Physiology and function of the ageing GI tract

The GI tract has a core function for the human body as it ensures adequate digestion and absorption of nutrients, involving a sequence of events from the mouth until the anus. These are facilitated by GI motility and digestive secretions, and regulated by neural and hormonal control. Age-related functional declines have been reported for some of the organs involved (figure 1).

• Download figure
• Open in new tab
• Download powerpoint

Figure 1

Non-exclusive listing of key changes in GI function and the intestinal microbiota during ageing, including potential influencing factors as well as interventions to beneficially manipulate the intestinal microbiota. *Frailty related; ≈no significant difference;  a few or the minority of studies showing a significant increase;  several or the majority of studies showing a significant increase;  a few or the minority of studies showing a significant decrease;  several or the majority of studies showing a significant decrease. CCK, cholecystokinin; NK, natural killer; NR, not reported.

In the mouth, masticatory function and taste are often found to be impaired in elderly in general.11 Moreover, Watanabe et al 12 found that frail elderly had significantly fewer teeth, lower occlusal force and muscle thickness when compared with healthy and prefrail elderly, indicating that impaired masticatory function becomes more pronounced with frailty.12 Swallowing problems were reported by 10%–30%, in a heterogeneous group of individuals aged 65 years and over.13 Swallowing depends among others on the presence of saliva. Results from a meta-analysis, including 47 original controlled studies, showed that salivary flow rate decreases with healthy ageing, resulting from degenerative changes of cellular structures of the salivary glands.14 While reduced salivary secretion has been associated with medication use such as anticholinergic drugs, psychotropic drugs, antihistamines and diuretics, subanalyses showed that medication use does not impact salivary flow rate.14 Frailty criteria were, however, not taken into account. A recent study by Rogus-Pulia et al 15 showed that perception of mouth dryness was also associated with increasing age, although potential contributing factors like comorbidities and medication use were not addressed.15 The observed dryness is probably due to compositional changes in saliva, which may negatively impact thickness and adherence of the oral salivary film.15 16 Increased impairment in mouth functions as reported for elderly in general, can contribute to food avoidance, reduced or altered intake (eg, more easily digestible food) and eventually poor nutritional status.11 This can also impact intestinal microbiota composition and activity. Deteriorated oesophageal functions repeatedly reported in elderly in general, include reduced peristalsis,17 18 increased number of non-propulsive contractions18 and decreased compliance of the oesophagus.18 These alterations can be found already from the age of 40 years.19 Healthy ageing was not or only to a modest extent found to be associated with slowing of gastric emptying of both solids and liquids.20 21 In frail compared with non-frail elderly, gastric emptying of liquids was even found to be enhanced.21 Furthermore, the gastric compliance was reduced, while gallbladder emptying and oro-caecal transit time were not different between frail and non-frail elderly.21 On the other hand, in a recent review it was stated that healthy elderly have a longer oro-caecal and colonic transit time than healthy young adults.22 The decreased rectal compliance and decreased rectal sensation associates with healthy ageing, and may contribute to complaints such as constipation.18 Several studies have provided evidence for alterations in motility associated with healthy ageing, being most pronounced for the oesophagus and large intestine. It should be acknowledged that increased intestinal transit time affects composition and activity of intestinal microbiota, both in vitro23 and in vivo24, but data in elderly or frailty are lacking.

Most GI functions, including the secretion of gastric juice, bile and digestive enzymes, as well as GI motility, are regulated by a complex interplay of hormonal and neuronal factors, involving the central and the enteric nervous system. In the stomach, marked alterations in gastric acid secretion could not be demonstrated in healthy elderly.25 Although, the higher prevalence of atrophic gastritis and proton pump inhibitor use in elderly20 will lead to decreased acid production and subsequently bacterial overgrowth in subgroups. Rémond et al 26 reviewed studies on the effects of ageing on excretion of digestive secretions and found that bicarbonate secretion, as well as enzyme concentrations of pepsin in the stomach, and lipase, chymotrypsin and amylase in duodenal fluids were lower in healthy elderly compared with young adults. However, bile acid secretion was not affected by ageing.26 In an extensive review on (an)orexigenic GI hormones, strongest evidence was found for elevated fasted and postprandial concentrations of cholecystokinin (CCK) in elderly in general compared with younger adults.27 Although gallbladder emptying was similar, gallbladder sensitivity to endogenous CCK was significantly reduced in healthy elderly compared with young adults.28 Evidence on the effects of ageing on peptide YY, glucagon-like peptide-1 and ghrelin levels were inconclusive, partly as a consequence of different methodologies used, whereas pancreatic polypeptide and oxyntomodulin are hardly studied.27 Data on other relevant GI hormones and peptides (eg, secretin, gastrin, motilin, somatostatin, chromogranin A) as well as specifically addressing subgroups of elderly are scarce. More studies using standardised methods and clear definitions of the target population are needed. The enteric nervous system also plays an important role in the regulation of motility, secretions and local blood flood, by bidirectional communication between the brain and the gut and by local reflexes. Several rodent studies found the ageing process to induce neuronal loss as determined by lower neuronal density in oesophageal, small intestinal and colonic tissue.20 This effect was more pronounced in cholinergic when compared with nitrergic myenteric neurons.29 Human data are, however, lacking.

