Compromised intestinal integrity in older adults during daily activities: a pilot study

Malnutrition is an important condition that negatively affects the health of older adults. It is associated with frailty, osteoporotic fractures, postoperative complications, and an elevated risk of mortality [1‐4]. Unfortunately, malnutrition is common in older adults, especially in hospital settings, where up to 40% are reportedly malnourished and almost 50% are at risk [5]. Given the aging population, having a better understanding of malnutrition may help to prevent its occurrence in this vulnerable population and would be of great clinical and economic importance [6].

Malnutrition has a complex multifactorial etiology [7]. Important factors include a decreased sense of smell and taste, compromised gastrointestinal motility, and social factors such as loneliness and depression [8]. Certain diseases and their treatments can also negatively affect nutritional status, of which malignancies are a prime example [9]. Also, chronic inflammation, in the sight of inflammaging, affects the nutritional status in older adults [10, 11]. In addition to these established contributory factors, our overall hypothesis is that a compromised intestinal integrity due to hypoperfusion of the gut wall may impair nutritional absorption and therefore play a role in malnutrition in older adults.

An intact intestinal barrier is essential to protect the bowel from an influx of pathogens, toxins, and other harmful substances, as well as for facilitating nutrient and water transport [12]. A compromised intestinal integrity is therefore detrimental to the health of the individual and is assumed to play a role in inflammatory bowel disease, infectious diarrhea, and extra-intestinal disorders, such as the systemic inflammatory response syndrome, sepsis, and multi-organ failure [13]. Hypoperfusion of the intestinal wall is one of the key factors in compromised intestinal integrity and is thought to result in shortening of bowel villi through abrasion, thereby reducing the absorptive surface area of the gut wall and affecting nutrient absorption [14].

In several conditions, the adaptive capacity of the gut wall is affected, resulting in gut wall hypoxia. For instance, in the event of a reduced circulating volume and shock, blood flow to vital organs such as the brain and kidneys is preserved by severe vasoconstriction in the splanchnic vascular bed [15]. Gut wall hypoxia can also occur during strenuous exercise because splanchnic perfusion decreases to increase muscle perfusion, explaining the high rate of gastrointestinal symptoms in many athletes [16‐18]. Another example is non-occlusive chronic mesenteric ischemia, in which the mesenteric vessels have a normal caliber but in which hypoperfusion or hypo-oxygenation are caused by cardiac and pulmonary disease respectively [18‐21].

The aging gastrointestinal tract is prone to hypoperfusion and loss of intestinal function due to multiple factors, including atherosclerosis. Specifically, atherosclerosis of the mesenteric arteries, which is present in 20% of older adults. May impair the capacity to adjust splanchnic perfusion to oxygen demands [22, 23]. During daily activities, this plasticity is needed. Whereas the presence of food in the gastrointestinal tract demands a rapid increase of splanchnic blood flow by 100% to meet the increased oxygen demands of digestion and absorption, physical activity limits gastrointestinal tract perfusion to improve blood flow to the muscles [15, 16]. Activities that require an increase of mesenteric perfusion such as consuming a meal after physical activity, may induce hypoperfusion of the intestinal wall and compromise intestinal integrity (Fig. 1).

Before exploring in depth how compromised intestinal integrity affects nutritional status, nutrient absorption, and digestion in hospitalized older patients, this study was set up to obtain a proof-of-principle that older adults are indeed prone to a compromised intestinal integrity during daily activities.

This proof-of-concept study showed that I-FABP plasma levels increase at least 50% above baseline when a walking test is followed by a meal in 35% of a group of independently living older adults. These findings indicate that intestinal integrity is disturbed to some extent during daily life activities that challenge the mesenteric blood flow. As such, the study can be used to guide future research into the clinical relevance of compromised intestinal integrity and the pathogenesis of malnutrition in older adults.

The overall hypothesis is that loss of the plasticity that is needed to adjust splanchnic perfusion, to the oxygen needs of the gut wall in older adults contributes to a compromised intestinal integrity and nutritional malabsorption, even under normal conditions [13, 33]. Splanchnic atherosclerosis is a potential key factor, effectively reducing vascular plasticity and compensatory mechanisms. In turn, this may increase the arterial blood flow and lead to transiently inadequate intestinal perfusion either postprandially or during exercise [16, 17, 23].

Even short periods of asymptomatic intestinal hypoperfusion can induce tissue damage and contribute to disturbed bowel integrity [14, 30]. In healthy young men performing resistance-type exercise, protein malabsorption has been found to occur in the post-exercise recovery period, with the extent of malabsorption related to the extent of intestinal compromise, as measured by I-FABP levels [37]. The post-exercise recovery period for blood flow, and thus the period of protein malabsorption, was relatively short in that study. By contrast, we found that older adults with an I-FABP increase ≥50% did not show a return to baseline values by the end of the experiment, potentially indicating that intestinal integrity had not yet been restored. It is therefore plausible that impaired intestinal function might persist for longer in older adults after provocation, especially if several episodes of intestinal compromise occur in rapid succession without adequate time for the intestinal wall to recover. When hypoperfusion occurs often, the intestinal surface area may diminish due to a shortening of bowel villi, leading to a decreased nutrient absorption capacity of the gut wall [23, 30].

