Diet, gut microbiota, and health: a review

Abstract

The relationship between diet and human physical and mental health is highly interconnected and has been significantly correlated with the occurrence of various diseases, including neurological disorders, cancer, and chronic inflammatory diseases. Moreover, diet has been demonstrated to play a pivotal role in governing gut microbiota composition, making it one of the most influential factors. The diet is crucial in connecting humans and their gut microorganisms. The nutrients ingested supply energy to the body and serve as substrates for the metabolic processes of the gut microorganisms. Consequently, the gut flora and their metabolites reciprocally impact the host’s metabolism, thereby influencing the physiological state of the human body. Extensive investigations on human and mouse models have revealed that diet potentially underlies various effects on human health and disease.

Graphical abstract

Introduction

The concept of the “microbiome” dates back to the early twentieth century. Studies have revealed that various microorganisms, such as bacteria, yeasts, and viruses, inhabit different human body regions, including the intestines, skin, lungs, and mouth (Ursell et al., 2014). Moreover, the human microbiome, often called the “hidden organ”, contains genetic information that surpasses the human genome by 150-fold (Grice and Segre, 2012). Most microbial organisms inhabit the gastrointestinal tract, with the gut microbiota being the most extensively studied biogeographic niche due to its intricate complexity and the ability of certain gut microbes to thrive in laboratory conditions. While the gut harbors a diverse array of microorganisms, including yeasts, archaea, parasites, viruses, and protozoa, bacterial populations are the most thoroughly characterized. In recent years, a substantial body of research has elucidated the association between microbiota and various diseases, including cancers (Kadosh et al., 2020), diabetes (Aron-Wisnewsky et al., 2021), and neurological disorders (Yu et al., 2022). Furthermore, manipulating microbiota within the human body has emerged as a potential cornerstone for disease management (Liu and Shah, 2022; Park et al., 2023; Stewart Campbell et al., 2022; Sun et al., 2023). Diet has been identified as a significant determinant among the factors influencing microbiota, serving as both a short-term and long-term regulator of gut microbiota. It is also a significant pattern for the intake and supply of critical precursors to the microbiota. The host provides nutrients to the gut microbiota, and the intestinal microbiota influence the absorption, metabolism, and storage of the ingested nutrients while producing new substances to give feedback to the host, with potential and essential effects on a range of physiological processes in the host. This process affects the microbiota and the host. At the same time, there are many potential and delicate equilibrium relationships. Once these equilibrium relationships are broken, they will cause consequences such as chronic diseases, metabolic dysfunction, and other fatal consequences. Meanwhile, the abundance and diversity of intestinal microbiota are often used as indicators of intestinal health, as they are associated with chronic diseases and metabolic dysfunction (Cotillard et al., 2013; Schlechte et al., 2023). Another study shows that aging has been linked to alterations in the composition of the gut microbiota and increased levels of inflammation. This phenomenon is expedited by a diet that lacks diversity in its food components (Claesson et al., 2012). Consequently, diet plays a crucial role in determining the functionality of the gut microbiome and significantly affects the overall well-being of the host (Asnicar et al., 2021; Zmora et al., 2019). This review explores recent evidence supporting diet’s regulatory role in the microbiota, both in maintaining health and in the context of disease.

The gut microbiota at the interaction of diet and human health

The gut-brain-microbiota axis is a reciprocal communication system through which gut microbes and the brain can communicate bi-directionally. In the last decades, the gut microbiota has been determined to be a crucial regulator of the gut-brain axis. This axis through the autonomic nervous system (Ulrich-Lai and Herman, 2009), enteric nervous system (Obata and Pachnis, 2016; Yoo and Mazmanian, 2017), immune system and neuroimmunit (Agirman et al., 2021; Papotto et al., 2021; Xu et al., 2020; Yu et al., 2022), enteroendocrine signaling (Gribble and Reimann, 2016), neurotransmitters (Lyte et al., 1998), bacterial metabolite (Gabanyi et al., 2022; Teng et al., 2022), Bile acids (Cai et al., 2022; Fogelson et al., 2023; Martínez et al., 2018), spinal mechanisms and hypothalamic–pituitary–adrenal axis correlate the gastrointestinal tract and the central nervous system. Changes to host dietary patterns alter bacterial metabolism, thereby changing the ecology of microorganisms. Thus, the changes in microbial structure induced by diet can affect human physiology and disease processes (Todoric et al., 2020; Wastyk et al., 2021). The diagram in Fig. 1 illustrates the diverse mechanisms through which dietary patterns influence the brain-gut axis.

