The Role of the Gut Microbiome and Ultra Processed Food in Obesity and Sleep Disorders

Abstract

In the last decade, scientific studies have explored how obesity is linked to heightened susceptibility to sleep disturbances and disorders. While the mechanisms underlying sleep disorder connections to obesity are not fully understood, the gut microbiome and the consumption of highly processed foods have been reported as significant factors. Ultra processed foods contain added emulsifiers, sugars, and fats, which change gut microbiome composition and diversity and can lead to low grade inflammation, a hallmark of obesity, suggesting that the gut contributes to the established connection between ultra processed foods and obesity. Changes in gut microbiome diversity and composition also influence production of short-chain fatty acids, neurotransmitters, and hormones involved in appetite and sleep regulation. Disrupted levels of these components, which are critical for communication between the gut and brain, potentially increase risk for weight gain and sleep disorders related to circadian rhythm. This review explains how ultra processed foods directly cause changes in the gut microbiome, simultaneously impacting both obesity and sleep quality, as well as potential methods of targeting the gut microbiome and diet to reduce obesity and sleep disorders.

Introduction

Obesity, defined as excessive fat accumulation or a body mass index above 30, is a widespread public health crisis that affects as many as 40 percent of adults in America¹.  Genetic predisposition, sedentary behavior, and technology usage, exacerbated by the COVID-19 pandemic, significantly increase susceptibility to obesity. Another factor is ultra processed food (UPF), food items manufactured to last for long periods of time that contain added sugar, salt, fat, and preservatives. UPFs account for 75-80% of sodium consumed in developed countries, putting individuals at higher risk for developing hypertension and cardiovascular diseases. Saturated fat, trans fat, and high fructose corn syrup, mostly found in processed foods², directly cause obesity and lead to numerous health complications including heart disease and gastrointestinal disorders³. While the correlation between obesity and UPFs, such as packaged meats and snacks, has long been established due to the unhealthy and addictive nature of UPFs³, recent findings have revealed a more surprising correlation between obesity and sleep disturbances and disorders. Sleep takes on a critical role in maintaining mental and physical wellness and regulating various functions in the body. These functions include the regulation of the immune system, metabolism, hormones, and chronic disease risk⁴. Sleep is vital to brain and body wellbeing, as many as 70 million Americans suffer from sleep disorders. Sleep disorders are defined as abnormal sleeping patterns, including excessive somnolence, difficulty initiating and maintaining sleep, and other dysfunctions associated with sleep, sleep stages, or sleep arousal⁵. Sleep disorders have a myriad of detrimental short-term and long-term consequences including emotional distress, memory and performance deficits, behavior problems, and continuous increased activity of the nervous system. Obesity is another long-term effect of insufficient sleep; research has shown that obese individuals are more likely to develop sleep disorders including sleep apnea and insomnia, and inversely, that sleep disorders also correlate with weight-related issues⁶.The specific mechanisms causing the connection between obesity, sleep disorders, and UPFs are not entirely understood, but scientists have identified the gut microbiome as a key factor for this connection. The gut microbiome is a diverse ecosystem of bacteria, archaea, and eukarya that colonize the gastrointestinal tract and interact with the host⁷. The human gastrointestinal tract contains trillions of diverse microbiota, which provide numerous health benefits, such as modulating sleep quality, disease prevention, and overall health⁸. However, adverse changes in gut microbiota composition and reduced microbiota diversity can result in a state of dysbiosis, or imbalance of gut microorganisms, increased gut permeability, and inflammation, all of which are hallmarks of obesity. It is also increasingly recognized that the gut microbiome is extremely important not only for maintaining optimal weight, but also for regulating sleep patterns through the gut-brain axis (GBA), a bidirectional communication network between the intestinal tract and the central nervous system through neural and hormonal signals.In this review, the influence of ultra processed foods on the levels of hormones and metabolites produced by the gut will be examined. This paper will also detail the effects of gut microbiome changes on the GBA and certain regions of the brain responsible for regulating sleep. Finally, treatments targeting the gut and GBA, involving dietary changes and hormone level adjustments, will be suggested to potentially lessen risk of developing obesity and sleep disturbances. These treatments are extremely essential in today’s society when nearly half of Americans are projected to have obesity by 2030⁹, and at least 50 million Americans suffer from sleep disorders¹⁰. It is becoming even more critical to understand how the gut regulates neurotransmitters, hormones, the brain, and overall health in order to understand and mitigate sleep loss and obesity epidemics.

keywords:

Ultra processed food, gut microbiome, sleep disorders, obesity, melatonin, short chain fatty acids, appetite hormones, gut-brain axis.

