Gut Frailty: Its Concept and Pathogenesis Open Access

Japan has achieved the highest average life expectancy globally and stands at the threshold of the centenarian era. However, bridging the gap between average life expectancy and healthy life expectancy has become increasingly imperative. This necessitates the development of effective preventive and therapeutic strategies for conditions like sarcopenia and frailty, which impede the extension of healthy life expectancy. In this review, we present the current state of longevity in Japan and introduce the concept of “gut frailty.” Our objective was not only to attain healthy longevity but also to foster lifelong well-being. We anticipate that advanced research into the molecular pathogenesis of gut frailty will pave the way for innovative preventive and therapeutic interventions focused on the gastrointestinal system.

Japan has witnessed an almost linear increase in average life expectancy over the past half-century. As of 2022, it has been reported as 87.09 years for women (ranking 1st globally) and 81.05 years for men (ranking 4th globally). However, it is crucial to note that the Japanese population historically did not have inherently healthy dietary practices. Around 1850, the average life expectancy in Japan was approximately 50 years, indicating a relatively short-lived nation. Advances in nutritional science have significantly contributed to the increase in average life expectancy through two primary avenues. First, nutritional deficiencies were prevalent issues in Japan before and after World War II. Identifying causes such as vitamin B1 deficiency (e.g., beriberi) and implementing nutritional interventions played a substantial role in extending average life expectancy. Second, progress in nutrition focused on addressing metabolic syndrome, which began increasing around the 1960s and also made a significant contribution. The current healthy dietary patterns in the Japanese population can be attributed to improvements in nutrition science rather than pre-existing dietary traditions.

Nonetheless, in Japan, there persists a substantial disparity between average life expectancy and healthy life expectancy, with a difference of approximately 9 years for men and 12 years for women. This gap has not undergone significant changes, although there has been slight improvement since 2000. Projections indicate that one out of every two babies born this year will live to be 100 years old, marking the era of the centenarian society. Achieving healthy longevity in this 100-year life era necessitates extending healthy life expectancy and narrowing the gap between average life expectancy and healthy life expectancy. To comprehend the current situation, specific examples can be provided. First, data from the longest-running cohort study conducted in Japan, known as the “Hisayama Town Study,” can be introduced [1]. In this cohort study, changes in the prevalence of metabolic disorders over the past 50 years, including obesity, high cholesterol, and impaired glucose tolerance, have been observed to increase over time. The prevalence of impaired glucose tolerance has significantly risen from 12% in men and 5% in women in 1961 to 54% and 35% in 2002, respectively [1]. While the increase in obesity and decrease in physical activity are considered significant factors, it is also believed that the proportion of animal fat intake relative to total lipid intake (animal fat ratio) has increased despite no significant changes in total calorie intake. Second, the prognosis data for early-stage gastric cancer patients can be examined. Helicobacter pylori infection is a major cause of gastric cancer, and in Japan, due to advancements in endoscopic screening, many gastric cancer cases are detected at early stages, leading to an increased opportunity for endoscopic resection. However, the prognosis survey of patients who underwent endoscopic treatment for early-stage gastric cancer revealed a clear decrease in survival rates among those with complications or poor nutritional status, regardless of age [2]. The causes of death were not due to gastric cancer recurrence but rather benign diseases (approximately 50%) and malignancies outside the stomach (approximately 50%), providing insights into the current status of medical care in Japan. While endoscopic treatment for early-stage gastric cancer has achieved successful outcomes in terms of “Happiness,” the attainment of sustainable happiness or “Well-being” remains elusive.

According to the World Health Organization (WHO) Charter, “Well-being” refers to a state where “not only the absence of disease or infirmity but also the physical, mental, and social well-being” are fulfilled. It is assessed through various factors, including social support (the presence of relatives or friends to rely on in times of trouble), freedom of life choices (satisfaction with the freedom of life choices), corruption (within the government or corporations), societal tolerance (engagement in donations within the past month), per capita GDP, and healthy life expectancy. In the World Happiness Report 2023 [3], Japan ranked 47th, South Korea 57th, and China 64th. Thus, considering Japan and other East Asian countries, the pursuit of well-being remains unfinished.

Frailty is a medical term that refers to a vulnerable state between health and the need for care, characterized by a decline in muscle strength, physical and mental vigor, and an increased risk of requiring assistance with daily activities as individuals’ age. Various criteria exist for defining frailty, but in Japan, the screening criteria proposed by Fried et al. [4] are commonly used. Fried’s criteria consist of five items, and if three or more criteria are met, the individual is classified as frail, while one or two criteria indicate a pre-frail stage. The five criteria are as follows:

• 1.