Fig. 1.

Dietary patterns easily influence the gut-brain axis. There are multiple mechanisms by which diet modulates the gut-brain axis, including immune responses, hormonal pathways, microbial metabolites, the nervous system, and metabolic routes. Healthy dietary practices, such as the Mediterranean diet, require a rich array of polyphenols, flavonoids, and short-chain/branched-chain fatty acids, which benefit the growth of beneficial microbes. These microorganisms can stimulate the production of substances like urolithin A, tryptophan metabolites, neurotransmitters, and intestinal hormones, which impact the brain and behavior, ameliorating pathological conditions in the human body. In contrast, unhealthy dietary habits, like alcohol consumption, processed foods, and excessive food additives, can induce changes in the microbial community structure and its components (like LPS). Such gut dysbiosis can detrimentally affect brain function and even the physiological and disease processes in the human body through alterations in intestinal permeability, bile acid metabolism, inflammation, synaptic signaling, synthesis and secretion of neurotransmitters, hypothalamic–pituitary–adrenal (HPA), and the permeability of the blood–brain barrier (BBB)

Mediterranean diet

The Mediterranean diet (MD) is widely recognized for including grains (specifically whole grains), nuts, beans, vegetables, fruits, and moderate amounts of poultry and fish. Additionally, olive oil is the primary source of fat, while wine and coffee are consumed at low to moderate levels (Correia, 2018). Extensive evidence suggests that this dietary pattern offers beneficial effects in preventing various diseases, such as cardiovascular disease (Wang et al., 2021), type 2 diabetes (Association, 2018), obesity (Meslier et al., 2020), inflammatory (Ghosh et al., 2020) and degenerative diseases (Karstens et al., 2019), and cancer (Bolte et al., 2023). These positive outcomes may be attributed to polyphenols, xanthine, and monounsaturated fatty acids within the MD (Papsdorf et al., 2023). In a recent study conducted by researchers at Brigham, investigating the mechanisms behind the proliferation of specific cell types in the gastrointestinal tract revealed a potential involvement of xanthine, a compound present in coffee, tea, and chocolate, in the differentiation of Th17 cells. Additionally, the study proposed that purine metabolism might underlie the Th17 response in individuals with inflammatory bowel disease (Duan et al., 2023). Furthermore, the study observed that mice fed an isocaloric diet abundant in long-chain saturated fats derived mainly from meat products exhibited higher levels of insulin resistance and inflammation in adipose tissue compared to mice fed a diet rich in fish oil. The metabolic disruptions observed in the mice fed a diet high in saturated fat were accompanied by decreased phylogenetic diversity. However, the transplanted microbiota from mice-fed fish oil effectively prevented the inflammation induced by saturated fat consumption (Martinez-Guryn et al., 2018). Additionally, transgenic mice that consistently produce ω3 polyunsaturated fatty acids exhibited a microbiome with heightened phylogenetic diversity, which protected against the metabolic effects of a diet high in saturated fat and sugar (Bidu et al., 2018). Numerous studies have provided evidence for the anti-inflammatory effectiveness of the MD, potentially attributable to alterations in microbial composition and metabolites induced by dietary intake. Research indicates that adherence to the MD is linked to elevated levels of particular taxonomic groups that exhibit positive correlations with indicators of decreased frailty and improved cognitive function while displaying negative associations with inflammation markers such as C-reactive protein and IL-17 (Ghosh et al., 2020). These observations were independent of body mass index and age, which is particularly interesting. Furthermore, two recent intervention studies have established a correlation between the MD and various taxonomic characteristics. These include increased levels of Faecalibacterium prausnitzii and Roseburia, decreased levels of Collinsella aerofaciens, and Ruminococcus torques (Ghosh et al., 2020). Additionally, empirical support indicates that alterations in the microbiome, influenced by adherence to the MD, are linked to heightened synthesis of short-chain/branched-chain fatty acids. In contrast, the production of secondary bile acids, p-cresol, ethanol, and carbon dioxide is diminished. Notably, the implementation of the MD intervention led to a noteworthy surge in whole grain consumption and nut intake, which subsequently led to a reduction in acylcarnitine levels in urine (Ross et al., 2013) and an elevation in urolithin A (UroA) levels (Garcia-Aloy et al., 2019). As acylcarnitines are associated with an increased risk of cardiovascular disease (Guasch-Ferré et al., 2016), the reduction in urinary acylcarnitines observed in individuals following the MD can be attributed to the increased intake of fiber, which may have a beneficial effect on energy metabolism. Additionally, UroA, a compound found in the MD, has been found to enhance gut barrier function (Singh et al., 2019) and is associated with reduced cardiometabolic risk (Selma et al., 2018). Furthermore, UroA has also been implicated in the prevention of prostate cancer (Stanisławska et al., 2019), endometrium cancer (Zhang et al., 2016), and breast cancer (Teixeira et al., 2017). Another microbial metabolite, Indole-3-propionic acid (IPA), derived from tryptophan, has been shown to maintain intestinal homeostasis and prevent experimental colitis (Alexeev et al., 2018). Recent studies have demonstrated the anti-inflammatory effects of indole-3-acetate, a metabolite of tryptophan produced by bacteria, on hepatocytes and macrophages (Krishnan et al., 2018). Additionally, indole-3-acetic acid, another bacterial derivative of a tryptophan metabolite, has been found to affect chemotherapy treatment through the ROS-autophagy axis (Tintelnot et al., 2023). Numerous investigations have reported a decreased risk of developing CD in individuals adhering to the MD, and even after a CD diagnosis, MD consumption has been linked to symptom alleviation and enhanced quality of life (Papada et al., 2020). Additionally, research has demonstrated a positive correlation between adherence to the MD and increased likelihood of response in patients with advanced melanoma undergoing immune checkpoint blockade (ICB) therapy. These findings imply that diet may significantly enhance the efficacy of ICB treatment outcomes (Bolte et al., 2023). Furthermore, evidence has indicated a strong association between the MD and a notable decrease in subclinical gut inflammation (47%). This finding indicates that the influence of the gut microbiome (Clostridium, Parvimonas, RF32 (Alphaproteobacteria) and Dialister) played a role in the observed effect, implying that potential interventions targeting the reduction or prevention of gut inflammation in asymptomatic first-degree relatives of individuals with Crohn’s disease should take into account the implementation of the MD to alter the composition of the gut microbiota (Turpin et al., 2022). Consequently, this supports the hypothesis that adopting the MD may have advantageous effects on human health by modulating the metabolism of the gut microbiota.