The Gut Microbiome and Obesity

Obesity is a long-standing issue, and the gut microbiome has been increasingly recognized as a major cause of obesity¹¹. In a healthy gut, microbiota diversity increases with age until three main phyla based on shared characteristics, Firmicutes, Bacteroidetes, and Actinobacteria, dominate microbiota composition. Particularly, the ratio between Firmicutes and Bacteroidetes will be examined in this paper, as they are the most abundant. Environmental factors, lifestyle, genetics, and weight affect the ratio of each phylum and overall diversity of gut microbiota¹². Gut health is measured with global ecological parameters richness, evenness, and diversity. Richness is defined as the number of different species of microbes, evenness is defined as the relative abundance of each species, and diversity is a measurement of both richness and evenness¹³. Greater bacterial diversity has been correlated with great nutritional status and overall health in elderly individuals¹⁴. In contrast, worsened bacterial diversity was found in preterm infants with enterocolitis in comparison to preterm infants without inflammation¹⁵.Changes in diversity of bacteria communities in the gut, specifically the Firmicutes/Bacteroidetes ratio, are hallmarks of obesity. For instance, the Western diet yields higher rates of obesity compared to other diets with less UPF consumption, as shown in a recent study in which germ-free mice were transplanted with humanized microbial communities from adult donors who had high-fat and high-sugar Western diets. These mice with Western diets had a nearly 35% increase in total body fat compared to humanized mice with a low-fat, plant polysaccharide-rich diet¹⁶. The cause of this increase in body weight is likely related to changes in gut microbiome. U.S. immigrants who partook in the Western diet exhibited significant weight gain and reduced gut microbial diversity and function immediately after arriving in the U.S., and their microbiome diversity continued to decrease according to their duration of stay in the U.S¹⁷. These individuals who consumed the Western diet exhibited lower proportions of Bacteroidetes and higher proportions of Firmicutes. Firmicutes are more effective in extracting energy from food than Bacteroidetes, therefore promoting greater absorption of calories and subsequent weight gain¹⁸. While the physiological mechanism linking gut diversity with weight gain is still under investigation, it is becoming increasingly evident that the gut microbiome plays a major role in an individual’s risk for obesity.Carbohydrate metabolism changes gut microbiome composition and the Bacteroidetes/Firmicutes ratio. The gut significantly contributes to the digestion, absorption, and metabolic processing of carbohydrates¹⁹. There are only around 17 types of glycoside hydrolases, enzymes that break the glycosidic linkages in a carbohydrate molecule, in the upper gastrointestinal tract. Bacteroidetes, however, can produce up to 260 types of glycoside hydrolases, allowing the host to obtain energy from and indirectly metabolize carbohydrates more efficiently²⁰. Inversely, different types of carbohydrates impact the gut microbiome. For example, wheat starch, which is obtained by removing protein from flour and is commonly used as a food additive, has been associated with decreases in the Firmicutes phylum²¹. Another starch, resistant starch, does not break down into glucose, but is fermented by bacteria in the large intestine²². Due to the longer period of digestion, resistant starches are widely considered beneficial in improving glucose tolerance and has been associated with improved gut health, such as an increase in the Firmicutes phylum in humans²³. However, one study concluded that resistant starches lowered levels of Firmicutes and raised levels of Bacteroidetes found in fecal samples of mice²⁴. These opposing results in human and animal experiments are due to many possible factors. Type 2 resistant starch, which has a semi-crystalline indigestible structure, was investigated in the human study, but is not specified in the animal study. The standard diet of the mice consisted mostly of starch and hemicellulose, differing from the varied human diet. Differences in diet, as well as complexity of gut microbiome, potentially contributed to differences in carbohydrate metabolism between mice and humans. In both cases, the different types of starches had various effects on the Firmicutes/Bacteroidetes, highlighting the significance of dietary choices on gut microbiome composition and obesity. Microbiota composition is also a key factor that affects the production of short chain fatty acids (SCFAs), a subset of fatty acids that play a major role in the homeostasis and maintenance of the gut and immune system. In healthy individuals, certain bacteria groups including Bacteroides, Roseburia, Bifidobacterium, Faecalibacterium, and Enterobacteria synthesize SCFAs, which provide energy to the host from the fermentation of dietary fibers, contribute to satiety regulation, and reduce obesity related intestinal inflammation. However, in individuals who over consume UPFs typically high in fat and sugar, most nutrients are absorbed in the duodenum and fewer substrates are left for the colonic bacteria. This process often results in dysbiosis, an imbalance of the gut microbiome diversity. Dysbiosis of the gut microbiome has been implicated in the pathophysiology of a number metabolic and cardiovascular diseases, low-grade inflammation²⁵, and increased susceptibility to inflammatory diseases such as inflammatory bowel disease and colon cancer²⁶. Both gut microbial dysbiosis and inflammation negatively affect gut microbiome