  Unintentional weight loss of 4.5 kg or more per year or a weight loss of 5% or more.

• 2.

  Self-reported exhaustion occurring on 3–4 days or more per week.

• 3.

  Slow walking speed.

• 4.

  Decreased grip strength.

• 5.

  Decreased physical activity.

The term “gut” refers to the digestive tract, including the stomach and intestines. “Gut frailty” is named in the sense of the “weakening” of gastrointestinal functions. Recent research has revealed that gut frailty may exacerbate various diseases, cause chronic inflammation, and serve as a precursor to frailty. Currently, there is no consensus on the clinical screening and diagnostic methods for gut frailty. However, the following symptoms are considered potential indicators:

• 1.

  Epigastric pain and discomfort.

• 2.

  Bowel irregularities such as constipation or diarrhea.

• 3.

  Abdominal pain and bloating.

• 4.

  Stress-related symptoms.

• 5.

  Decreased appetite and weight loss.

Several comprehensive indicators have been reported to assess the decline in the quality of life (QOL) due to symptoms related to the entire gastrointestinal tract. Not only patients with functional gastrointestinal disorders but also healthy individuals in the general population experience decreased QOL and reduced work productivity due to uncomfortable gastrointestinal symptoms. Therefore, it is suggested that an individual’s health status should be determined by the severity of self-reported symptoms and their resulting impact on QOL. To elucidate the reality of gut frailty, it is desirable to utilize a QOL scale that can comprehensively evaluate symptoms related to the gastrointestinal tract. In this regard, the Izumo Scale reported by Furura et al. [5, 6] is considered suitable. The Izumo Scale not only assesses symptoms related to the upper and lower gastrointestinal tracts but also measures the severity of each symptom using a Visual Analog Scale (VAS) and examines their relationship with other factors (Fig. 1). Specifically, the Izumo Scale consists of 15 items in five domains: heartburn (questions 1–3), gastralgia (questions 4–6), postprandial fullness (questions 7–9), constipation (questions 10–12), and diarrhea (questions 13–15), allowing the selection of a severity level on a six-point scale with higher values indicating more severe symptoms [6]. This scale has been shown to have good internal consistency and reproducibility, as well as good correlations with the visual analog scale of abdominal symptoms and the Gastrointestinal Symptom Rating Scale, and is thus widely utilized in Japan [7‒9]. It can also contribute to the diagnosis of evident functional gastrointestinal disorders. Our goal is to create a convenient and useful gut frailty checklist similar to the frailty checklist.

Among self-reported symptoms, constipation is particularly significant as one of the key symptoms of gut frailty. Studies have demonstrated that individuals with constipation have significantly lower survival rates after 10 or 15 years compared to those without constipation [10]. They are also at a higher risk of developing various diseases such as chronic kidney disease [11], cardiovascular diseases [12], and neurodegenerative disorders like Parkinson’s disease [13]. While constipation is thought to be associated with decreased physiological function of the colon, it is actually a symptom or exacerbating factor that precedes the onset of various systemic diseases. In a cross-sectional survey conducted among 620 healthy Japanese individuals aged 60–80 years, constipation was found to be more prevalent in the frail group than in the non-frail group [14]. Additionally, a cross-sectional study targeting patients visiting hospitals by the group at Juntendo University revealed a significantly higher frequency of constipation symptoms in the sarcopenia group compared to the non-sarcopenia group [15]. A study investigating cognitive decline in the elderly found that the rate of cognitive decline was 2.7 times faster in the constipation group compared to the non-constipation group.

Furthermore, the frequency of constipation increases with aging, but it is also prevalent among working-age individuals and children. In terms of its association with work productivity, individuals who report constipation have been found to incur a loss of approximately 1.22 million yen per year. It has been suggested that infants born nearly sterile acquire a resident microbial community by the age of three, and constipation at the age of three is associated with a higher risk of subsequent development of autism spectrum disorders [16]. Strategies for addressing gut frailty are crucial not only for patients with diseases but also for aiming at lifelong well-being.

In the future, large-scale surveys should be conducted, not only among patients but also among the general population, to investigate the frequency and severity of self-reported and observed gastrointestinal symptoms. It is essential to explore the associations between these symptoms and various dietary and lifestyle factors, as well as the degree of well-being, stress levels, and work productivity. Ultimately, the goal is to develop a simple and useful gut frailty checklist.