Intermittent fasting

Intermittent fasting (IF) is a dietary regimen characterized by alternating periods of eating and fasting. Since ancient times, fasting has been crucial in various cultural and religious practices. The underlying principle of the circadian fasting method posits that abstaining from carbohydrate consumption results in heightened fat metabolism within 12–24 h, potentially resulting in weight loss and improved health outcomes. The drastic restriction of calories affects the microbiome as well as the health and physiology of the host (Frost et al., 2019; Ozkul et al., 2020). There is mounting evidence that IF positively affects metabolic disorders, cancer, and aging (Chaix et al., 2019; de Cabo and Mattson, 2019; Di Francesco et al., 2018; Stekovic et al., 2019). In modern times, people recognize diet composition and begin to consider whether the microbiota might mediate the beneficial effects of IF. Studies have shown that IF modulates the gut microbiota and microbial metabolite composition to ameliorate insulin resistance and hepatic steatosis, promote adipose tissue browning, protect against central nervous system autoimmunity, reduce obesity-induced cognitive impairment, and ameliorate diabetic retinopathy in rodent models (Beli et al., 2018; Cignarella et al., 2018; Li et al., 2017; Liu et al., 2020). In diabetic mice, IF improved cognitive function by modulating the microbiota-metabolite-brain axis. This was achieved through upregulating genes related to mitochondrial biogenesis and energy metabolism in the hippocampus, restoring gut microbiota composition, and enhancing microbial metabolites associated with cognitive function. Integrated modeling revealed a significant correlation between genes affected by IF, gut microbiota composition, and microbial metabolites. The neuroprotective effects of IF were partially diminished upon depletion of gut microbiota with antibiotics. Consumption of IPA, 5-hydroxytryptamine, short-chain fatty acids, or taurine ursodeoxycholic acid demonstrated similar effects to IF in improving cognitive function (Liu et al., 2020). It has been shown that IF positively impacts the clinical progression and pathological characteristics of experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis. IF is associated with heightened intestinal bacterial populations, particularly the Lactobacillaceae, Bacteroidetes, and Prevotellaceae families, and enhanced antioxidant microbial metabolic pathways. Furthermore, alterations in T cell populations within the gut result in a reduction of IL-17-producing T cells and an elevation of regulatory T cells. In immunoreceptor mice maintained on a standard diet, fecal microbiome transplantation from mice subjected to IF ameliorated EAE, indicating that the beneficial effects of IF may be attributed, in part, to alterations in gut microbiota. Clinical trials in multiple sclerosis patients demonstrated that intermittent energy restriction led to changes in blood adipokines and gut microbiota, resembling the protective modifications observed in murine models. Therefore, it can be concluded that IF exerts potent immunomodulatory effects, potentially mediated through interactions with the gut microbiome (Cignarella et al., 2018). Furthermore, animal models have demonstrated that IF designed for alternate-day fasting can ameliorate brain structure and cognitive function in age-related and Alzheimer’s disease (AD) (Singh et al., 2015; Vasconcelos et al., 2014; Zhang et al., 2017). IF has demonstrated efficacy in enhancing cognitive function and reducing Alzheimer’s disease-like pathology in a transgenic AD mouse model (5XFAD). IF induces alterations in the gut microbiota composition, particularly enriching probiotic strains such as lactobacilli. These changes in gut microbiota composition affect metabolic activity and metabolite production. Metabolomic analysis of cecum contents revealed that IF decreases carbohydrate metabolism, notably glucose, and increases amino acid abundance, including sarcosine and dimethylglycine. Research revealed that the administration of IF-induced