composition, reducing the population of beneficial bacteria associated with SCFA production including acetate and butyrate. Acetate and butyrate in the cecum and colon contribute to decreasing body weight by breaking down fatty acids and increasing energy expenditure²⁷. Over-consumption of ultra processed food is linked to altered gut composition, dysbiosis, and inflammation, which decrease concentration of SCFAs and directly increase risk for obesity. In addition to maintaining gut health and body weight, optimal amounts of SCFAs also play a critical role in regulating appetite hormones such as Peptide YY (PYY) and ghrelin. PYY is an anorexigenic gut hormone released by enteroendocrine cells that affects production of   SCFAs and acts on receptors in the hypothalamus to signal appetite reduction²⁸. An underproduction of SCFAs causes imbalanced production of PYY and gut microbiota. Ghrelin, another gut hormone that stimulates appetite, is also directly affected by changes in gut composition, with ghrelin being negatively correlated with the quantity of Bifidobacterium and Lactobacillus and positively correlated with the number of Bacteroides and Prevotella²⁹. Because SCFAs promote the fermentation of dietary fibers, reduce gut dysbiosis, decrease obesity-related inflammation, and contribute to regulation of appetite hormones, they are strongly associated with weight loss. The gut microbiome extracts energy from food through the production of SCFAs, maintaining gut homeostasis³⁰. Though increases in the Firmicutes phylum and decreases in the Bacteriodetes phylum have been associated with obesity and supported by numerous studies³¹;³², these results are inconsistent with SCFA production. Firmicutes mainly produces butyrate, a health-promoting type of SCFA with the ability to reduce inflammation, regulate metabolism, and increase insulin sensitivity³⁰. Theoretically, increases in the population of Firmicutes would increase production of butyrate, which maintains homeostasis, is known as an anti-obesogenic molecule, and has been linked to lower rates of metabolic diseases including diabetes³³. However, this reasoning contradicts numerous experiments that associate an increase in Firmicutes with obesity. Research methods may contribute to discrepancies in SCFA levels and microbiota levels. Butyrate is often collected in stool samples, an inaccurate representation of butyrate concentrations as less than ten percent of total butyrate is excreted in feces. Butyrate-producing bacteria belonging to the Firmicutes phylum may be replaced by other bacteria also belonging to the Firmicutes phylum, such as Staphylococcus spp. and Lactobacillus reuteri³⁴ (See Table 1). While the number of total bacteria in the Firmicutes phylum increases, the number of specific butyrate-producing bacteria in the colon decreases, resulting in obesity and obesity-related inflammation. Researchers have begun to conduct studies on various methods and target pathways to reduce risk for obesity in relation to gut microbiota composition and appetite hormones. Bariatric surgery is a popular and effective method to treat severe obesity that has been shown to increase gut diversity, primarily through improving the Firmicutes/Bacteroidetes ratio³⁵ and the microbiota Shannon’s Diversity Index. Studies have also shown that both types of bariatric surgery, gastric bypass surgery and sleeve gastrectomy, decrease levels of serum ghrelin and mitigate leptin resistance³⁶. Prebiotic and probiotic therapy is another method in reducing obesity. Prebiotics, indigestible high-fiber food fermented by gut microbes, and probiotics, live bacteria cells, are common weight loss supplements affecting the lower gastrointestinal tract. For instance, oligofructose is a prebiotic that was shown to increase concentration of Bifidobacteria, a healthy bacteria involved with producing fatty acids. In mice, increased concentration of Bifidobacteria negatively correlated with weight gain and fat mass³⁷. In addition to altering bacteria composition, prebiotics stimulate the production of SCFAs and anorexigenic hormones in enteroendocrine cells. Prebiotics serve as a source of carbon for healthy bacteria in the gut, which ferment the high-fiber prebiotics and produce SCFAs, weight-reducing molecules, as end products. Zhou et al. concluded that fermentation of fibers, increased by prebiotics, is most likely the primary mechanism for higher concentrations and gene expression of PYY in rats independent of blood glucose levels³⁸. Higher levels of PYY have been correlated with lower risk for obesity in preclinical models. Probiotics are also known to contribute to weight loss and reduce SCFA production, dysbiosis, and inflammation. In a meta-analysis of the effects of probiotics on 38,802 adults, 13.1 percent ingested probiotics from yogurt or from dietary supplements daily. The prevalence of obesity and average BMI was significantly lower in this group compared to the rest of the individuals who did not ingest probiotics³⁹.In infants, probiotics have been found to reduce antibiotic-related gut dysbiosis, which increased risk for developing childhood obesity⁴⁰. Because probiotics are live bacteria, the most common being Lactobacillus, Bifidobacterium, Saccharomyces, and Bacillus, they directly change gut microbiome composition. For instance, by ingesting Lactobacillus plantarum and rhamnosus, the level of Lactobacillus in the gut increases, producing prohealthy conjugated linoleic acid, a type of fatty acid. Ingesting the prebiotic Akkermansia muciniphila has a positive effect on thickening mucus and the intestinal barrier, reducing chronic obesity-related inflammation⁴¹ and risk of weight gain (see Table 1). 

