The composition of the human gut microbiome is dependent on, amongst other things, age, diet, health, and geographical location, with significant individual variability [ 94 95 ]. It is dynamic across the lifespan, changing rapidly between birth and early childhood, and then becoming more stable [ 36 ]. In older life, however, research shows that the propensity for compositional change accelerates once again [ 36 97 ]. Multiple cross-sectional studies have found associations between gut microbiome composition and frailty [ 98 100 ], while the ELDERMET study showed significant loss of diversity amongst people in a care-home setting versus community dwellers [ 95 ]. Among older hospitalised patients, polypharmacy has been associated with gut microbiota dysbiosis [ 99 ]. It is well established that antibiotics cause significant changes in microbiota composition [ 101 ], and older adults tend to have more frequent antibiotic therapy.

Age-related chronic inflammation (‘inflammaging’), is implicated in the development of sarcopenia [ 102 103 ]. Changes in the gut microbiota have been suggested to contribute to inflammaging [ 37 105 ]. A recent animal study showed that transferring gut microbes of young killifish to older ones ameliorates ageing conditions, and extends the lifespan of the older fish [ 106 ]. Notably, the transplanted older fish also displayed increased ‘spontaneous exploratory behaviour’ [ 106 ], essentially physical activity. Few studies to date have had the ability to delve into the operational capacity and functional readout of the gut microbiome in relation to aging, but this is likely to shed more light on possible mechanisms of the interaction between dietary intake and host utilisation of protein in skeletal muscle.

Amongst older adults, a single randomised controlled trial has explored the effect of modulating the gut microbiota on muscle function and frailty. Here, 60 older adults received a prebiotic (F-GOS) or placebo for 13 weeks. While the study remains to be replicated, promisingly, both exhaustion and handgrip strength were significantly improved in the treatment arm [ 129 ], highlighting the potential role for the gut microbiome in future interventions. The science of pre- and probiotic use is in its infancy, as are studies of faecal transplantation, with much scope for further investigation of these therapeutic options.

In terms of human data, two probiotic trials have shown improvements in athletic performance amongst elite athletes. A small, four week trial of probiotic capsules in male runners reported increased run time to fatigue in the probiotic group [ 117 ], while a trial of probiotic yoghurt in teenage female endurance swimmers reported improved aerobic performance, measured by maximal oxygen consumption (VO2 max) [ 118 ]. Dietary standardisation was carried out in the male runner study, however in the swimmer study participants continued their regular diet which may have confounded results. These studies build on evidence from observational studies for an association between exercise and gut microbiota [ 119 124 ]. Clark et al. (2014) compared the gut microbial diversity of professional male athletes to healthy controls and reported significantly higher diversity amongst the athletes [ 125 ]. Furthermore, moderate exercise has been shown to increase intestinal mobility [ 126 ], which is known to affect gut microbiota [ 127 128 ]. These changes in gut health with exercise implicate skeletal muscle as a potential regulator of gut microbiota composition and suggest a bi-directional relationship between skeletal muscle and the gut microbiome.

Gut microbiota modulation in animal models has also produced preliminary supportive data for effect on skeletal muscle. This includes lower intestinal permeability and lower plasma LPS and cytokines noted in prebiotic-treated mice [ 112 ], reduced expression of muscle atrophy markers in mice models of leukaemia supplemented with aspecies [ 113 ], and increased muscle mass and function (measured by grip strength and swim time) in healthy mice supplemented with 114 ]. These studies and others [ 115 116 ], suggest that targeting the gut microbiota may be used as a tool to modulate muscle mass.