sarcosine or dimethylglycine replicated the beneficial effects of IF in 5XFAD mice, such as improvement in cognitive function, reduction in β-amyloid accumulation, and attenuation of glial hyperactivation. These findings suggest that IF could be a promising strategy for halting AD progression, mainly through the gut-microbiota-metabolite-brain axis, offering a novel therapeutic approach to the condition (Pan et al., 2022). Likewise, research has demonstrated that IF facilitates axonal regeneration following sciatic nerve crush in mice by a mechanism reliant on the enhancement of Gram-positive gut microbiota and serum IPA, a metabolite derived from intestinal bacteria. Clostridium perfringens produces IPA, which is essential for successful axonal regeneration. Supplementation of IPA post-sciatic injury notably enhances axonal regeneration and expedites the restoration of sensory function. The findings of an RNA sequencing analysis conducted on the sciatic dorsal root ganglion mechanistically suggest that neutrophil chemotaxis contributes to the IPA-dependent regenerative phenotype. This hypothesis was subsequently validated by inhibiting neutrophil chemotaxis (Serger et al., 2022). Hence, exploring regenerative bioactive compounds originating from gut microbiota intended for oral or intravenous delivery holds potential for novel therapeutic avenues in nerve injury treatment, as it can stimulate axonal regeneration and facilitate nerve recovery. Besides, a study has demonstrated that IF effectively halted the pathologic advancement of colitis through enhancements in intestinal barrier integrity and colon length. Additionally, IF exhibited a dual role in mitigating inflammatory responses and oxidative stress in colonic tissues, it ameliorated anxiety-like and obsessive–compulsive behaviors linked to colitis and diminished neuroinflammation and oxidative stress. Notably, IF induced alterations in the gut microbiota composition, explicitly reducing the prevalence of colitis-associated microbes such as Shigella and Escherichia Coli and enhancing the presence of anti-inflammatory-associated microbes. It also improved short-chain fatty acid formation in colitis mice. In conclusion, IF exhibited a protective effect against colitis and associated behavioral deficits, partly explained by improving gut microbial composition and preventing leaky gut, thereby inhibiting inflammation and oxidative damage in the colon and brain. An appropriate IF regimen may be an effective strategy for nutritional intervention in preventing and treating colitis (Zhang et al., 2020). Moreover, empirical studies have demonstrated that IF substantially reduces blood pressure in both experimental models and hypertensive patients. Notably, these favorable effects persist even after the reintroduction of food (Grundler et al., 2020; Kord-Varkaneh et al., 2020). Interestingly, gut dysbiosis has been implicated as a potential factor in the development of hypertension in recent years. Several recent studies have suggested that the antihypertensive effects of IF involve manipulation of the gut microbiota and metabolome and that disruption of bile acid signaling is a novel mechanism by which gut dysbiosis contributes to hypertension (Shi et al., 2021). The prevention of dysbiosis may lead to a reduction or elimination of hypertension. However, it is essential to note that certain clinical conditions such as uncontrolled diabetes, pregnancy, eating disorders, and chronic kidney disease may have negative consequences despite the documented health benefits of fasting in experimental and clinical studies, which include improvements in cardiovascular health, cognition, metabolism, and blood pressure. Therefore, the utilization of IF must be approached with careful consideration. However, Shi et al.’s findings (2021) are intellectually stimulating. They propose that IF could address hypertension by reinstating gut microbiota, normalizing bile salt production, and regulating TGR5 signaling in experimental models. Nevertheless, it is imperative to validate these preclinical investigations in human subjects.