Bacteria	Taxa	Shift resulting in weight loss	Reference
Lactobacillus reuteri	Firmicutes	decrease	Benítez-Páez et. al., (2016)42
Lactobacillus plantarum, Lactobacillus rhamnosus	Firmicutes	increase	Aguilera, et. al., (2022)43
Bifidobacterium	Actinobacteria	increase	Zhou et. al., (2008)44; Daniali et al., (2020)45
Bacteroides	Bacteroidetes	increase	Aguilera et. al., (2022)43
Prevotella	Bacteroidetes	decrease	Appanna, V. D. (2018)46
Staphylococcus	Bacillus-Lactobacillus-Streptococcus cluster of Gram-positive bacteria	decrease	Bervoets et. al., (2013)47
Anaerostipes	Bacillota	increase	Bier et. al.,48

The Gut Microbiome and Sleep Disorders:

The gut microbiome not only directly affects metabolism and obesity but can also impact an individual’s risk for developing sleep disturbances and disorders. Recent studies have correlated various sleep disturbances and disorders, such as sleep apnea and sleep insomnia, with changes in gut microbiome composition. For instance, intermittent hypoxia, a hallmark of obstructive sleep apnea, was associated with various levels of oxygen in portions of the gut microbiome, leading to higher abundance of Firmicutes and a smaller abundance of healthy bacteria such as Bacteroidetes and Proteobacteria phyla⁵³, which play a role in producing SCFAs, provide nutrients to other gut microbes, and synthesize essential vitamins⁵⁴. Recent investigations of the gut-brain axis have suggested that the gut brain axis is a possible mechanism for the connection between the gut and sleep. The gut-brain axis (GBA) is a bidirectional communication network between the intestinal tract and the central nervous system through neural and hormonal signals that affect many physiological functions including metabolism, the immune response, and sleep. In a study of traditional Chinese medicine with herbal formulas, significant gut microbiome profile alterations were observed in patients with sleep insomnia and spleen qi deficiency in response to treatment. One type of gut microbe, ASV783-Phascolarctobacterium, increased with treatment and was associated with better sleep, while ASV655-Bacteroides decreased with treatment and was linked to worse sleep, supporting the connection between the gut and sleep and the role of the GBA in sleep regulation⁵⁵.Scientists have proposed that changes in gut microbiota and diversity affect the gut-brain axis, influencing various cognitive processes including sleep. The GBA has come under recent attention as a promising target to combat both mental health and sleep disorders. In a recent experiment, Wu et al. administered quercetin, an antioxidant that modulates microbiome diversity by promoting the abundance of healthy bacteria including Bifidobacterium and Lactobacillus, to mice with sleep disturbances. Quercetin, a potential drug to regulate the GBA, ameliorated sleep disturbances related to acute mountain sickness in mice⁵⁶. Greater abundance of Bifidobacterium is not only linked with improved sleep quality, but is also associated with increased SCFA production and lower levels of ghrelin (see figure1), which both contribute to lower risk of obesity. 