The influence of the gut microbiome in metabolic health has been one of the primary focuses of research in this area thus far, particularly in the context of obesity and insulin resistance [ 107 ]. Studies have used faecal transplants in germ-free mice to demonstrate changes in body fat, insulin resistance and glucose tolerance [ 108 ], highlighting the key role of the microbiome in these metabolic pathways. Considering the role of skeletal muscle in glucose metabolism, animal studies have investigated the relationship between gut microbiota and skeletal muscle metabolism. For example, skeletal muscle from colonised versus germ free mice appears to have altered metabolic efficiency, with higher levels of the enzyme adenosine monophosphate (AMP)-activated protein kinase, a central regulator of metabolism at both a cellular and organismal level, found in the skeletal muscle of germ-free mice [ 109 ]. CD-14 mutant mice, who lack an endotoxin receptor on their innate immune cells, have increased levels of circulating lipopolysaccharide (LPS), and this LPS was found to induce skeletal muscle inflammation, as well as insulin resistance [ 36 ]. This is important because the healthy gut microbiome is considered to contribute to gut barrier function ( Section 3.3 below), providing gut enterocytes with essential nutrition [ 110 ] and reducing LPS levels in the blood. Lastly, Yan et al. (2016) carried out a study in which gut microbiota was transferred from obese pigs to germ free mice [ 111 ]. Fibre characteristics and the metabolic profile of the skeletal muscle were replicated in the recipients [ 111 ], again implicating the gut microbiome in skeletal muscle composition and metabolism. Some of the fibre changes noted were similar to those seen in aging skeletal muscle (e.g., increased proportion of slower contracting fibres). This raises the possibility that faecal microbial transplantation could be used as a means to transmit muscle fibre characteristics between humans, perhaps even from young to old, as a means of improving skeletal muscle function.

The gut microbiomes of critically ill patients on average display enrichment of virulent pathogens, and loss of health-promoting microbes [ 141 ]. Protein supplementation has shown some benefits for muscle parameters in this population [ 142 143 ], but whether this effect is modulated by the gut microbiome remains to be tested. Evidently dietary protein has a significant effect on gut microbiota composition and vice versa, however more research is needed to further characterise this relationship. It is notable that almost exclusively, studies to date have focused on composition of the microbiota rather than functional capacity of the microbiome. Investigation into the differences in microbial genes involved in protein metabolism between individuals differing in anabolic response to protein could lead to the engineering of new probiotics with specific capacity to influence MPS.

It has been reported that protein consumption is correlated positively with gut microbiota diversity [ 136 ]. This is based on studies carried out on healthy volunteers [ 137 ], elite athletes [ 125 ], and obese/overweight individuals [ 138 ]. The source of protein appears influential, with plant protein associated with more, and; and lessand 137 ]. Meanwhile animal protein was associated with higher levels ofand, and lower levels of 137 ]. High levels ofhave also been reported with Western diets, which are high in protein and animal fat [ 33 ], although it has been suggested that differences in fat content, rather than protein, is the major influencing factor here [ 139 ]. Significant associations have been reported between increased levels of faecal short chain fatty acids (SCFAs),and some, with consumption of a Mediterranean diet [ 35 140 ], which is typically lower in protein than animal-based diets, although may contain high levels of plant-source protein. Dietary fibre is an important factor in gut microbiome diversity and composition and it is important to note that most plant sources of protein are also high in fibre, whereas animal source protein are not. This is likely to be an influential factor in the findings of these studies.

Studies carried out in mice, rats, and hamsters have shown higher microbial diversity in those fed soy protein versus animal protein [ 133 134 ] and increased abundance offamily S24-7 in those fed soy protein versus other diets [ 79 ]. Li et al. (2017) assessed high protein, low carbohydrate diets in dogs and found decreasedtoratio, increasedtoratio and increased abundance of, and, the latter of which has been proposed to have beneficial effects in the human gut [ 135 ].

The digestive system consists of a complex interaction between digestive secretions, intestinal conditions, and the gut microbiome. Nutrients, especially dietary proteins, provide energy sources for the host, as well as substrates for the gut microbiota [ 130 ]. A significant proportion of undigested peptides and proteins can reach the colon, and this is increased in the context of a high protein diet [ 131 ]. Consumption of proteins with high digestibility, or a low protein diet, results in less protein reaching the colon, limiting the amount available for protein-fermenting bacteria [ 130 ]. Furthermore, changes in the gut microbiota can impact the bioavailability of dietary amino acids [ 104 132 ].