Although several of the above processes will impact GI function, studies on intestinal absorption of nutrients per se are largely lacking. In rodent studies, ageing was associated with a decrease in surface area because of villus degeneration20 and malabsorption of carbohydrates, lipids, proteins, minerals and vitamins,30 but these findings need confirmation in humans. Food intake was, however, found to be altered in healthy elderly, which was associated with decreased hunger and appetite scores.27 A meta-analysis including 59 studies confirmed that hunger scores were 25% and 39% lower after overnight fasting and in postprandial state, respectively, and fullness 37% higher in healthy elderly compared with young adults.31 Furthermore, reduced nutritional status was found to be related to frailty in elderly.32

Apart from the segment-specific functions with regard to digestion and absorption, an adequate GI barrier function is pivotal for protection against the external environment, including epithelial integrity, mucus and defensin secretion, as well as the gut-associated lymphoid tissue. Although studies in primates suggest an impaired epithelial barrier function in older animals,33 Wilms et al 34 did not observe differences between healthy elderly versus adults based on results from a combined in vivo (using the multisugar permeability test) and ex vivo approach (evaluating colonic biopsies in Ussing chambers).34 Although not specifically studied in elderly, factors associated with ageing such as non-steroidal anti-inflammatory drugs (NSAID) use, alcohol intake, obesity and diabetes have, however, been shown to increase intestinal permeability. The ‘chemical’ barrier is hardly studied in elderly. One study showed that serum levels of the host defensive peptides cathelicidin and β-defensin 2 were similar between healthy elderly and young adults.35 Data on mucosal and/or faecal samples as well as on the role of other antimicrobial peptides or mucus and analyses in frail elderly specifically are lacking. Many studies explored the impact of ageing on the intestinal immune response. It has repeatedly been shown that the human intestinal mucosal immune system is compromised with ageing, as nicely reviewed by Mabbott et al.36 Alterations in dendritic cell subsets have been reported in elderly in general.36 Furthermore, healthy ageing is characterised among others by a pro-inflammatory cytokine profile (‘inflammaging’, ie, increased levels of among others tumour necrosis factor-α and interleukin-6), a decreased humoral response such as reduced secretory IgA levels and decreased natural killing and phagocytic cell activity.37 This will be further affected by immune-related comorbid conditions and/or frailty.37 The observed immunosenescence can contribute to the increased risk of recurrent and persistent infections reported in the elderly.37

Intestinal microbiota in elderly

Ageing is associated with several alterations in GI physiology and function, which can impact the amount and types of nutrients delivered to the small intestine and colon, thereby affecting intestinal microbiota composition and functionality in these segments. Additionally, the altered immune function will impact host-microbe interactions, which can also contribute to alterations in intestinal microbiota composition and functionality in this population.

The GI tract encompasses different biotic environments. Although different types of microorganisms, such as archaea and fungi, may play a role in intestinal health,38 most studies focus on bacteria. Furthermore, it is evident that different locations of the GI tract harbour distinct microbial communities,39 but determination of the bacterial composition is mostly performed on faecal samples as their collection is non-invasive and feasible for large ((pre)clinical) populations. Nevertheless, other intestinal sites can be sampled using luminal brushes, rectal swabs, colonic lavage and mucosal biopsies as reviewed earlier.38 In elderly, studies have mainly focused on analyses of the microbiota composition in faecal samples, which is generally considered to be representative for the distal large intestinal content. In this section, we summarise the current knowledge on microbiota composition of elderly, and discuss whether the faecal microbiota of young adults is different from elderly, paying special attention to age-related health status (ie, (pre)frail and centenarians) and confounding factors.