In human participants, the positive correlation of improved gut health and microbiome abundance with higher sleep quality persists. In a survey of 2,041 Chinese nurses and midwives, those who reported sleep disturbances and low sleep quality were more likely to have poorer gut health and experience gastrointestinal disorders⁵⁷. This positive correlation between gut health and sleep quality occurs conversely, further suggesting a bidirectional connection through the GBA. Another study provided dietary supplements, including saffron extract, to subjects with disordered sleep to investigate how changing the GBA would improve sleep⁵⁸. Studies have even supported that sleep disturbances are a potential precursor for gastrointestinal cancer.One of the main biological processes involved in regulating sleep that may directly connect to the GBA is the circadian clock in the suprachiasmatic nucleus.The clock switches certain genes, known as clock genes, on and off to induce or prevent sleep in response to different factors including hormone levels, glucose and fatty acid metabolism, and external stimuli. The clock operates with a central and peripheral oscillator; the central oscillator accounts for environmental cues and regulates timing and rhythm, while the peripheral oscillator conveys and controls metabolic and physiological processes. For example, research has shown that levels of external bacteria normally fluctuate daily, but disruption of circadian rhythm eliminates external bacteria patterns or fluctuations⁵⁹. This implies that even slight changes in circadian rhythm can lead to significant adverse changes to bacteria, possibly through the GBA. In addition, diet choices including meal frequency, timing, and regularity have been known to influence the circadian rhythm and vice versa. In a study of mice exposed to nighttime light, the mice experiencing nighttime light had excess weight gain, suggesting that disruptions to circadian rhythm from excessive light exposure are directly connected with metabolic dysfunction and obesity⁶⁰. Scientists further studied the connection between circadian rhythm and obesity by genetically deactivating Bmal1 genes, regulators of the circadian clock, in the adipose cells of mice. During the light phase, the mice demonstrated increased food intake and also gained weight, possibly due to abnormal fatty acid levels in the hypothalamus that resulted in abnormal feeding habits⁵⁹. While the exact mechanisms are unknown, researchers continue to investigate the connection between the gut microbiome and circadian rhythm, relating to the hosts’ risk for developing sleep disorders and obesity.In addition to changes in gut microbiome diversity and feeding behavior, microbial metabolites and hormones, specifically SCFAs and melatonin, can significantly alter the circadian rhythm and sleep regulation. Reduced intestinal levels of SCFAs in fecal samples have been correlated with chronic sleep deprivation in rats and greater diversity of microbiomes related to SCFA-production⁶¹. In several animal studies, reduced levels of SCFAs have also been correlated with several sleep disorders including intermittent hypoxia and obstructive sleep apnea⁶². While causes for the association between reduced SCFAs and greater risk for developing sleep disturbances remain generally unknown, recent evidence may suggest that SCFAs play a role in modulating the GBA by crossing the blood-brain barrier⁶³, affecting communication between the gut microbiome and brain. SCFAs can also affect the GBA by influencing serotonin production⁶⁴. Serotonin is a key neurotransmitter for the communication between the central nervous system and the gut. Interaction between enteroendocrine cell receptors and SCFAs can trigger the release of serotonin, widely known for sleep-wake regulation, which travels through the bloodstream to send signals to the brain⁶⁵. SCFAs therefore indirectly influence sleep quality through the GBA and serotonin production.95% of the body’s total serotonin is produced by the gut microbiota⁶⁴ and is affected by different factors including SCFAs. Adults who were given 5-HTP, a precursor of serotonin, had improved sleep quality when they showed an increase in microbiota diversity as well as greater relative abundance of SCFAs produced by the gut⁶⁶. In the intestine, the gut metabolizes serotonin to melatonin, which contributes to circadian clock regulation⁶⁷. Increased melatonin has been correlated with improved sleep quality and is a potential target for patients with insomnia. By its production in response to darkness, melatonin helps regulate circadian rhythm and synchronize the internal circadian rhythm with the natural day and night cycle. Because of its ability to induce sleep and influence circadian timing, externally administered melatonin has been investigated as a potential treatment for insomnia and other circadian rhythm sleep disorders⁶⁸. For instance, one clinical trial examined the efficacy of melatonin as a treatment for sleep disturbances in children with autism spectrum disorder⁶⁹. In another double-blind experiment, healthy participants with sleep disturbances were given melatonin in the form of coffee pods, and they showed improved sleep quality but still scored poorly on the Pittsburgh Sleep Quality Index⁷⁰. Although experiments show inconsistent findings for melatonin as an effective treatment for sleep disturbances, melatonin has long been established to influence the sleep-wake cycle and the gut microbiome. Melatonin contributes to the synchronization of the circadian rhythms of gut microbiota and the timing of the gut’s metabolic processes⁶⁷. Conversely, the gut microbiome affects the circadian clock and sleep quality both directly through the GBA and indirectly through neurotransmitters including serotonin and melatonin (see figure 1).