3.3. Gut Microbiota and Anabolic Resistance

A healthy gut microbiome plays a role in many of the physiological processes implicated in the various mechanisms proposed for the development of anabolic resistance (see Table 2 and Figure 3 ). These include suppression of chronic inflammation, prevention of insulin resistance, modulation of host gene expression, enhancement of antioxidant activity, and maintenance of gut barrier function [ 35 104 ].

Inflammation has been proposed as a contributing factor to anabolic resistance in aging, and indeed inflammaging has been suggested as a major aetiological factor in the development of sarcopenia. Biagi et al. (2010) studied age-related differences in both the gut microbiota and the inflammatory status among different stages of the whole adult life, including centenarians, and reported dysbiosis in the older population, which correlated with increased inflammatory status, as determined by peripheral blood inflammatory markers [ 37 ].

104, Work in animal models has shown evidence of increased intestinal permeability in association with age-associated microbial dysbiosis [ 36 144 ]. This can facilitate translocation of microbial byproducts into the circulation, including endotoxins, and may influence a number of the mechanisms listed in Table 2 , such as protein digestion and absorption. It has been suggested that pathogenic drivers of inflammation and muscle atrophy may enter the system via this process [ 132 ]. Within humans, a randomised controlled trial of probiotic use in athletic men reported reduced zonulin in faeces, a surrogate marker of enhanced gut permeability [ 145 ], suggesting that modulation of the gut microbiota can affect the gut’s barrier function.

Older adults tend to have reduced intestinal motility, which may unfavourably affect the utilisation of dietary protein by the gut [ 104 ]. Indeed it has been reported that the proteolytic potential of the gut microbiota appeared to be enhanced in older age [ 146 ], and may therefore contribute to anabolic resistance to ingested protein. There is also some evidence that probiotics may improve amino acid absorption from protein [ 147 148 ], which adds weight to the suggestion that targeting the gut microbiota may ameliorate anabolic resistance in older adults. Production of SCFAs by the gut microbiota has been associated with anabolism itself [ 110 ] and depletion of taxa producing SCFAs may promote anabolic resistance [ 149 ]. Of note, an age-related reduction of the abundance of genes in pathways that are involved in SCFA production has been reported [ 146 ]. SCFAs are mainly produced by the fermentation of dietary fibre, so the fibre content of dietary protein sources is likely too, to influence protein metabolism.

Bifidobacterium , was found to be protective of muscle atrophy in mice [ Faecalibacterium prausnitzii [95, Treatment with butyrate (a SCFA), which is associated with, was found to be protective of muscle atrophy in mice [ 116 ]. Notably, studies showing correlation between frailty and gut microbiota composition have also reported dysbiotic shifts in higher functioning older adults towards a greater abundance of butyrate-producing bacteria such as 150 ], which suggests these microbes may have a positive role in protection against muscle loss and frailty. Butyrate also has a role in intestinal barrier function [ 151 ], and therefore may be implicated in intestinal permeability. Notably, a randomised controlled trial of symbiotic (a combination of pre- and probiotic) use in older people noted an increase in butyrate production in those given the synbiotic [ 152 ].

Mitochondrial dysfunction and impaired autophagy have both been suggested as possible mechanisms for anabolic resistance (see Table 2 ). Interestingly, they have also been implicated in animal models of aging [ 153 ] and in the development of sarcopenia and cachexia [ 154 155 ]. A recent paper has postulated that dysfunctional mitochondria may represent a key link between chronic inflammation and age-related muscle loss, and that dysbiosis of the gut microbiota may be a key mediator in this gut-muscle crosstalk [ 104 ].