The current study was specifically designed to create a challenge to the mesenteric blood flow by exposing older adults to physical activity followed immediately by a meal. This provocation led to a relevant increase in I-FABP levels in 35% of participants. Two participants had an increase ≥50% of the baseline I-FABP immediately after the walking test (before the meal), raising the question whether physical activity alone might be sufficient to cause disturbed intestinal integrity in older adults. Unfortunately, participants were not asked about gastrointestinal symptoms during the experiment and the caliber of the mesenteric arteries was not measured, so whether the 12 participants with increased I-FABP levels had mesenteric artery stenosis, atherosclerosis, or chronic intestinal ischemia is unknown [19]. Future research should distinguish if other important factors contribute to the disturbed intestinal integrity.

Regular exercise may condition the colon to tolerate reduced flow by making vascular adaptations to the intestinal wall that make it less prone to damage by hypoperfusion. This principle is used in prehabilitation programs in which patients planned for colon resection are physically trained to generate optimal intestinal blood flow and which is thought to result in better anastomotic healing [38]. Given that almost three-quarters of participants engaged in at least 150 min/week of physical activity, we conclude that the present study was performed in active older adults. In line, many participants also achieved the maximum score in the walking test. It is possible that inactive or frail older adults show a more pronounced loss of intestinal integrity after physical activity than the relatively healthy and active participants included in this pilot study.

Comorbidities can negatively influence intestinal integrity. In a study comparing healthy controls to patients with moderate chronic obstructive pulmonary disease (COPD), it was shown that I-FABP levels were significantly higher in the latter when performing activities of daily living [20]. The general oxygen deficit in patients with COPD was suggested to cause hypoperfusion of the intestinal wall. Similarly, patients with chronic heart failure, a condition in which a systemic oxygen deficit is caused by decreased cardiac output, have been shown to have increased gastrointestinal permeability compared with healthy controls [21]. Given that most comorbidities are age-related, it is possible that a systemic oxygen deficit negatively affected intestinal integrity in our cohort when the splanchnic blood flow is challenged. Furthermore, possible vasoconstrictor effects of smoking on the superior mesenteric artery are described, possibly producing unwanted results in patients who are chronic smokers, such as stenotic lesions in this artery and chronic intestinal ischemia [39, 40]. To our knowledge, the effects of smoking on I-FABP levels have not been described. In this cohort, smoking could influence splanchnic blood flow and intestinal integrity but was not asked for. In future studies, it would be useful to perform studies like these in larger cohorts to be able to perform multifactorial analysis.

In addition to comorbidities, age related changes of the gastrointestinal tract can negatively influence intestinal integrity. Age effects all functions of the gastrointestinal tract: motility, enzyme and hormone secretion, digestion and absorption [41]. For example, small intestinal bacterial overgrowth is common in older adults. This condition is associated with chronic diarrhea, malabsorption, weight loss and secondary nutritional deficiencies [42]. Also, Shintouo et al. found that age related changes in gut microbiota are associated with inflammaging, a chronic low-grade inflammation that develops with advanced age that affects nutritional status in older adults [10, 11, 43]. Taken together, age related changes are important in the understanding of the development of malnutrition and should be taken into account in future studies.

This study was not designed to investigate the mechanisms underlying compromised intestinal integrity. None of the included baseline characteristics were significantly associated with an I-FABP increase. Therefore, risk factors for the loss of intestinal integrity during provocation of the splanchnic vasculature need to be clarified. Future research on this topic should include assessment of splanchnic atherosclerosis. Another issue is that participants were not asked to perform or avoid any activities before the experiment, so we cannot exclude that some may have undertaken physical activity prior to the test, resulting in an altered I-FABP at baseline. Noteworthy, I-FABP levels decreased in six participants during the experiment. For future studies, we advocate a more controlled research environment where participants are fasted and have a few hours of rest prior to the experiment, and multiple baseline measurements are taken.

A potential limitation of this study is the unknown use of over-the-counter nonsteroidal anti-inflammatory drugs (NSAIDs), which is important given that high levels of I-FABP occur during exercise in healthy individuals using NSAIDs [44]. However, we did record prescribed medication use, and a sub-analysis showed not only that the seven participants who used a prescribed NSAID (acetylsalicylic acid) had comparable I-FABP levels but also that there was no difference in NSAID use between the groups with and without a ≥ 50% increase in I-FABP levels. Further, intestinal integrity was only assessed using I-FABP, and although this is an early and sensitive marker of compromised intestinal integrity, the gold standard for assessing gastrointestinal mucosal perfusion is tonometry [45]. In future studies renal function should be determined as plasma I-FABP concentrations are elevated in patients with diminished kidney function [46]. Finally, to determine if the compromised intestinal integrity found in this study is specific for older adults, the experiment should be repeated in younger adults.

Based on this proof-of-concept study, further studies are being set up to study intestinal integrity in older and younger adults when challenging splanchnic blood flow in daily activities and in clinical settings. Next to I-FABP, gut wall permeability, inflammatory parameters, nutrient absorption and mesenteric blood flow will be assessed. A better understanding of the role of compromised intestinal integrity in the development of malnutrition may also provide novel directions to prevent or treat malnutrition, for example by addressing the effects of timing of consuming meals and performing exercise. Furthermore, the determination of intestinal integrity is a potential tool to aid patients and health care professionals in making treatment decisions for example regarding major surgery and or chemotherapy.

This proof-of-concept study shows that intestinal integrity is compromised in a considerable part of community-dwelling older adults following daily life activities. These results can be used in future studies that investigate more in-depth the relation between food intake, exercise, intestinal integrity and nutritional status in the elderly population.