Ultra Processed Food, Obesity, and Sleep

The association between processed food and obesity has been well established for years. In one study of 110,260 adults from the NutriNet-Santé cohort who were assessed for ten years from 2009-2019, the participants who consumed more ultra processed foods had higher incidences of becoming overweight or obese in the following years, independent of baseline body mass index⁷¹. Consumption of UPFs is more common in developing countries, where foods especially high in sugar and caffeine cause malnutrition and risk of non-communicable diseases. In Lilongwe, South Africa, schoolchildren aged 11-14 who consumed UPFs were more likely to be overweight than children aged 7-10, suggesting a direct relationship between UPF consumption and body weight. Children ages 11-14 also consumed more UPFs, potentially due to the food’s addictive nature and other factors such as increased independence exposure to marketing⁷². Children and adults who over consume UPFs experience frequent spikes in blood sugar, contributing to insulin resistance and worsened metabolism, possibly leading to obesity.UPF consumption and increased sugar intake has been linked to intestinal inflammation⁷³ and permeability⁷⁴, hallmarks of obesity. This link may be associated with emulsifiers, a food additive that combines immiscible liquids such as water and oil, and sweeteners commonly found in processed foods⁷⁵. Bier et al. reported that a high sodium diet significantly altered the microbiome composition of mice, including increased abundance of the Erwinia genus, a harmful bacteria species, and decreased abundance of the Anaerostipes genus⁷⁶ (see table 1). The Anaerostipes genus is involved in buyrate production, which is crucial for a healthy gut barrier and anti-inflammatory properties. Because abundance of the Anaerostipes genus decreased as high salt concentrations increased, the mice were at higher risk for developing intestinal inflammation and a leaky gut, and thus more prone to obesity. In a simulation of the human intestinal microbial ecosystem, Chassaing et al found that emulsifiers, specifically polysorbate 80 and carboxymethylcellulose, altered microbial gene expression related to flagella expression in a simulation of the human intestinal microbial system by transferring emulsifier-treated microbiota to germ-free mice. Similarly, gut microbiome composition changed, with a decrease in Bacteroidaceae and increase in Proteobacteria and flagellin, causing low-grade inflammation⁷⁷. Therefore, emulsifiers are likely directly linked to obesity through changes in gut microbiome composition, resulting in low grade inflammation and gut permeability, which are hallmarks of obesity. The gut microbiome is becoming an increasingly popular field of study; recent experiments have shown the profound effects of the gut microbiome composition and diversity on obesity and overall human health.Confounding factors such as antibiotics, exercise, age, sex, and genetics limit the study of the direct cause of UPFs on the gut microbiome and obesity⁷⁸. Most studies account for these confounding factors by randomizing samples, controlling participant dietary and exercise behavior, or including the factors in the overall experimental design. For instance, in a randomized controlled trial, overweight participants’ calorie intake, physical activity, and lifestyle changes were monitored during a one-year behavior weight loss intervention. Stool and blood samples were taken to determine any significant correlation between genetics, specifically DNA methylation, and the gut microbiome during weight loss. By taking into account genetics, diet, and exercise, the study found that Ruminococcus 1 from the Firmicutes phylum positively correlated with DNA methylation and was advantageous for weight loss⁷⁹.Consumption of UPFs evidently increases risk of obesity, but researchers have also recently determined a correlation between obesity and sleep quality. A meta-analysis of 93 articles related to sleep and obesity found that the relationship between childhood obesity and inadequate sleep is reciprocal, with a correlation between increased weight and shorter sleep duration⁸⁰. This correlation is especially prevalent in children; one study concluded that the weight of children decreased by 0.75 kg/m^2 each additional hour of sleep obtained during childhood between the ages of 3 and 12⁸¹. Children who slept very little between the ages of 2.5 and 6 were at higher risk for developing obesity⁸². The reciprocal relationship between sleep and obesity is also present in adulthood. Short sleepers in a trial of 9431 adult men