IN a series of InSight+ articles (here, here and here), a group of researchers from the Peter MacCallum Cancer Centre and University of Melbourne discussed some information about advances in our knowledge about the gut microbiome. Some of this information was presented at a community-focused seminar, which was prompted by clinical interactions where patients indicated that they wished to learn more about the role of gut health in the immunocompromised setting.
In this article, I will summarise some of the literature on the gut microbiome and ageing.
Physiological changes associated with ageing
Ageing is accompanied by neuromuscular, cognitive, cardiovascular, metabolic and other changes. It has recently been suggested that disease-based approaches to research on ageing can be complemented by an integrative framework that acknowledges the interconnectedness of age-related diseases. The term “geroscience” is now used in fields such as molecular biology and immunology to refer to this framework, which encompasses a number of integrated approaches to the study of age-related physiological processes.
As Brian Kennedy and colleagues have argued: “Pathologies thought to be disparate are now understood to be connected… [The goals of geroscience are to]: (1) develop a systematic understanding of aging mechanisms; (2) elaborate mechanistic links between aging and chronic disease; and (3) recommend pathways to identify and develop therapies or preventative approaches for age-associated diseases”.
Kennedy and colleagues have proposed an influential conceptual framework for geroscience research. Dubbed the “seven pillars of ageing”, their framework delineates seven categories that represent and encapsulate the (interconnected) dimensions of age-associated physiological change. This framework can help guide research on the physiological mechanisms that underlie age-associated diseases and integrated therapeutic strategies.
The effects of ageing on the immune system include reduced B and T cell production in bone marrow and thymus; diminished function and proliferation of mature lymphocytes; and diminished host-vaccine responses, including reduced antibody production following vaccination. “Immunosenescence”, or the ageing of the immune system, is accompanied by “inflamm-ageing”, chronic, low grade inflammation that contributes to the pathogenesis of age-related diseases.
Infections, and their treatment, can accelerate the pathogenesis of (unrelated) age-associated diseases. For example, long term cytomegalovirus infection and human immunodeficiency virus (HIV) infection can induce chronic inflammation and exhaust adaptive immune responses, thereby influencing the development and progression of other diseases such as diabetes, cardiovascular disease, cancer and liver disease. HIV and cancer treatments may also have similar effects, potentially influencing the pathogenesis of a number of chronic health conditions.
Professor Mike McGuckin is the associate dean of research at the University of Melbourne’s Faculty of Medicine, Dentistry and Health Sciences. He is a biomedical researcher whose work has focused on mucosal infection, chronic inflammation and cancer in the gastrointestinal tract. In a personal communication with me, Professor McGuckin says that inflammation plays a critical role in the progression of chronic diseases:
“Inflammation is a normal process required to fight infection and to aid repair of our tissues following injury. However, inappropriate inflammation is a key underlying feature of many of the common chronic diseases that impact on community health and place a heavy burden on our health care systems. While inflammation may not itself be the initial trigger – for example, in type 2 diabetes, where excessive calorie intake and obesity are primary drivers – inflammation is often what drives the progressive nature of these diseases. In the type 2 diabetes example, where high blood sugar is the big problem, inflammation in the pancreas adversely affects production of insulin, which is the hormone that controls blood sugar, and inflammation in fat and liver adversely affects insulin action on these target tissues.
“Consequently, targeting inflammation is emerging as a major arm of therapies for many chronic diseases, and this is becoming more sophisticated, enabling us to target the underlying inflammatory pathology without unduly increasing an individual’s risk of infection.”
The role of the gut microbiota
Ageing affects the gut microbiota. Studies have attempted to characterise age-associated changes in the composition of the gut microbiota and describe their implications for health and disease. It has been suggested that the immunomodulatory activity of the gut microbiota is affected by these changes and alterations in the integrity of the gut lining (which can result in increased microbial translocation). Age-associated dysbiosis has been linked to chronic inflammation, neurodegeneration, diabetes, and liver and cardiovascular disease. Chronic, low grade inflammation appears to be a key feature of chronological ageing.
Differences in microbiota composition appear to be associated with differences in healthspan between groups of older people. Some age-associated gut microbiota changes appear to mirror changes seen during HIV infection.
Loss of diversity in the gut microbiota has been associated with frailty and loss of vitality in older people. Dysbiosis has also been associated with cognitive frailty and dementia, and the gut–brain axis has been identified as having a role in cognitive impairment. It is not known whether these links are causal or consequential, but they have been marked as potential targets for diagnostic surveillance and intervention.
The gut microbiota also appears to play a role in diabetes and metabolic disorders. Specific changes in microbiota composition have been linked to diabetes, and it has been suggested that certain microbes may play a role in modulating the onset and development of diabetes. Studies have also attempted to identify targets and strategies for the reversal of age-associated metabolic decline.
Caution about potential therapeutic interventions
Professor Fabienne Mackay is the head of the School of Biomedical Sciences at the University of Melbourne. She is a biomedical researcher whose work has focused on autoimmunity and cancer, and she has a keen interest in the microbiome. Professor Mackay says that advances in our knowledge about the gut microbiota have profound implications (personal communication):
“We always knew that we had a gut microbiota, but until recently did we not fully appreciate the profound effect that changes in the gut microbiota can have on health. It is now quite clear that changes in the gut microbiota, often referred to as dysbiosis, have profound effects not just in the gut but remotely in many organs, including the brain. Gut microbiota abnormalities linked to disease-promoting microbes have an impact on many biological functions and are associated with many health issues such as obesity, cardiovascular diseases, inflammation and autoimmunity, and neurological diseases such as Parkinson’s disease and cognitive impairment. A recent finding has indicated that the response of patients to a new cancer therapy called immune checkpoint inhibitors is also dependent on their gut microbiota. This finding is now prompting clinicians to test faecal matter transfer in cancer patients who are receiving immune checkpoint inhibitors.”
Professor Mackay says that a more cautious approach to testing therapeutic interventions is needed. She mentions experiments conducted by the American surgical oncologist William Coley in the 19th century. Dr Coley inoculated cancer patients with a bacterial product (Coley’s toxin) to necrose tumours. This treatment necrosed some tumours in patients but it killed more patients than it cured cancer. Professor Mackay notes that the reason for this was finally understood nearly a century later when the factor responsible for necrosing the tumour, tumour necrosis factor (TNF), was identified:
“Research on TNF showed us that it could not be used to treat cancer because it is a powerful inflammatory factor, triggering a dangerous condition akin to septic shock. Instead, inhibitors of TNF, such as infliximab and etanercept, were developed, and these are now used in the clinic to treat inflammatory conditions such as rheumatoid arthritis.”
Professor Mackay says that we have more to learn about the gut microbiota and we need to better understand its biological functions:
“The gut microbiota, which digests food products, works by producing a multitude of small molecules, called metabolites, which diffuse into the blood stream and have a biological function and effect (harmful or beneficial, depending on the type of microbiota) remotely in organs and tissues. Unless we understand the exact nature and function of these metabolites and the molecular mechanisms behind this biology, we will not properly harness the gut microbiota for therapeutic purposes.
“On the positive side, unlike Coley in the 19th century, we now use very sophisticated techniques that will fast-track new discoveries and lead us to more targeted approaches.”
Dr Arjun Rajkhowa is the centre manager of the National Centre for Antimicrobial Stewardship at the Department of Medicine, University of Melbourne, Doherty Institute, and Royal Melbourne Hospital in Melbourne, Australia.
The statements or opinions expressed in this article reflect the views of the authors and do not represent the official policy of the AMA, the MJA or InSight+ unless so stated.