Are self-reported gastrointestinal symptoms among older adults associated with increased intestinal permeability and psychological distress?

In the last decades lifespan has increased dramatically, but even though a longer lifespan is a success story in itself, it cannot be neglected that old age correlates with an increased need for health care [1]. Thus, it is important to identify areas through which a healthy ageing process can be promoted in order to increase the proportion of independent free-living older adults [2]. Gastrointestinal (GI) symptoms are common among older adults. Fifty to seventy % of older adults report symptoms of constipation [3, 4] and 4-14% experience problems with diarrhoea [5‐7]. In addition, older adults suffering from diseases of the digestive system are at risk of a higher total symptom burden. [8]. Moreover, it has been established that a well functioning gut is essential in order for older adults to experience life-satisfaction and meaningfulness in everyday life [9, 10] [11]. Thus, gut health represents an important area through which health and wellbeing might be promoted. In support of this, we recently showed that senior orienteering athletes, a new potential model of healthy ageing, experience less GI symptoms than general older adults [10]. Even though age-associated GI symptoms are common in the older population, knowledge regarding the mechanisms behind these symptoms remains poor. Increased intestinal permeability is a hallmark of many GI diseases [12‐14] but has not been investigated in older adults who self-report GI symptoms. The intestinal epithelium is the major interface with the external environment and while absorbing nutrients and water it simultaneously restrict the free movement of luminal material to the underlying mucosa [15, 16]. A disruption of the intestinal barrier may result in the passage of microbial antigens and toxins [17], and are associated with intestinal inflammation as well as neurological diseases [18, 19]. Furthermore, elevated levels of reactive oxygen species (ROS) (e.g. oxidative stress) have been suggested to drive intestinal inflammation [20]. Understanding the characteristics of GI symptoms in older adults and their underlying pathophysiology is important in order to facilitate diagnosis and treatment. Here, we aim to investigate how self-reported GI symptoms among older adults correlate to plasma zonulin (an indicator of increased intestinal permeability) [21, 22] and psychological distress.

To our knowledge this is the first study that investigated the characteristics of self-reported GI symptoms. This is important to facilitate treatment and diagnosis for older adults experiencing moderate GI symptoms. No treatment regimens solely designed for age-associated GI symptoms exist today, and knowledge regarding gut and intestinal barrier function in older adults is poor. As a first step to identify the mechanisms behind age-associated GI symptoms we investigated the relationship between self-reported GI symptoms and intestinal permeability. Furthermore, the impact of GI symptoms on wellbeing was assessed, by investigating the level of psychological distress in relation to experience of gut problems.

As outlined in the results section, we identified that depression-like characteristics were more prominent among older adults suffering from GI symptoms and less common among senior orienteering athletes. The low level of psychological distress among senior orienteering athletes is in line with our previous results [10]. Senior orienteering athletes were also found to suffer from less GI symptoms. Experience of anxiety did not differ between older adults with and without GI symptoms. An increased prevalence of anxiety disorders among older adults has been reported previously [31‐33]. However, the levels of psychological distress estimated by HADS were below the cut-off value (≥ 8) for severe anxiety and depression. Hence, indicating that none of the study participants suffered from severe psychological disease. It should also be taken into consideration that the results presented here are based on self-reported data, which relied on the respondents’ honesty, accuracy, and interpretation of the question asked.

GI symptoms were found to be associated with elevated levels of plasma zonulin, which indicate that older adults suffering from GI symptoms have increased small intestinal permeability. Moreover, the PCA analysis showed that GI symptoms were found to be associated with psychological distress and zonulin among older adults with GI symptoms. Females (n = 18) were further overrepresented among elderly suffering from GI symptoms (n = 24). This could reflect the normal distribution of GI symptoms in the population as previous studies report an increased frequency of GI symptoms, such as constipation, among women [34‐36]. Stratification for gender did not reveal a significant difference between men and women in regard to GI symptoms, zonulin levels and depression-like characteristics. Anxiety-like characteristics were, on the contrary, found to be significantly higher among elderly men with GI symptoms (n = 6). However, this finding could be due to the small study population and further studies using larger sample sets will need to be performed in order to thoroughly elucidate the difference between men and women in relation to psychological distress, GI symptoms and intestinal barrier function.