and women had higher regional fat mass index across subgroups including race and gender. Men and women with less than 7 hours of sleep had significantly higher fat mass index compared to the adults with more than 9 hours of sleep⁸³. UPFs may directly and indirectly cause obesity and sleep disorders simultaneously, accounting for the positive correlation between obesity and sleep. While UPFs directly cause obesity through excessive calorie intake, worsened metabolism, and the gut microbiome, the connection between UPFs and sleep disorders remains unclear and is still under investigation. Commonly displayed sleep disorder symptoms include shortened sleep duration, difficulty initiating sleep, and poor quality of sleep, all of which are associated with sleep insomnia, sleep apnea, and other sleep disorders. These symptoms have been directly linked to UPFs in a questionnaire that assessed 38,570 individuals and found statistically significant associations of these common symptoms for chronic insomnia with ultra processed food consumption⁸⁴. More research is beginning to connect UPF consumption with the prevalence of sleep disturbances like insomnia. Specifically, fibers, vegetables, fruits, and legumes, have been found to be sleep-promoting compounds. Diets with these compounds, such as the Mediterranean diet, are often more nutrition-dense, lowering risks of developing insomnia and improving sleep health⁸⁵. Contrastingly, diets with high levels of saturated and trans-fat, sodium, sugar, and energy density found in UPFs lead to higher risks for insomnia⁸⁶. Inversely, sleep disorder symptoms, including shortened sleep duration, can lead to greater fatigue and higher energy intake throughout the day, often from unhealthy fats and carbohydrates, resulting in a continuous cycle of worsened sleep quality. Sleep duration and the consumption of UPFs have a bidirectional relationship that can result in not only deterioration of sleep quality, but obesity as well.Intake of carbohydrates leads to increased insulin levels, raising levels of tryptophan in comparison to all other large neutral amino acids in the brain⁸⁷. Tryptophan can therefore pass through the blood brain barrier much more quickly, and this expedited transportation of tryptophan facilitates the production of serotonin and melatonin, important sleep hormones. Increased glucose levels before sleep can result in altered sleep-wake cycles due to changes in levels of sleep hormones⁸⁸. Sleep hormones are closely linked with sleep quality, body weight, and metabolism, suggesting a greater connection with hormones as a possible mechanism. In a study by Hong et al., mice with sleep fragmentation, a common symptom of sleep insomnia and apnea that has been associated with Type 2 diabetes, weakened glucose tolerance, and insulin resistance, were injected with melatonin prior to blood tests to measure levels of glucose and insulin. The mice with induced sleep fragmentation without melatonin injections gained significantly more weight and had significantly higher levels of glucose than the mice with melatonin injections⁸⁹. As melatonin levels increase, sleep fragmentation symptoms may lessen and metabolism may improve, leading to reduced gain. While the exact reasons for this interconnection are largely unknown, the study demonstrates the complex interplay between obesity, sleep, and metabolism, significantly impacted by diet and UPF consumption. Researchers hypothesize that misalignment in circadian rhythm and homeostasis due to sleep symptoms and disorders can result in insufficient levels of melatonin. Melatonin is critical for activating AMP-activated protein kinase (AMPK), an energy sensor in each cell that regulates cellular metabolism, improving glucose tolerance and insulin resistance⁹⁰. Sleep disorders and sleep disorder symptoms, such as sleep fragmentation, can change gene expression levels of metabolic pathways associated with AMPK. In mice with sleep fragmentation, the expression of HMGCR (3-hydroxy-3-methyl-glutaryl-CoA reductase) and SREBP-1 (sterol regulatory element-binding protein-1) increased⁹¹, indicating the role of sleep on AMPK production. With reduced AMPK production due to dysregulated levels of melatonin and sleep disorder symptoms, glucose tolerance and insulin resistance become disrupted. Therefore, melatonin and AMPK may be key mechanisms and potential targets for studying the link between sleep, metabolism, and obesity. AMPK, melatonin, and other hormones that significantly affect obesity and sleep are all interconnected with the gut microbiome, a recently discovered but transformative mechanism (see Figure 2).