Alcohol

Alcohol consumption is a prevalent global practice that contributes to liver disease and accounts for approximately 4% of global deaths (Xiao et al., 2019). Alcohol can harm various organs, including the liver, intestines, and brain. The liver injury affects about 20–30% of those who abuse alcohol, with a smaller proportion progressing to liver cirrhosis or alcoholic hepatitis. Understanding the pathogenesis of alcohol addiction is, therefore, crucial. At the same time, previous research has primarily focused on its impact on the brain (Mathurin and Bataller, 2015). Recent studies have illuminated the influence of modifiable factors, particularly the gut microbiome, on this complex process. Table 1 provides a summary of the research studies that have documented alterations in the gut microbiota among individuals with Alcoholic Liver Disease (ALD). Dysbiosis of the gut microbiota, in conjunction with alcohol exposure, facilitates the development of ALD through a variety of mechanisms. The natural gut microbiota of the human digestive tract is predominantly composed of Bacteroidetes, Actinobacteria, and Firmicutes (Liang et al., 2018). Endotoxins, integral components of Gram-negative bacteria, are released in more significant quantities due to the increased quantity of these bacteria in the digestive tract due to chronic alcohol consumption (Malaguarnera et al., 2014). Endotoxins, upon binding with LPS-binding protein and activating Kupffer cells through CD-14 and Toll-like receptor-4, subsequently lead to the generation of free radicals, activation of nuclear factor kappa B (NF-κB), and the production of inflammatory mediators. The inflammatory mediators ultimately induce necro-inflammatory and fibrotic alterations within the liver (Purohit et al., 2008). Furthermore, changes in microbial metabolism, specifically the abundance of short-chain fatty acids like acetic acid, grain propionic acid, and butyrate acid, have been linked to conditions such as major depressive disorder, generalized anxiety disorder, chronic stress, and psychotic disorders (Taylor and Holscher, 2020).

Table 1.

Studies That Assessed Dysbacteriosis in ALD Patients

Participant (n)	Methodology	Overgrown Microbes and Depleted Microbes in the ALD Group	Study
Healthy control group (n = 18); Patients with alcoholic cirrhosis (n = 19); Alcoholics without liver disease (n = 29)	Sigmoid mucosa biopsies; PCR and multi-tag pyrosequencing	Bacteroidetes↓, Proteobacteria↑. Dysbiosis was linked with endotoxin	Mutlu et al (2012)
Alcohol dependence and cirrhosis (n = 27); Alcohol dependence without cirrhosis (n = 72)	Stool samples; Metagenomic sequencing	Lactobacillus spp.↑, Bifidobacterium spp.↑, Oral microbiota↑	Dubinkina et al (2017)
Cirrhosis without alcoholic hepatitis (n = 17); Cirrhosis with alcoholic hepatitis (n = 17); Without cirrhosis or alcoholic hepatitis (n = 61); Without cirrhosis with alcoholic hepatitis (n = 13)	16S RNA sequencing	Patients with cirrhosis and alcoholic hepatitis had higher relative abundance of Actinobacteria and lower relative abundance of Bacteroidetes	Ciocan et al (2018)
Patients with liver cirrhosis (n = 36); Healthy control group (n = 24)	Stool samples; 16S rRNA and PCR	Prevotellaceae↑, Bacteroidetes↓, Proteobacteria↑, Fusobacteria↑, Lachnospiraceae↓	Chen et al (2011)
Alcoholic patients (n = 66); Healthy control group (n = 24)	Stool samples; Quantitative culturing	Bifidobacteria↓, Enterococci↓, Lactobacilli↓	Kirpich et al (2008)

Since many ALD patients are ineligible for life-saving liver transplantation due to their unwillingness or inability to abstain from alcohol, and based on growing evidence that the gut microbiota plays an essential role in alcohol use disorder, it may be a relevant therapeutic target. Recent advances in high-throughput sequencing technologies have led to an increased understanding of the composition and function of this complex microbial community. An improved understanding of the host microbiota’s ecological, metabolic, and signaling networks could enable the development of a new generation of microbiome-targeted disease treatment and prevention strategies.