To elucidate the pathogenesis of gut frailty, it is essential to investigate how host-side factors and luminal-side factors, as depicted in Table 1, contribute to the development of gut frailty through various mechanisms. Furthermore, it is imperative to consistently consider their interactions. Rather than considering that dysbiosis directly induces gut frailty, it should be contemplated that alterations in gut microbiota-derived metabolites due to dysbiosis intricately interact with host-side factors, contributing to the development of this pathological condition.

Among host-side factors, a decrease in mucin secretion is believed to be a key factor in the very early stages of the pathology. Administration of a high-fat diet to animal models, such as mice, results in a thinning of the colonic mucus layer and a reduction in intestinal motility, leading to chronic constipation [17]. It is known that drugs such as aspirin [18] and a diet lacking in dietary fiber also decrease intestinal mucus [19], which has been reported to be associated with increased intestinal permeability and intestinal inflammation. Importantly, the reduction of goblet cells and thinning of the mucus layer have been shown to progress with aging [20], suggesting a common pathophysiology between age-related intestinal changes and gut frailty. Furthermore, the analysis of aging cells and inflammatory cells is necessary as host-side factors. The digestive tract mucosa is constructed with various types of cells, and the maintenance of barrier function relies on the coordinated relationship between multiple cell types. While there is a possibility that stem cells may age primarily, it is also conceivable that stem cells may age secondarily as a result of the aging of goblet cells, myofibroblasts, and immune cells.

Regarding luminal-side factors, it is crucial to consider the involvement of the vast array of approximately 1,000 species and 100 trillion gut bacteria. Dysbiosis, an imbalance of the gut microbiota, should be taken into account in the context of gut frailty. For instance, dysbiosis has been observed in patients with chronic fatigue syndrome, where a reduction in the representative butyrate-producing bacterium, Faecalibacterium prausnitzii (F. prausnitzii), has been notably documented [21]. The decline of F. prausnitzii not only triggers gut frailty but also exacerbates the condition by promoting local inflammation, further deteriorating the pathology of chronic fatigue syndrome. Such a brain-gut correlation pathology is becoming increasingly elucidated to involve the gut microbiota and its metabolites. Similar pathologies have been reported in conditions such as long-term complications after COVID-19 [22] and irritable bowel syndrome (IBS) [23].

It is also becoming apparent that the gut microbiota and its metabolites influence aging. Wilmanski et al. [24] proposed a uniqueness index based on the Bray-Curtis uniqueness, a new measure of β-diversity at the genus or amplicon sequence variant level, to investigate the diversity of the gut microbiota. They demonstrated that the uniqueness index increased with aging and showed the strongest correlation with chronological age compared to various clinical biomarkers. Additionally, when analyzing the gut bacteria correlated with uniqueness, they found that the increase in uniqueness index was associated with a decrease in Bacteroides, and individuals with low uniqueness index or high Bacteroides occupancy had lower survival rates 4 years later, as revealed by cohort studies. Salosensaari et al. [25] conducted a 15-year follow-up study on the association between the gut microbiota of a population cohort of 7,211 individuals and mortality rates, identifying the characteristics of the gut microbiota related to mortality. They found that α-diversity (Shannon, observed) did not correlate with mortality, but the third principal component (PC3) in principal component analysis of β-diversity showed a positive correlation with mortality. Further analysis of factors influencing PC3 revealed that the correlation between PC3 and mortality was strongly influenced by the family Enterobacteriaceae. Bacteria of the Enterobacteriaceae family, which are dominant in Proteobacteria, are facultative anaerobes that ferment glucose and exhibit nitrate-reducing activity. This family includes Escherichia, Klebsiella, Proteus, Salmonella, Shigella, Yersinia, et al. [25] Furthermore, it was shown that individuals with a high occupancy rate of the Enterobacteriaceae family had a higher mortality rate from cancer, particularly gastrointestinal cancer (HR: 1.80, 95% CI: 1.35–2.41).