Conclusion

The idea that consuming processed foods increases one’s risk for obesity is a longstanding and well-accepted notion. More recently investigated is the association between processed foods and one’s risk for developing sleeping disturbances. Studies have shown that UPFs high in fat, sugar, and energy density lead to greater occurrence of insomnia⁸⁶ and sleep apnea. Elevated insulin levels correlate with increased tryptophan levels, facilitating the production of serotonin and melatonin which may alter sleep-wake cycles⁸⁸. In addition to hormones and neurotransmitters, researchers have proposed that UPF consumption causes obesity through changes in gut microbial composition and diversity. UPFs are also linked with gut dysbiosis, including increases in the Firmicutes and Bacteroidetes ratio, contributing to obesity-related inflammation and reduced carbohydrate metabolism. These factors affect the production of SCFAs, specifically acetate and butyrate in the cecum and colon, which contribute to decreasing body weight by breaking down fatty acids and increasing energy expenditure²⁷. While the role of SCFAs in decreasing body weight is supported, one study compared germ-free mice with obese mice and found the obese mice had significantly more genes that encoded enzymes involved in SCFA production and had greater capacity to extract more calories from their diet, potentially resulting in a continuous cycle of weight gain⁹². Hormones related to appetite suppression, including ghrelin and PYY, affect gut microbiome composition, suggesting a connection between body weight and the gut. The gut microbiome may simultaneously impact both body weight and sleep quality. The biological mechanisms underlying the correlation between increased microbiome diversity and improved sleep quality are largely unknown, but the GBA is a promising explanation. Key microbial metabolites, neurotransmitters, and hormones, including SCFAs and melatonin, are produced in the gut and facilitate communication between the intestine and brain through the central nervous system and GBA. The GBA affects circadian clock regulation and microbial composition. Therefore, consuming processed foods can indirectly cause higher risks for obesity and sleep disorders. 

Discussion

In this paper, most of the sources used were fairly recent and included updated information. However, this paper also had some limitations, as most of the sources were either review or primary research on rats and mice. Because the gut and sleep connection is a relatively new field of study, completed clinical trials and human trials were scarce. Currently, researchers have attempted to treat obesity using various intervention methods, including non-invasive methods like prebiotics and dietary changes.  Some animal studies have found that prebiotics can stimulate SCFA production and production of anorexigenic hormones in enteroendocrine cells and promote satiety by the secretion of PYY³⁸. However, in a clinical study, administering prebiotics to obese children did not lead to significant weight loss⁵². The difference in findings may be due to the lack of knowledge of the biological mechanisms connecting gut health with obesity and the difficulty of translating preclinical animal studies to human health. More clinical trials on humans are needed to support prebiotics and probiotics as an effective treatment for obesity. Changing eating habits is another approach; consuming food high in fiber and limiting intake of UPFs and emulsifiers has been widely shown to improve gut microbiome diversity, in turn likely improving weight and sleep quality. Fecal transplants, or transferring healthy bacteria into the recipient’s intestine, are a more direct target of the gut microbiome but their effectiveness in treating obesity in humans is still under investigation, as some studies show no significant reduction in weight⁹³. A more invasive, but possibly more effective, method of reducing obesity is bariatric surgery. By reducing the size of the stomach and the intestine during bariatric surgery, patients’ food intake and nutrition absorption is limited. While the gut microbiome is not directly targeted, studies have shown that the gut microbiome composition changes, with a significant decrease in the Firmicutes to Bacteroidetes ratio, correlated with weight loss³⁵. However, many of these treatments are losing popularity with the rise of GLP-1 agonists as a hormone-based therapeutic for treating obesity. GLP-1 is a hormone produced in the intestinal tract, specifically enteroendocrine cells, that increases insulin release, slows down digestion, and reduces appetite⁹⁴. The discovery of the connection between the endocrine system and the GBA has sparked interest in treatments involving hormones and neurotransmitters, like GLP-1, and their effect on the hypothalamus to reduce appetite. Targeting the gut microbiome and the GBA directly to reduce appetite, increase microbiome diversity, and treat obesity, must be considered as a more effective approach with fewer adverse side effects.

Acknowledgements

I would like to acknowledge my mentor, Yoo Jin Jung, who helped guide me through the writing process and supported my curiosity for neuroscience.

References

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