Manipulating the intestinal microbiota of elderly

Although a typical microbiota profile of elderly is hard to define, manipulating the intestinal microbiota of elderly and host outcome has been subject of several studies. Supplementation of functional foods like probiotics, prebiotics or synbiotics are nutritional approaches to beneficially alter the microbiota (figure 1). Several studies have been performed on the effect of probiotics in elderly, of which many focus on the risk of infections and immunosenescence. In a systematic review, including 15 randomised clinical trials in 5916 patients with a mean age of 75 years, Wachholz et al did not find significant effects of probiotics on the occurrence and durations of infections, nor on mortality rate, when compared with placebo.82 Also with regard to inflammatory and immunosenescence markers, Calder et al concluded in a recent review that the evidence for the efficacy of probiotics in elderly is limited and/or inconsistent.83 Several elderly studies did, however, show changes in faecal microbiota composition, being most pronounced for increased abundances of bifidobacteria, after use of, for example, Bifidobacterium lactis HN019, Bifidobacterium longum 46 and Bifidobacterium longum 2C or multispecies probiotics.84 Although probiotic use is often considered to be safe, specific safety studies in elderly are still limited and extra caution is warranted, especially in subjects with impaired host defence mechanisms.

Well-known prebiotics, including galacto-oligosaccharides, inulin and fructo-oligosaccharides,85 have often been evaluated for their effect on bowel habits in constipated elderly, and showed an increase in defecation frequency.86 With regard to immune function, a limited number of prebiotic intervention studies have been performed in elderly. Although beneficial effects on specific parameters have been reported,87 no effect was shown on vaccination efficacy.88 In a synbiotic study, Costabile et al observed a significant and more pronounced effect on NK cell activity, microbiota composition and blood lipids in elderly treated with the combination of Lactobacillus rhamnosus GG and soluble corn fibre, when compared with soluble corn fibre alone.89 Furthermore, different prebiotic and synbiotic food supplement studies have been shown to lead to an increased abundance of faecal bifidobacteria and/or lactobacilli in elderly.84 The clinical relevance hereof, without additional effects on health outcome parameters, is still a matter of debate.

It should be noted that effects of probiotic strains, prebiotic compounds and/or combinations thereof, differ and largely depend on the duration of the intervention period, subject population and mechanism84 to be targeted. We are only at the beginning of understanding the association between specific microbes and our health, especially in elderly and their associated comorbidity or frailty. Although several probiotic, prebiotic and synbiotic studies have been performed in adults in general, caution is needed when extrapolating these findings to elderly and subgroups thereof. Therefore, more insights in the exact microbial composition and underlying mechanistic effects are needed to enable more targeted interventions in relevant subgroups.

Several studies have evaluated dietary intake in general, showing for example, changes in macronutrient intake as well as deficiencies in micronutrients,84 but studies targeting the microbiota composition by changing habitual dietary intake in the elderly are still scarce. Current studies are mainly performed in young adults, showing changes in microbiota composition and especially metabolic activity, relatively quickly after major changes in dietary habits.81 90 91 It should be noted, however, that the observed compositional changes did not exceed the interindividual variation. At present, analyses of the Nu-Age dietary intervention study92 are ongoing, investigating the effect of major diet changes (Mediterranean diet, 1-year randomised, single-blind controlled trial) on the intestinal health in 1250 elderly subjects.

Other strategies to manipulate the intestinal microbiota include faecal microbiota transplantation (FMT). The success rate is variable, and largely depends on the disease or disorder to be treated.93 FMT efficacy is most convincing for treating C. difficile infection,93 which has a rather high incidence in the elderly, also because of the high antibiotic use.94 In a specific review focusing on elderly, Cheng et al confirms the efficacy of FMT for C. difficile in this group, but recommends to use this treatment strategy early in disease course to prevent complications.95 Clear criteria for stool donor selection and screening are still warranted, especially in susceptible (frail) elderly given the risk of transplanting concomitant pathogens and or antibiotic resistance genes.

Summary and conclusions

Several small, age-related declines in the physiology of the GI tract have been reported for ageing in general, whereas frailty and impaired health status seem to play a role in the (further) decline (figure 1). Studies on GI physiology and function in subjects with age-related health decline or being resilient to diseases while ageing, for example, centenarians, as well as studies directly linking host function and outcome in elderly to microbiota composition and activity are, however, still scarce. Regarding the intestinal microbiota composition, alterations are more pronounced in frail or comorbid elderly, although age-related changes in the abundance of Bifidobacterium and Enterobacteriaceae have been reported in general. However, a ‘typical’ intestinal microbiota of elderly is hard to define, given the large interindividual differences in the intestinal microbiota of elderly. Moreover, intestinal microbiota of elderly is more likely to be affected by a broad range of potentially confounding factors, such as lifestyle (eg, including diet and smoking), health status, medical treatment (including medication) and living situation rather than by ageing per se. Although, we acknowledge that unravelling causes and consequences will be challenging since possible confounders such as diet will influence both the microbiota and GI physiology. Based on our current knowledge, future longitudinal studies should shift towards investigating the role of GI physiology and intestinal microbiota as well as their dynamics over time in specific well-characterised subgroups of elderly, such as frailty and elderly with a specific health decline, and how these can be modulated by targeted interventions or improvements in lifestyle and living situation.