Definitive treatments and prevention methods are currently in the research phase, and several potential approaches have been suggested (Table 2). Approaches using the gut microbiota for the management of gut frailty have shown promising results. Two particularly interesting studies include fecal microbiota transplantation (FMT) from young mice to aged mice [26] and the administration of Akkermansia muciniphila to aged mice [27]. In the FMT study, 12-month-old aged mice that received fecal transplantation from 5-week-old young mice showed improvements in gut microbiota composition, increased grip strength, and rejuvenation effects on the skin’s stratum corneum and moisture content [26]. In the study with Akkermansia muciniphila administration to 60-week-old aged mice, gene expression in the intestinal mucosa was analyzed for gut frailty evaluation after 36 weeks. The results showed enhanced expression of genes involved in tight junction proteins, Muc2 mucin, intestinal stem cells, and cell turnover, as well as inhibition of increased intestinal permeability evaluated by lipopolysaccharide [27]. The involvement of secondary bile acids and their metabolites in the rejuvenation effects of the gut has also been revealed.

Evidence for FMT therapy in humans is also increasing. In IBS, dysbiosis has been observed, and long-term outcomes of FMT have been reported [28]. According to these reports, the effectiveness rate 3 years after FMT exceeds 60%, with a remission rate of around 20%. The improvement of symptoms and the enhancement of QOL are important findings. Furthermore, it has been demonstrated that the concentration of butyric acid in feces is inversely correlated with the severity of self-reported symptoms and fatigue as evaluated by QOL assessment.

Approaches utilizing the metabolites of gut bacteria have also been proposed for the management of gut frailty. Short-chain fatty acids produced through the fermentation of dietary fiber have systemic effects on inflammation and immune responses, not only in the gut. Bile acids, which are synthesized in the liver and secreted into the duodenum, undergo diverse transformations by gut microbiota. A gnotobiotic experiment has revealed that decreased levels of secondary bile acids and short-chain fatty acids are involved in the pathophysiology of chronic constipation with delayed transit time [29]. Treatment with a bile acid transporter inhibitor (elobixibat) increases colonic bile acid, particularly secondary bile acids, and has been shown to be effective in the treatment of constipation [30].

Gut frailty may not be limited to the large intestine but could also occur in the stomach, small intestine, and other parts of the gut. For example, observations of the small intestine in mice raised on a fiber-deficient diet have revealed that inflammation-related immune cells, such as natural killer cells and macrophages, undergo pro-inflammatory changes, leading to micro-inflammation in the small intestinal mucosa. This inflammatory response contributes to systemic chronic inflammation and is also involved in the development of skeletal muscle sarcopenia [31]. Indeed, administration of a water-soluble highly fermentable dietary fiber has been shown to improve changes in immune cells of the natural immune system and subsequently suppress sarcopenia.

Recently, exercise has been considered as a potentially effective intervention for gut frailty. A study using a mouse exercise model demonstrated that fecal microbiota changed with exercise, resulting in increased levels of bile acids as revealed by metabolomic analysis [32]. Absorbed bile acids are involved in the maintenance of skeletal muscle through the TGR-5 receptor present in the muscle. This study provides evidence that the effects of exercise are partly mediated by the gut microbiota.

In this paper, we present research findings that highlight the importance of understanding the pathophysiology of gut frailty and developing strategies to address it in the pursuit of healthy longevity. The underlying nature of gut frailty is the aging of the digestive tract, referred to as the “Aging Gut.” We believe that by targeting the gut environment with therapeutic interventions, it may be possible to rejuvenate the aged gut and potentially prevent the progression of systemic frailty (Fig. 2). Although the concept of gut frailty has not yet gained widespread recognition, we hope to propose more practical screening methods, diagnostic approaches, and specific interventions with the support of many individuals in the future.

Y.N. received scholarship funds from Taiyo Kagaku Co. Ltd., Morinaga Co. Ltd., Miyarisan Pharma Co. Ltd, Morishita-Jintan Co. Ltd., Fujikko Co. Ltd., Mizkan Co. Ltd.; a collaboration research fund from Taiyo Kagaku Co., Ltd.; and received lecture fees by Takeda Pharma. Co. Ltd., Mochida Pharma. Co. Ltd., Biofermin. Co. Ltd., Otsuka Pharma. Co. Ltd., and Miyarisan Pharma. Co. Ltd. The present research was partly supported by these funds. Neither the funding agency nor any outside organization has participated in the study design or has any competing interests. These companies have approved the final version of the manuscript.

This work was partly supported by MAFF Commissioned project study on “Project for the realization of foods and dietary habits to extend healthy life expectancy” allotted to Y.N. (Grant No. JPJ009842), and partly supported by COI-NEXT, JST Grant No. JPMJPF2210.

Y.N. designed, organized, and wrote the manuscript.