Processed food

Processed foods have always been known for their high levels of saturated fat, sugar, salt, and low levels of fiber in processed foods. With the development of industrialization, more and more processed foods have come into people’s sight and onto their tables. Gradually, they have become an indispensable part of people’s diets. However, as research progresses, it is found that processed foods are not harmless and even endanger people’s health and safety (Zinöcker and Lindseth, 2018). An increasing body of data links chronic consumption of processed foods to cancer (Fiolet et al., 2018), cardiovascular disease (Rico-Campà et al., 2019; Schnabel et al., 2019), and overall mortality (Schnabel et al., 2019).

Current advances have shown that prolonged consumption of processed foods may compromise intestinal permeability. For example, chronic consumption of a processed diet has been shown to increase intestinal barrier permeability and increase the risk of chronic kidney disease in a rodent model. However, in a diabetic mouse model, a diet high in resistant starch and dietary fiber maintained the integrity of the intestinal barrier. It reduces the severity of kidney injury by inhibiting complement (Snelson et al., 2021). In addition, it has been shown that the diet-induced loss of protective Th17 cells is because sugar and type 3 innate lymphoid cells promote the growth of Faecalibaculum rodentium, a replacement for the Th17-inducing microbiota. While removing sugar from a high-fat diet protects mice against obesity and metabolic syndrome, this protection depends on symbiont-specific Th17 cells (Kawano et al., 2022). Numerous functional investigations have consistently revealed that food processing influences intestinal microbiota composition. This influence manifests in the form of heightened intestinal permeability and inflammation, primarily attributed to the proliferation of mucus-degrading bacteria, namely ruminococci, Akkermansia muciniphila, and Proteobacteria, and food processing contributes to endotoxin production and the activation of TH17 cells (Chassaing et al., 2015; Constante et al., 2017; Racine et al., 2016; Shen et al., 2014; Suez et al., 2014; Wilck et al., 2017; Yang et al., 2018). Besides, a study revealed that mice fed with fried, processed meat exhibited a notable increase in the proportion of Firmicutes and Bacteroidetes compared to the control group. Furthermore, the intervention with fried meat led to significant alterations in fecal co-metabolites, including a reduction in butyric acid, valeric acid, and IPA and an elevation in carnitine levels.

There remains a scarcity of research examining the impact of processed foods on the gut microbiota, and the underlying mechanisms elucidating the present results are not sufficiently understood. Actively investigates and explores the mechanisms through which processed foods induce inflammation, subsequently contributing to the containment of chronic diseases. This could be a potential therapeutic option in the future for the prevention of the harmful effects of the consumption of processed foods. Figure 2 depicts the impact of excessive alcohol consumption, processed foods, and food additives on gut microbiota and the host organism.

Fig. 2.

The gut microbiota intricately connects the intestine with other organs through the portal venous system and the enterohepatic circulation of bile acids. Excessive alcohol consumption, processed foods, and food additives can lead to an imbalance of gut microbiota, which can impact other bodily organs through various mechanisms such as metabolic byproducts, neurotransmitters, cytokines, intestinal permeability, and Th17 cells