Increased intestinal permeability is a hallmark in the pathophysiology of chronic inflammatory gastrointestinal diseases, such as Crohn’s disease [13]. An altered intestinal permeability has previously been associated with psychiatric disorders such as depression and anxiety [37]. Thus, our results support the notion that intestinal permeability might be an important target for new treatment regimes for age-associated GI symptoms that might have a positive impact on mental wellbeing. Moreover, elderly individuals are known to have a low fibre intake [38] that in addition to a disturbed intestinal motility could alter the gut microbiota and result in a diminished diversity that could have a negative impact on the intestinal barrier function [37]. Recently, we showed that a dietary fibre from yeast was able to attenuate stress-induced hyperpermeability ex vivo across small intestinal tissue from Crohn’s disease patients mounted in the Ussing Chamber [39]. Thus, dietary fibres could be a potential therapeutic able to strengthen the intestinal barrier in elderly individuals, however, this needs to be thoroughly investigated in pre-clinical and clinical settings.

Zonulin is the only physiological mediator known to reversibly regulate intestinal permeability by modulating intercellular tight junctions [21, 40]. Circulating zonulin in serum/plasma is considered a useful marker of small intestinal permeability [21, 41] and has been validated using lactulose/mannitol tests [22]. However, zonulin as a marker of small intestinal permeability has been, and is, under debate. Levels of zonulin have been found to fluctuate over time making interpretation of the results difficult [42]. Moreover, a recent study suggests that circulating zonulin might not only be derived from the gastrointestinal tract but may be associated with obesity and hyperlipidaemia [43, 44]. However, the body mass index (BMI) of the general older adults (25.6 ± 4.3 Std) and older adults with GI symptoms (26.7 ± 5.0 Std) included in the present study was normally distributed and no significant differences were observed between the two groups. In addition, stratification of the data revealed no association between cardiovascular disease, including hypertension, and increased zonulin levels. Unfortunately, the BMI was not available for the senior orienteering athletes in the present study. However, the BMI of eleven newly recruited senior orienteering athletes enrolled in an additional study was found to be normally distributed with a mean value of 23.8 ± 3.2 Std. This is in accordance with a recent study showing a lower BMI value of senior athletes compared to general older adults [45]. Hence, these findings indicate that the increased zonulin levels in the present study were not a result of overweight/obesity or cardiovascular disease.

Nevertheless, the findings presented here needs to be confirmed in future studies using more advanced techniques, such as the Ussing Chamber methodology. This will allow for a thorough assessment ex vivo of the intestinal barrier function in elderly using mucosal biopsies [12, 39, 46] and hence add important information to the results presented here.

Moreover, it is important to point out that older adults with GI symptoms were found to suffer from more comorbidities and did also use more medications. Fifty percent were identified to suffer from cardiovascular disease, were hypertension was found to be the most common condition. A low dose (75 mg) of acetylsalicylic acid (ASA) is commonly prescribed to treat hypertension [47, 48]. ASA is known to affect the intestinal barrier negatively and induce an increased permeability [49]. In addition, beta-adrenoceptor blocking agents (beta-blockers, mainly used to treat angina pectoris) have been found to decrease bacterial translocation [50]. However, only three participants reported use of ASA and two used beta-blockers. Moreover, the median plasma zonulin value in the participants taking medications did not differ from the median of the whole study group. Antibiotic use was also higher among the participants suffering from GI symptoms (16.7%). Antibiotic use is known to influence the gut microbiota negatively and can cause antibiotic associated diarrhoea [51, 52]. Interestingly, three out of four participants suffered from diarrhoea. However, none of these participants displayed zonulin levels above the median for older adults suffering from GI symptoms. Moreover, it is important to point out that assessment of the gut microbiota was not performed in the present study. Thus, we cannot exclude that the increased intestinal permeability is a consequence of an altered gut flora with an increased number of pathobionts. Nevertheless, assessment of confounding effect showed that medication and comorbidities did not influence intestinal permeability or psychological distress.

In addition, assessment of biomarkers showed no change in inflammatory status in regard to GI symptoms. Thus, confirming that none of the study participants suffered from severe inflammation and infection. It should, however, be noted that in order to thoroughly assess low-grade inflammation pro-inflammatory cytokines, such as IL-6, TNF-α and IL-1β, should be investigated. Moreover, absence of intestinal inflammation was confirmed by the low calprotectin levels, which fell within the normal range. Thus, indicating that the increased intestinal permeability was not dependent on intestinal inflammation. Hence, our data suggest that moderate GI symptoms area associated with an altered intestinal barrier function and psychological distress. However, in future studies it will be important to perform thorough analysis of the gut microbiota and assess intestinal barrier function using more advanced technology.

Here we demonstrate that self-reported GI symptoms among older adults are associated with an altered intestinal barrier function as assessed by plasma zonulin levels. Furthermore, both GI symptoms and zonulin levels are associated with increased psychological distress. These findings suggest that even moderate levels of GI symptoms can be reflected in a disturbed intestinal barrier function and increased psychological distress.