3 domains considering when food is: available (FA), present (FP), tasted (FT) and a total score (TS). At 6 months, a significant reduction was seen in all categories post-SG (p < 0.0001) and in TS (p = 0.003), FA (p = 0.0006) and FP (p = 0.0007) post-RYGB. A significantly larger reduction in FP scores was seen post-SG (p = 0.01). Post-SG, a significant correlation with 6-month %WL was noted for changes in FP (p = 0.03) and TS (p = 0.03). Post-SG changes in FP and TS predicted 24-month %WL. Post-RYGB significant correlations were seen between 6-month %WL and dFA (p = 0.04) and dFP (p = 0.03). Changes in FA, FP and TS were predictive of 12-month %WL. HH is reduced following both SG and RYGB with a greater reduction following SG and is related to post-operative %WL. PFS may have a role as a predictive tool for post-operative outcomes following SG and RYGB

Practical Recommendations of the Obesity Management Task Force of the European Association for the Study of Obesity for the Post-Bariatric Surgery Medical Management

Bariatric surgery is today the most effective long-term therapy for the management of patients with severe obesity, and its use is recommended by the relevant guidelines of the management of obesity in adults. Bariatric surgery is in general safe and effective, but it can cause new clinical problems and is associated with specific diagnostic, preventive and therapeutic needs. For clinicians, the acquisition of special knowledge and skills is required in order to deliver appropriate and effective care to the post-bariatric patient. In the present recommendations, the basic notions needed to provide first-level adequate medical care to post-bariatric patients are summarised. Basic information about nutrition, management of co-morbidities, pregnancy, psychological issues as well as weight regain prevention and management is derived from current evidences and existing guidelines. A short list of clinical practical recommendations is included for each item. It remains clear that referral to a bariatric multidisciplinary centre, preferably the one performing the original procedure, should be considered in case of more complex clinical situations

Reported appetite, taste and smell changes following Roux-en-Y gastric bypass and sleeve gastrectomy: Effect of gender, type 2 diabetes and relationship to post-operative weight loss.

Reduced energy intake drives weight loss following Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy (SG) procedures. Post-operative changes in subjective appetite, taste, and smell and food preferences are reported and suggested to contribute to reduced energy intake. We aimed to investigate the prevalence of these changes following RYGB and SG and to evaluate their relationship with weight loss. 98 patients post-RYGB and 155 post-SG from a single bariatric centre were recruited to a cross-sectional study. Participants completed a questionnaire, previously utilised in post-operative bariatric patients, to assess the prevalence of post-operative food aversions and subjective changes in appetite, taste and smell. Anthropometric data were collected and percentage weight loss (%WL) was calculated. The relationship between food aversions, changes in appetite, taste and smell and %WL was assessed. The influence of time post-surgery, gender and type 2 diabetes (T2D) were evaluated. Following RYGB and SG the majority of patients reported food aversions (RYGB = 62%, SG = 59%), appetite changes (RYGB = 91%, SG = 91%) and taste changes (RYGB = 64%, SG = 59%). Smell changes were more common post-RYGB than post-SG (RYGB = 41%, SG = 28%, p = 0.039). No temporal effect was observed post-RYGB. In contrast, the prevalence of appetite changes decreased significantly with time following SG. Post-operative appetite changes associated with and predicted higher %WL post-SG but not post-RYGB. Taste changes associated with and predicted higher %WL following RYGB but not post-SG. There was no gender effect post-RYGB. Post-SG taste changes were less common in males (female = 65%, males = 40%, p = 0.008). T2D status in females did not influence post-operative subjective changes. However, in males with T2D, taste changes were less common post-SG than post-RYGB together with lower %WL (RYGB = 27.5 ± 2.7, SG = 14.6 ± 2.1, p = 0.003). Further research is warranted to define the biology underlying these differences and to individualise treatments