Food additives

Artificial sweeteners are used as no-calorie sugar substitutes in many foods, and their consumption has grown dramatically in recent years (Sylvetsky and Rother, 2016). While the public consensus is that low-calorie sweeteners are harmless, some questions have been raised about the long-term health effects of consuming certain low-calorie sweeteners (Debras et al., 2022; Harrington et al., 2018; Rodriguez-Palacios et al., 2018). For example, according to the latest research, the World Health Organization under the International Agency for Research on Cancer announced that aspartame is “carcinogenic to humans may be substances” (class 2B carcinogens) (Wise, 2023). Recently, a preliminary study published in Nutrients found that in vivo and in vitro consumption of sugar substitutes modulates gene expression of cognate taste receptors and affects transcription of genes encoding regulatory proteins in neutrophils. Further studies showed that the regulation of transcription altered the state of the cells, making the isolated immune cells more sensitive to bacterial stimuli (Skurk et al., 2023). In addition, recent research suggests that high sucralose consumption may inhibit T-cell-mediated responses. This effect may be helpful in treating T-cell-dependent autoimmune diseases (Zani et al., 2023); however, it remains to be determined whether sucralose affects other cell types, including other immune cells, with different consequences. A study published in Diabetes Care, a leading journal in the field of diabetes, showed that a higher intake of sugar substitutes in the daily diet (> 16.4 mg/day for men; > 18. 5 mg/day for women, which is equivalent to drinking about 50 mL of sugar-sweetened beverages per day) were associated with a 69% increased risk of type 2 diabetes and that all three types of low-calorie sweeteners, namely aspartame, acesulfame, and sucralose, were associated with a 69% increased risk of type 2 diabetes (Debras et al., 2023). Other mice and human studies have shown that ingredients added during food processing, such as food emulsifying agents, antibacterial additives, and artificial sweeteners, promote gut permeability and inflammation by increasing mucus-forming bacteria and endotoxin levels (Chassaing et al., 2015; Suez et al., 2014; Yang et al., 2018). Moreover, scholarly research has provided evidence indicating that Sucralose leads to a reduction in the Firmicutes and an elevation in the Bifidobacterium (Wang et al., 2018). Similarly, Splenda has been found to induce an upsurge in the Proteobacteria phylum and an overabundance of Escherichia coli (Rodriguez-Palacios et al., 2018). Both carboxymethylcellulose and polysorbate-80 enhanced inflammation reduced the diversity of the microbiota and resulted in an increase in the relative abundance of the order Bacteroidales and a decrease in the relative abundance of the order Clostridiales (Chassaing et al., 2022, 2015; Viennois et al., 2017).

All indications are that food additives may do more harm than good to human health and well-being, but their beneficial side should not be ignored entirely. In short, research must further explore and prove this!

Future prospects

Hippocrates advocated for the therapeutic potential of food, a sentiment that can now be expanded to emphasize the medicinal properties of food-mediated microbes. While short-term dietary interventions have demonstrated the ability to modify the gut microbiota composition, long-term dietary patterns have been linked to a resilient microbiota configuration resistant to alteration (Carmody et al., 2015; Griffin et al., 2017). Furthermore, the subset of microbiota members that exhibit a response to dietary factors may constitute a minor proportion of the overall microbial community. Consequently, further investigations in both preclinical and clinical settings are imperative to comprehensively comprehend the etiologic-physiologic mechanisms involved and ascertain whether alterations in tractable populations are adequate to induce physiological modifications in the host, particularly for research. Dietary plasticity presents promising therapeutic avenues for modulating the microbiota; however, it is a double-edged sword, as it can also yield intricate adverse consequences, such as dysbiosis. Dysbiosis, characterized by alterations in microbiota composition, has been implicated in establishing a connection between an unhealthy diet and the development of chronic diseases and metabolic syndrome. The definition of dysbiosis presents an intriguing aspect. Recent hypotheses propose that it is not characterized by a specific pattern but rather by a disruption in the stability of the microbiota, resulting in a departure from the normal state (Zaneveld et al., 2017). Consequently, establishing a clear definition of a healthy microbiota becomes challenging and uncertain when considering individual perspectives. This difficulty arises due to the multifaceted influences of factors such as environment, genetics, past diet, exercise patterns, and geographic location, which continuously shape the microbiota. These influences can introduce biases that may not necessarily correlate with accurate and measurable health outcomes (Zmora et al., 2018).

In summary, dietary patterns and gut microbiota play a pivotal role in human health, with different dietary habits promoting or protecting against various diseases. The MD and IF have demonstrated beneficial effects on metabolic, cardiovascular, and neurodegenerative diseases, mainly due to their influence on gut microbiota composition and metabolism. On the contrary, excessive consumption of alcohol, processed foods, and food additives has been linked to dysbiosis and the development of inflammatory and metabolic disorders. The complex interactions between diet, gut microbiota, and health offer promising avenues for personalized medical strategies targeting specific microbial compositions. However, further research is needed to fully understand the long-term impacts of these dietary interventions on human health.

Data availability

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Declarations

Competing interests

On behalf of all authors, the corresponding author states that there is no conflict of interest.

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